50 results on '"Neumann, Silke"'
Search Results
2. Molecular monitoring of glioblastoma’s immunogenicity using a combination of Raman spectroscopy and chemometrics
- Author
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Robert, Chima, Tsiampali, Julia, Fraser-Miller, Sara J., Neumann, Silke, Maciaczyk, Donata, Young, Sarah L., Maciaczyk, Jaroslaw, and Gordon, Keith C.
- Published
- 2021
- Full Text
- View/download PDF
3. Primary prophylaxis of bacterial infections and Pneumocystis jirovecii pneumonia in patients with hematologic malignancies and solid tumors: 2020 updated guidelines of the Infectious Diseases Working Party of the German Society of Hematology and Medical Oncology (AGIHO/DGHO)
- Author
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Classen, Annika Y., Henze, Larissa, von Lilienfeld-Toal, Marie, Maschmeyer, Georg, Sandherr, Michael, Graeff, Luisa Durán, Alakel, Nael, Christopeit, Maximilian, Krause, Stefan W., Mayer, Karin, Neumann, Silke, Cornely, Oliver A., Penack, Olaf, Weißinger, Florian, Wolf, Hans-Heinrich, and Vehreschild, Jörg Janne
- Published
- 2021
- Full Text
- View/download PDF
4. Late-stage MC38 tumours recapitulate features of human colorectal cancer-implications for appropriate timepoint selection in preclinical studies.
- Author
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Shields, Nicholas J., Peyroux, Estelle M., Ferguson, Angela L., Steain, Megan, Neumann, Silke, and Young, Sarah L.
- Subjects
T-cell exhaustion ,TUMORS ,COLORECTAL cancer ,T cells ,ANIMAL models in research - Abstract
Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while latestage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
5. Epidemiology of invasive aspergillosis and azole resistance in patients with acute leukaemia: the SEPIA Study
- Author
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Koehler, Philipp, Hamprecht, Axel, Bader, Oliver, Bekeredjian-Ding, Isabelle, Buchheidt, Dieter, Doelken, Gottfried, Elias, Johannes, Haase, Gerhard, Hahn-Ast, Corinna, Karthaus, Meinolf, Kekulé, Alexander, Keller, Peter, Kiehl, Michael, Krause, Stefan W., Krämer, Carolin, Neumann, Silke, Rohde, Holger, La Rosée, Paul, Ruhnke, Markus, Schafhausen, Philippe, Schalk, Enrico, Schulz, Katrin, Schwartz, Stefan, Silling, Gerda, Staib, Peter, Ullmann, Andrew, Vergoulidou, Maria, Weber, Thomas, Cornely, Oliver A., and Vehreschild, Maria J.G.T.
- Published
- 2017
- Full Text
- View/download PDF
6. Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study)
- Author
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Kreuter, Michael, Vansteenkiste, Johan, Fischer, Jürgen R., Eberhardt, Wilfried E., Zabeck, Heike, Kollmeier, Jens, Serke, Monika, Frickhofen, Norbert, Reck, Martin, Engel-Riedel, Walburga, Neumann, Silke, Thomeer, Michiel, Schumann, Christian, De Leyn, Paul, Graeter, Thomas, Stamatis, Georgios, Griesinger, Frank, and Thomas, Michael
- Published
- 2016
- Full Text
- View/download PDF
7. Synthetic TRP2 long-peptide and α-galactosylceramide formulated into cationic liposomes elicit CD8+ T-cell responses and prevent tumour progression
- Author
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Neumann, Silke, Young, Katie, Compton, Benji, Anderson, Regan, Painter, Gavin, and Hook, Sarah
- Published
- 2015
- Full Text
- View/download PDF
8. The flavonoid, 2′-methoxy-6-methylflavone, affords neuroprotection following focal cerebral ischaemia
- Author
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Clarkson, Andrew N, Boothman-Burrell, Lily, Dósa, Zita, Nagaraja, Raghavendra Y, Jin, Liang, Parker, Kim, van Nieuwenhuijzen, Petra S, Neumann, Silke, Gowing, Emma K, Gavande, Navnath, Ahring, Philip K, Holm, Mai M, Hanrahan, Jane R, Nicolazzo, Joseph A, Jensen, Kimmo, and Chebib, Mary
- Published
- 2019
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9. The effects of wholegrain processing on appetite: randomised crossover trial in adults with type 2 diabetes.
- Author
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Reynolds, Andrew Nathan, Diep Pham, Huyen Tran, Åberg, Sebastian, Neumann, Silke, and Mann, Jim
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- 2023
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10. Acute or Delayed Systemic Administration of Human Amnion Epithelial Cells Improves Outcomes in Experimental Stroke
- Author
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Evans, Megan A., Lim, Rebecca, Kim, Hyun Ah, Chu, Hannah X., Gardiner-Mann, Chantelle V., Taylor, Kimberly W.E., Chan, Christopher T., Brait, Vanessa H., Lee, Seyoung, Dinh, Quynh Nhu, Vinh, Antony, Phan, Thanh G., Srikanth, Velandai K., Ma, Henry, Arumugam, Thiruma V., Fann, David Y., Poh, Luting, Hunt, Cameron P.J., Pouton, Colin W., Haynes, John M., Selemidis, Stavros, Kwan, William, Teo, Leon, Bourne, James A., Neumann, Silke, Young, Sarah, Gowing, Emma K., Drummond, Grant R., Clarkson, Andrew N., Wallace, Euan M., Sobey, Christopher G., and Broughton, Brad R.S.
