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  • 1
    Abstract: Tumor immune escape is a critical problem which frequently accounts for the failure of therapeutic tumor vaccines. Among the most potent suppressors of tumor immunity are myeloid derived suppressor cells (MDSCs). MDSCs can be targeted by all-trans-retinoic-acid (atRA), which reduced their numbers and increased response rates in several vaccination studies. However, not much is known about the optimal administration interval between atRA and the vaccine as well as about its mode of action. Here we demonstrate in 2 different murine tumor models that mice unresponsive to a therapeutic vaccine harbored higher MDSC numbers than did responders. Application of atRA overcame MDSC-mediated immunosuppression and restored tumor control. Importantly, atRA was protective only when administered 3 d after vaccination (delayed treatment), whereas simultaneous administration even decreased the anti-tumor immune response and reduced survival. When analyzing the underlying mechanisms, we found that delayed, but not simultaneous atRA treatment with vaccination abrogated the suppressive capacity in monocytic MDSCs and instead caused them to upregulate MHC-class-II. Consistently, MDSCs from patients with colorectal carcinoma also failed to upregulate HLA-DR after ex vivo treatment with TLR-ligation. Overall, we demonstrate that atRA can convert non-responders to responders to vaccination by suppressing MDSCs function and not only by reducing their number. Moreover, we identify a novel, strictly time-dependent mode of action of atRA to be considered during immunotherapeutic protocols in the future.
    Type of Publication: Journal article published
    PubMed ID: 28920004
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  • 2
    Keywords: RECEPTOR ; CANCER ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; Germany ; IN-VIVO ; VIVO ; liver ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; ACTIVATION ; CUTTING EDGE ; INFECTION ; INDUCTION ; DENDRITIC CELLS ; T-CELLS ; TOLERANCE ; bone marrow ; BONE-MARROW ; STIMULATION ; MOUSE ; DELIVERY ; CLONAL EXPANSION ; VIRAL-INFECTION ; CROSS-PRESENTATION ; endothelial cells ; EFFECTOR FUNCTION ; RIG-I ; T cell immunity ; HEPATITIS-B VIRUS ; MURINE CYTOMEGALOVIRUS-INFECTION ; TOLEROGENIC DENDRITIC CELLS
    Abstract: BACKGROUND & AIMS: Dendritic cell activation through ligation of pattern recognition receptors leading to full functional maturation causes induction of CD8(+) T-cell immunity through increased delivery of costimulatory signals instead of tolerance. Here we investigate whether organ-resident antigen-presenting cells, such as liver sinusoidal endothelial cells (LSECs), also switch from tolerogenic to immunogenic CD8(+) T-cell activation upon such stimulation. METHODS: Murine LSECs were isolated by immunomagnetic separation and analyzed for functional maturation upon triggering pattern recognition receptors or viral infection employing gene expression analysis and T cell coculture assays. In vivo relevance of the findings was confirmed with bone-marrow chimeric animals. RESULTS: LSECs expressed numerous pattern recognition receptors that allowed for sentinel function, but ligand-induced activation of these receptors was not sufficient to overcome tolerance induction of CD8(+) T cells. Importantly, viral infection with murine cytomegalovirus caused functional maturation of antigen-presenting LSECs and was sufficient to promote antigen-specific differentiation into effector CD8(+) T cells in the absence of dendritic cells and independent of CD80/86. CONCLUSIONS: These results shed new light on the generation of organ-specific immunity and may contribute to overcoming tolerance in relevant situations, such as cancer
    Type of Publication: Journal article published
    PubMed ID: 19737567
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  • 3
    ISSN: 1432-1238
    Keywords: Key words D-dimer ; Disseminated intravascular coagulation ; Mortality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: To determine if D-dimer predicts outcomes in critically ill patients. Design: Observational, cohort study. Setting: Medical intensive care unit (MICU) of a tertiary care hospital. Patients and participants: Seventy-four patients consecutively admitted to the MICU. Interventions: D-dimer was measured by latex agglutination within 12 h of admission to the MICU. Measurements and results: Of the study population, 43.2 % had positive D-dimers. The in-hospital mortality rate in D-dimer positive patients was 28.1 % as compared to 7.1 % in D-dimer negative subjects (p = 0.024). D-dimer positive patients had significantly greater frequencies of venous thromboses (21.9 % vs 4.8 %, p = 0.035). Conclusions: The D-dimer assay identifies patients at increased risk for mortality and may be a more sensitive test to determine the presence of underlying microvascular pathology in critically ill patients. A positive D-dimer at admission to the MICU is associated with an increased risk for the later development of a venous thromboembolic event (VTE).
