| 581. |
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| 582. |
- Shen, Li, et al.
(författare)
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Tasquinimod Modulates Suppressive Myeloid Cells and Enhances Cancer Immunotherapies in Murine Models
- 2015
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Ingår i: Cancer immunology research. - 2326-6074. ; 3:2, s. 136-148
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Tidskriftsartikel (refereegranskat)abstract
- A major barrier for cancer immunotherapy is the presence of suppressive cell populations in patients with cancer, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), which contribute to the immunosuppressive microenvironment that promotes tumor growth and metastasis. Tasquinimod is a novel antitumor agent that is currently at an advanced stage of clinical development for treatment of castration-resistant prostate cancer. A target of tasquinimod is the inflammatory protein S100A9, which has been demonstrated to affect the accumulation and function of tumor-suppressive myeloid cells. Here, we report that tasquinimod provided a significant enhancement to the antitumor effects of two different immunotherapeutics in mouse models of cancer: a tumor vaccine (SurVaxM) for prostate cancer and a tumor-targeted superantigen (TTS) for melanoma. In the combination strategies, tasquinimod inhibited distinct MDSC populations and TAMs of the M2-polarized phenotype (CD206(+)). CD11b(+) myeloid cells isolated from tumors of treated mice expressed lower levels of arginase-1 and higher levels of inducible nitric oxide synthase (iNOS), and were less immunosuppressive ex vivo, which translated into a significantly reduced tumor-promoting capacity in vivo when these cells were coinjected with tumor cells. Tumor-specific CD8(+) T cells were increased markedly in the circulation and in tumors. Furthermore, T-cell effector functions, including cell-mediated cytotoxicity and IFN gamma production, were potentiated. Taken together, these data suggest that pharmacologic targeting of suppressive myeloid cells by tasquinimod induces therapeutic benefit and provide the rationale for clinical testing of tasquinimod in combination with cancer immunotherapies. (C) 2014 AACR.
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| 583. |
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| 584. |
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| 585. |
- Stephens, Lucas, et al.
(författare)
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Archaeological assessment reveals Earth’s early transformation through land use
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 365:6456, s. 897-902
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Tidskriftsartikel (refereegranskat)abstract
- Humans began to leave lasting impacts on Earth’s surface starting 10,000 to 8000 years ago. Through a synthetic collaboration with archaeologists around the globe, Stephens et al. compiled a comprehensive picture of the trajectory of human land use worldwide during the Holocene (see the Perspective by Roberts). Hunter-gatherers, farmers, and pastoralists transformed the face of Earth earlier and to a greater extent than has been widely appreciated, a transformation that was essentially global by 3000 years before the present.Science, this issue p. 897; see also p. 865Environmentally transformative human use of land accelerated with the emergence of agriculture, but the extent, trajectory, and implications of these early changes are not well understood. An empirical global assessment of land use from 10,000 years before the present (yr B.P.) to 1850 CE reveals a planet largely transformed by hunter-gatherers, farmers, and pastoralists by 3000 years ago, considerably earlier than the dates in the land-use reconstructions commonly used by Earth scientists. Synthesis of knowledge contributed by more than 250 archaeologists highlighted gaps in archaeological expertise and data quality, which peaked for 2000 yr B.P. and in traditionally studied and wealthier regions. Archaeological reconstruction of global land-use history illuminates the deep roots of Earth’s transformation and challenges the emerging Anthropocene paradigm that large-scale anthropogenic global environmental change is mostly a recent phenomenon.
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| 586. |
- Sundh, Henrik, 1976, et al.
(författare)
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Reduced water quality associated with higher stocking density disturbs the intestinal barrier functions of Atlantic salmon (Salmo salar L.)
