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  • 1
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2017); 20171024-20171027; Berlin; DOCPO30-1106 /20171023/
    Publication Date: 2017-10-23
    Keywords: transtrochanteric anterior rotational osteotomy ; osteonecrosis of femoral head ; magnetic resonance imaging ; three-dimensional simulation ; image of three-dimensional reconstructed bone model ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 2
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  67. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 1. Joint Meeting mit der Koreanischen Gesellschaft für Neurochirurgie (KNS); 20160612-20160615; Frankfurt am Main; DOCMO.06.03 /20160608/
    Publication Date: 2016-06-17
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  70. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Skandinavischen Gesellschaft für Neurochirurgie; 20190512-20190515; Würzburg; DOCJM-SNS07 /20190508/
    Publication Date: 2019-05-09
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    Publication Date: 2018-02-10
    Description: Golgi phosphoprotein 2 (GOLPH2), a widely expressed Golgi type II transmembrane protein, has been implicated in several important physiological and pathological processes, including virus infections, cancer cell proliferation, and metastasis. However, its biological functions and mechanisms, particularly in the immune system, remain highly obscure. In this study, we report the biochemical identification of GOLPH2 from B cell lymphoma culture supernatant and show that the secreted protein could inhibit IL-12 production by dendritic cells (DCs) and IL-12–induced IFN- production by activated T cells. Further molecular analysis revealed that GOLPH2’s IL-12–inhibiting activity was mediated through a proximal IL12p35 promoter element involving a previously identified transcriptional repressor named GC-binding protein that is induced during phagocytosis of apoptotic cells by macrophages. We subsequently generated global golph2 knockout mice, which exhibited little developmental abnormality but were more susceptible to LPS-induced endotoxic shock than were wild-type mice with elevated serum IL-12 levels. Furthermore, we found that GOLPH2 played a regulatory role in macrophage polarization toward the M2 type. A comprehensive analysis of gene expression profiles of activated wild-type and GOLPH2-deficient DCs by RNA sequencing uncovered mechanistic insights into the way GOLPH2 potentially modulates DC function during inflammatory insults. Our functional study of GOLPH2 helps advance the scientific understanding of the biological and pathogenic roles of this novel and intriguing molecule with great potential as a diagnostic and prognostic marker as well as a therapeutic target in many acute and chronic inflammatory disorders.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 5
    Publication Date: 2018-09-18
    Description: Various malignancies are reproducibly cured in mouse models, but most cancer immunotherapies show objective responses in a fraction of treated patients. One reason for this disconnect may be the use of young, lean mice lacking immune-altering comorbidities present in cancer patients. Although many cancer patients are overweight or obese, the effect of obesity on antitumor immunity is understudied in preclinical tumor models. We examined the effect of obesity on two immunotherapeutic models: systemic anti–CTLA-4 mAb and intratumoral delivery of a TRAIL-encoding adenovirus plus CpG. Both therapies were effective in lean mice, but neither provided a survival benefit to diet-induced obese BALB/c mice. Interestingly, tumor-bearing leptin-deficient ( ob/ob ) obese BALB/c mice did respond to treatment. Moreover, reducing systemic leptin with soluble leptin receptor:Fc restored the antitumor response in diet-induced obese mice. These data demonstrate the potential of targeting leptin to improve tumor immunotherapy when immune-modulating comorbidities are present.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 6
    Publication Date: 2018-03-20
    Description: The non-receptor tyrosine kinase c-Src participates in bone metabolism by regulating the activities of both the bone-resorbing osteoclasts and bone-forming osteoblasts. In this study, we investigated whether megakaryocyte-associated tyrosine kinase (Matk), a potent inhibitor of c-Src, affects the functions of murine osteoclasts and osteoblasts. Results revealed that the formation of osteoclasts with actin rings was attenuated by Matk overexpression in osteoclast precursor cells but was enhanced by Matk knockdown. The inhibitory effect of Matk on osteoclasts was closely related with the inhibition of c-Src activity. Intriguingly, Matk overexpression in osteoblasts reduced bone nodule formation. Conversely, Matk knockdown increased osteoblast function. Most importantly, binding of Matk to Runx2 resulted in the inhibition of Runx2 translocation into the nucleus and downregulation of Runx2 target genes. Taken together, our findings demonstrated that Matk plays a critical role in bone metabolism by impairing the functions of osteoclasts and osteoblasts via distinct mechanisms involving inhibition of c-Src–dependent and –independent signaling pathways.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 7
    Publication Date: 2018-02-21