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-7357
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Adsorption isotherms of para-hydrogen adsorbed on graphite foam were measured for the temperature interval of 9 to 15 K up to about 25 layers, using the standard volumetric method. From these isotherms straight lines were obtained for ln(P 0/P) as a function ofd −3, d being the coverage. These plots obey an equation of the type ln(P 0/P)=ad−3+b. Considering capillary condensation and using the Frenkel-Halsey-Hill equation together with Kelvin's relation an average pore radius of (315±60) Å was found and the van der Waals potential calculated as (2.36±0.07)×10−12 erg Å3. From the data, there seems to be a transition at about 11 K, but it cannot be concluded definitely if it is a complete wetting transition. Whenever possible the obtained results were compared to existing data.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: We present intersubband absorption measurements performed on p-type quasistrain-compensated modulation-doped Si0.2Ge0.8/Si quantum wells grown on Si0.5Ge0.5 pseudosubstrates. Several intersubband absorption peaks are observed up to room temperature. A strong confinement shift of the resonance occuring between the ground and the first excited heavy hole states has been observed, with the absorption peak shifting from λ=5.3 μm to as short as 3.8 μm. Excellent overall agreement with a 6 band k⋅p calculation is obtained, proving the accuracy of recently predicted values of band offsets. © 2002 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1572-9540
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract Synthetic crystals of phosphoferrite were studied by Mössbauer spectroscopy for temperatures ranging from 4.2 to 17.5 K. The analysis of the behaviour of the hyperfine fields for the two unequivalent sites near the Néel temperature (17.4 K) allowed the determination of the critical exponentβ for each site asβ 1=0.171 andβ 2=0.314.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1569-8041
    Keywords: adaptation ; adjustment ; cancer survivors ; Hodgkin's disease ; leukemia ; quality of life
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The purpose of this study was to compare the long-term psychosocial adaptation of Hodgkin's disease and adult acute leukemia survivors. Patients and methods: Two hundred seventy-three Hodgkin's disease (HD) and 206 adult acute leukemia (AL) survivors were interviewed by telephone concerning their psychosocial adjustment and problems they attributed to having been treated for cancer, using identical research procedures and a common set of instruments. The following measures were used: Psychosocial Adjustment to Illness Scale (PAIS); Brief Symptom Inventory (BSI); current Conditioned Nausea and Vomiting triggered by treatment-related stimuli (CNVI); Indices of Employment, Insurance and Sexual Problems Attributed to Cancer; Negative Socioeconomic Impact of Cancer Index (NSI). All participants had been treated on one of nine Hodgkin's disease or 13 acute leukemia Cancer and Leukemia Group B (CALGB) clinical trials from 1966–1988, and had been off treatment for one year or more (mean years: HD = 5.9; AL = 5.6). Results: HD survivors' risk of having a high distress score on the BSI was almost twice that found for AL survivors (odds ratio = 1.90), with 21% of HD vs. 14% of AL survivors (P 〈 0.05) having scores that were 1.5 standard deviations above the norm, suggestive of a possible psychiatric disorder. HD survivors reported greater fatigue (POMS Fatigue, P = 0.01; Vigor Subscales, P = 0.001), greater conditioned nausea (CNVI, P 〈 0.05), greater impact of cancer on their family life (PAIS Domestic Environment, P = 0.004) and poorer sexual functioning (PAIS Sexual Relationships, P = 0.0001), than AL survivors. Conclusions: Treatment-related issues may have placed HD survivors at a greater risk for problems in long-term adaptation than AL survivors.