- 2019
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Ingår i: Aquaculture. - : Elsevier BV. - 0044-8486. ; 512
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Tidskriftsartikel (refereegranskat)abstract
- The stocking density of fish in aquaculture is of major importance as it may have profound effects on water quality resulting in impact on fish health and possibly affect the external barriers that protect against pathogens There are many husbandry conditions, including stocking density, that may affect the primary protective barriers, i.e. the skin, intestine and gills, against invading pathogens and other harmful substances. It is well known that increased fish density will lead to decreased dissolved oxygen (DO) levels and affect other water quality parameters such as carbon dioxide, pH and ammonia. It is not known if such changes in the rearing environment affect the intestinal primary barriers of Atlantic salmon. Groups of Atlantic salmon post-smolts were kept for 57 days in tanks supplied with seawater at a constant flow at stocking densities of 10, 30, 50 and 70 kg m−3; reduced water quality was associated with higher stocking density. Repeated sampling for plasma cortisol and water cortisol release rate indicate that the highest stocking density elicited a primary stress response in the fish, which decreased with time. The physical intestinal barrier was assessed using paracellular permeability measurements, i.e. transepithelial electrical resistance (TER) and diffusion rate of 14C-mannitol, in combination with the translocation rate of heat-inactivated Aeromonas salmonicida. The physical intestinal barrier decreased with increasing density, both when measured as decreased transepithelial electrical resistance and as elevated paracellular permeability for 14C-mannitol. As this was observed at a time point when no differences could be seen in plasma cortisol or cortisol release rate, it suggests that intestinal paracellular permeability can be a useful marker for chronic stress in salmon. The status of the intestinal immune system was assessed as degree of neutrophil infiltration as well as the mRNA expression of the pro-inflammatory cytokines, interferon γ (IFNγ), interleukin (IL) 1β and tumor necrosis factor (TNF) α, anti-inflammatory cytokines, IL-10 and transforming growth factor β (TGFβ) and other immune related-genes, IL-8 and the inhibitor of the transcription factor nuclear factor κB (IκB). The intestinal immune system was affected at the highest stocking density as observed by a decreased expression of IFNγ in parallel with higher infiltration of neutrophils. In conclusion, high stocking density associated with reduced water quality is chronically stressful to the fish as it elicits a primary stress response as well as a weakened physical and disturbed immunological primary barrier.
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| 587. |
- Telling, M. T. F., et al.
(författare)
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Pressure-dependent spin fluctuations and magnetic structure in the topologically frustrated spin glass alloy Y(Mn0.95Al0.05)(2)
- 2012
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Ingår i: Physical Review B (Condensed Matter and Materials Physics). - 1098-0121. ; 85:18
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Tidskriftsartikel (refereegranskat)abstract
- Longitudinal field (LF = 110 G) muon spin relaxation (mu SR) has been used to investigate the pressure dependence (P < 4.5 kbar) of paramagnetic spin fluctuations in the spin glass alloy Y(Mn0.95Al0.05)(2) via observation of the mu(+) spin depolarization. External mechanical force is seen to counteract the Al-induced chemical pressure, fully delocalizing the Mn moment and altering the nature of the spin fluctuation spectrum sensed by the muon. A qualitative change in the functional form of the mu(+) spin depolarization is observed. Complementary ambient and high-pressure neutron diffraction measurements suggest not only pressure-dependent structural transitions but also the instability of the localized manganese moment. The ambient and high-pressure mu(+) spin depolarization results from Y(Mn0.95Al0.05)(2) are likened to P = 0 results reported for other Y(Mn1-xAlx)(2) alloys. Finally, the possibility of using mu(+) spin depolarization rates to predict experimental inelastic neutron scattering (INS) line widths is considered; the muon having the potential to provide information equivalent to that obtained via INS but with greatly reduced data collection times.
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| 588. |
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| 589. |
- Threadgold, J, et al.
(författare)
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The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease
- 2002
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 50:5, s. 675-681
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mutations in the PRSS1 gene explain most occurrences of hereditary pancreatitis (HP) but many HP families have no PRSS1 mutation. Recently, an association between the mutation N34S in the pancreatic secretary trypsin inhibitor (SPINK1 or PSTI) gene and idiopathic chronic pancreatitis (ICP) was reported. It is unclear whether the N34S mutation is a cause of pancreatitis per se, whether it modifies the disease, or whether it is a marker of the disease. Patients and methods: A total of 327 individuals from 217 families affected by pancreatitis were tested: 152 from families with HP, 108 from families with ICP, and 67 with alcohol related CP (ACP). Seven patients with ICP had a family history of pancreatitis but no evidence of autosomal dominant disease (f-ICP) compared with 87 patients with true ICP (t-ICP). Two hundred controls were also tested for the N34S mutation. The findings were related to clinical outcome. Results: The N34S mutation was carried by five controls (2.5%; allele frequency 1.25%), 11/87 (13%) t-ICP patients (p=0.0013 v controls), and 6/7 (86%) affected (p<0.0001 v controls) and 1/9 (11%) unaffected f-ICP cases. N34S was found in 4/108 affected HP patients (p=0.724 v controls), in, 3/27 (11%) with wild-type and in 1/81 (1%) with mutant PRSS1, and 4/67 ACP patients (all p>0.05 v controls). The presence of the N34S mutation was not associated with early disease onset or disease severity. Conclusions: The prevalence of the N34S mutation was increased in patients with ICP and was greatest in f-ICP cases. Segregation of the N34S mutation in families with pancreatitis is unexplained and points to a complex association between N34S and another putative pancreatitis related gene.
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| 590. |
- Van Deerlin, Vivian M, et al.
(författare)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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