    Description: Endoplasmic reticulum (ER) stress is triggered by various metabolic factors, such as cholesterol and proinflammatory cytokines. Recent studies have revealed that ER stress is closely related to skeletal disorders, such as osteoporosis. However, the precise mechanism by which ER stress regulates osteoclast differentiation has not been elucidated. In this study, we identified an ER-bound transcription factor, cAMP response element-binding protein H (CREBH), as a downstream effector of ER stress during RANKL-induced osteoclast differentiation. RANKL induced mild ER stress and the simultaneous accumulation of active nuclear CREBH (CREBH-N) in the nucleus during osteoclastogenesis. Overexpression of CREBH-N in osteoclast precursors enhanced RANKL-induced osteoclast formation through NFATc1 upregulation. Inhibiting ER stress using a specific inhibitor attenuated the expression of osteoclast-related genes and CREBH activation. In addition, inhibition of reactive oxygen species using N -acetylcysteine attenuated ER stress, expression of osteoclast-specific marker genes, and RANKL-induced CREBH activation. Furthermore, inhibition of ER stress and CREBH signaling pathways using an ER stress–specific inhibitor or CREBH small interfering RNAs prevented RANKL-induced bone destruction in vivo. Taken together, our results suggest that reactive oxygen species/ER stress signaling-dependent CREBH activation plays an important role in RANKL-induced osteoclastogenesis. Therefore, inactivation of ER stress and CREBH signaling pathways may represent a new treatment strategy for osteoporosis.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 8
    Publication Date: 2018-06-05
    Description: Neutrophils, basophils, and monocytes are continuously produced in bone marrow via myelopoiesis, circulate in blood, and are eventually removed from circulation to maintain homeostasis. To quantitate the kinetics of myeloid cell movement during homeostasis, we applied 5-bromo-2'-deoxyuridine pulse labeling in healthy rhesus macaques ( Macaca mulatta ) followed by hematology and flow cytometry analyses. Results were applied to a mathematical model, and the blood circulating half-life and daily production, respectively, of each cell type from macaques aged 5–10 y old were calculated for neutrophils (1.63 ± 0.16 d, 1.42 x 10 9 cells/l/d), basophils (1.78 ± 0.30 d, 5.89 x 10 6 cells/l/d), and CD14 + CD16 – classical monocytes (1.01 ± 0.15 d, 3.09 x 10 8 cells/l/d). Classical monocytes were released into the blood circulation as early as 1 d after dividing, whereas neutrophils remained in bone marrow 4–5 d before being released. Among granulocytes, neutrophils and basophils exhibited distinct kinetics in bone marrow maturation time and blood circulation. With increasing chronological age, there was a significant decrease in daily production of neutrophils and basophils, but the half-life of these granulocytes remained unchanged between 3 and 19 y of age. In contrast, daily production of classical monocytes remained stable through 19 y of age but exhibited a significant decline in half-life. These results demonstrated relatively short half-lives and continuous replenishment of neutrophils, basophils, and classical monocytes during homeostasis in adult rhesus macaques with compensations observed during increasing chronological age.
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    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 9
    Publication Date: 2018-07-24
    Description: The role for kidney TLR9 in ischemic acute kidney injury (AKI) remains unclear. In this study, we tested the hypothesis that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular epithelial apoptosis and inflammation. To test this hypothesis, we generated mice lacking TLR9 in renal proximal tubules (TLR9 fl/fl PEPCK Cre mice). Contrasting previous studies in global TLR9 knockout mice, mice lacking renal proximal tubular TLR9 were protected against renal ischemia/reperfusion (IR) injury, with reduced renal tubular necrosis, inflammation (decreased proinflammatory cytokine synthesis and neutrophil infiltration), and apoptosis (decreased DNA fragmentation and caspase activation) when compared with wild-type (TLR9 fl/fl ) mice. Consistent with this, a selective TLR9 agonist oligonucleotide 1668 exacerbated renal IR injury in TLR9 fl/fl mice but not in renal proximal tubular TLR9-null mice. Furthermore, in cultured human and mouse proximal tubule cells, TLR9-selective ligands induced NF-B activation, proinflammatory cytokine mRNA synthesis, as well as caspase activation. We further confirm in the present study that global TLR9 deficiency had no impact on murine ischemic AKI. Taken together, our studies show that renal proximal tubular TLR9 activation exacerbates ischemic AKI by promoting renal tubular inflammation, apoptosis as well as necrosis, after IR via NF-B and caspase activation. Our studies further suggest the complex nature of TLR9 activation, as renal tubular epithelial TLR9 promotes cell injury and death whereas TLR9 signaling in other cell types may promote cytoprotective effects.
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    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 10
    Publication Date: 2018-10-10
    Description: Immunotherapy with checkpoint inhibitors has proved to be highly effective, with durable responses in a subset of patients. Given their encouraging clinical activity, checkpoint inhibitors are increasingly being tested in clinical trials in combination with chemotherapy. In many instances, there is little understanding of how chemotherapy might influence the quality of the immune response generated by checkpoint inhibitors. In this study, we evaluated the impact of chemotherapy alone or in combination with anti–PD-L1 in a responsive syngeneic tumor model. Although multiple classes of chemotherapy treatment reduced immune cell numbers and activity in peripheral tissues, chemotherapy did not antagonize but in many cases augmented the antitumor activity mediated by anti–PD-L1. This dichotomy between the detrimental effects in peripheral tissues and enhanced antitumor activity was largely explained by the reduced dependence on incoming cells for antitumor efficacy in already established tumors. The effects of the various chemotherapies were also agent specific, and synergy with anti–PD-L1 was achieved by different mechanisms that ultimately helped establish a new threshold for response. These results rationalize the combination of chemotherapy with immunotherapy and suggest that, despite the negative systemic effects of chemotherapy, effective combinations can be obtained through distinct mechanisms acting within the tumor.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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