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: anthracycline ; chemotherapy ; liposomal daunorubicin ; lymphoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background:Standard therapy for lymphoma consists of acyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P) (CHOP)combination regimen. Liposomal daunorubicin (DaunoXome®) is an alternativeto doxorubicin for patients with lymphoma because of its more favorable safetyprofile and potentially more selective uptake in lymphoma. The objectives ofthis study were to determine the maximum tolerated dose (MTD) of liposomaldaunorubucin with CVP (COP-X) and the tolerability of the regimen in patientswith indolent lymphoma. Patients and methods:Patients with low-grade andintermediate-grade lymphoma having adequate cardiac, hepatic, and renalfunction were enrolled. Patients received C 750 mg/m2, V 1.4mg/m2 (maximum 2.0 mg), and liposomal daunorubicin 50–100mg/m2 i.v. on day 1 and P 100 mg p.o. on days 1–5. MTD wasthe liposomal daunorubicin dose associated with 20% dose-limitingtoxicity (ANC 〈500/mm3 for 〉5 days or febrile neutropenia). Results:Twenty patients, median age 59 years, were treated. Theliposomal daunorubicin MTD combined with CVP was 70–80 mg/m2,depending on patient population. No significant non-hematologic toxicityoccurred. Response rate was 44% (2 complete and 5 partial responses). Conclusions:A liposomal daunorubicin dose of 80 mg/m2in the COP-X regimen was well tolerated with little non-hematologic toxicity.
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2014-08-15
    Description: The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaoting -- Ota, Naruhisa -- Manzanillo, Paolo -- Kates, Lance -- Zavala-Solorio, Jose -- Eidenschenk, Celine -- Zhang, Juan -- Lesch, Justin -- Lee, Wyne P -- Ross, Jed -- Diehl, Lauri -- van Bruggen, Nicholas -- Kolumam, Ganesh -- Ouyang, Wenjun -- England -- Nature. 2014 Oct 9;514(7521):237-41. doi: 10.1038/nature13564. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Immunology, Genentech, South San Francisco, California 94080, USA [2]. ; Department of Immunology, Genentech, South San Francisco, California 94080, USA. ; Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119041" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/drug effects/metabolism ; Animals ; CD4-Positive T-Lymphocytes/immunology/secretion ; Chronic Disease ; Citrobacter rodentium/drug effects/immunology/physiology ; Colon/drug effects/immunology/microbiology ; Diabetes Mellitus/*immunology/*metabolism/pathology ; Diet, High-Fat ; Female ; Hyperglycemia/diet therapy/drug therapy/metabolism ; *Immunity, Mucosal/drug effects ; Inflammation/drug therapy/metabolism/pathology ; Insulin/metabolism ; Insulin Resistance ; Interleukin-23/immunology/metabolism/pharmacology ; Interleukins/*immunology/*metabolism/pharmacology/therapeutic use ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Male ; Metabolic Diseases/diet therapy/drug therapy/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/metabolism ; Receptors, Interleukin/deficiency/metabolism ; Receptors, Leptin/deficiency/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2018-07-17
    Description: Acetylation blocks DNA damage–induced chromatin ADP-ribosylation Acetylation blocks DNA damage–induced chromatin ADP-ribosylation, Published online: 16 July 2018; doi:10.1038/s41589-018-0097-1 Histone H3 serine 10 is found to be the major chromatin acceptor residue for DNA damage–induced ADP-ribosylation and is blocked by specific acetylation sites on PARP1 and/or H3.
    Print ISSN: 1552-4450
    Electronic ISSN: 1552-4469
    Topics: Biology , Chemistry and Pharmacology
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