- Published
- 2018
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11. Late-stage MC38 tumours recapitulate features of human colorectal cancer - implications for appropriate timepoint selection in preclinical studies.
- Author
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Shields, Nicholas J., Peyroux, Estelle M., Ferguson, Angela L., Steain, Megan, Neumann, Silke, and Young, Sarah L.
- Subjects
COLORECTAL cancer ,T-cell exhaustion ,TUMORS ,T cells - Abstract
Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while latestage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
12. Infectious diseases in allogeneic haematopoietic stem cell transplantation: prevention and prophylaxis strategy guidelines 2016
- Author
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Ullmann, Andrew J., Schmidt-Hieber, Martin, Bertz, Hartmut, Heinz, Werner J., Kiehl, Michael, Krüger, William, Mousset, Sabine, Neuburger, Stefan, Neumann, Silke, Penack, Olaf, Silling, Gerda, Vehreschild, Jörg Janne, Einsele, Hermann, Maschmeyer, Georg, and on behalf of the Infectious Diseases Working Party of the German Society for Hematology and Medical Oncology (AGIHO/DGHO) and the DAG-KBT (German Working Group for Blood and Marrow Transplantation)
- Published
- 2016
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- View/download PDF
13. Antiviral prophylaxis in patients with solid tumours and haematological malignancies—update of the Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Medical Oncology (DGHO)
- Author
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Sandherr, Michael, Hentrich, Marcus, von Lilienfeld-Toal, Marie, Massenkeil, Gero, Neumann, Silke, Penack, Olaf, Biehl, Lena, and Cornely, Oliver A.
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- 2015
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14. Chemotactic signaling via carbohydrate phosphotransferase systems in Escherichia coli
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Neumann, Silke, Grosse, Karin, and Sourjik, Victor
- Published
- 2012
15. Corrigendum: Late-stage MC38 tumours recapitulate features of human colorectal cancer-implications for appropriate timepoint selection in preclinical studies.
- Author
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Shields, Nicholas J., Peyroux, Estelle M., Ferguson, Angela L., Steain, Megan, Neumann, Silke, and Young, Sarah L.
- Subjects
TUMORS ,T-cell exhaustion ,PEPTIDES ,MEDICAL sciences - Abstract
This document is a corrigendum published in the journal Frontiers in Immunology. It corrects an error in Figure 10 of a previously published article titled "Late-stage MC38 tumours recapitulate features of human colorectal cancer - implications for appropriate timepoint selection in preclinical studies." The error involved a duplicated density plot in the figure. The authors apologize for the mistake but state that it does not affect the scientific conclusions of the article. The original article has been updated. [Extracted from the article]
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- 2024
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16. Primary prophylaxis of invasive fungal infections in patients with haematologic malignancies. 2014 update of the recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology
- Author
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Tacke, Daniela, Buchheidt, Dieter, Karthaus, Meinolf, Krause, Stefan W., Maschmeyer, Georg, Neumann, Silke, Ostermann, Helmut, Penack, Olaf, Rieger, Christina, Ruhnke, Markus, Sandherr, Michael, Schweer, Katharina E., Ullmann, Andrew J., and Cornely, Oliver A.
- Published
- 2014
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17. Treatment of invasive fungal infections in cancer patients—updated recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO)
- Author
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Mousset, Sabine, Buchheidt, Dieter, Heinz, Werner, Ruhnke, Markus, Cornely, Oliver A., Egerer, Gerlinde, Krüger, William, Link, Hartmut, Neumann, Silke, Ostermann, Helmut, Panse, Jens, Penack, Olaf, Rieger, Christina, Schmidt-Hieber, Martin, Silling, Gerda, Südhoff, Thomas, Ullmann, Andrew J., Wolf, Hans-Heinrich, Maschmeyer, Georg, and Böhme, Angelika
- Published
- 2014
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- View/download PDF
18. WNT/β-Catenin-Mediated Resistance to Glucose Deprivation in Glioblastoma Stem-like Cells.
- Author
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Yusuf, Suad, Aretz, Philippe, Nickel, Ann-Christin, Westhoff, Philipp, Sharma, Amit, Qin, Nan, Remke, Marc, Steiger, Hans-Jakob, Hänggi, Daniel, Liu, Hongjia, Liu, Hongde, Neumann, Silke, Reifenberger, Guido, and Maciaczyk, Jarek
- Subjects
CELL culture ,GLIOMAS ,CYTOSKELETAL proteins ,CELLULAR signal transduction ,CELL survival ,GENE expression ,STEM cells ,SURVIVAL analysis (Biometry) ,GLUCOSE - Abstract
Simple Summary: The malignant growth and therapy resistance of isocitrate dehydrogenase (IDH)-wildtype glioblastoma is thought to be driven by a subpopulation of tumor cells with cancer stem-like cell (CSC) properties. Employing a high-throughput in vitro drug screen, we identified LGK974 and berberine as drugs that impair wingless (WNT) signaling and can thereby sensitize glioblastoma stem-like cells (GSCs) to glucose starvation-induced cell death. The main goal of this study was to characterize the role of the WNT pathway in mediating the survival and metabolic plasticity of GSCs under nutrient-restricted growth conditions. Gas chromatography mass spectrometry (GC-MS) was used to determine WNT-specific alterations of intracellular metabolites in GSCs grown under nutrient restriction, i.e., glucose depletion, or under standard conditions. Metabolic fingerprints hold the promise to complement classic biomarkers, thus potentially aiding the prediction of tumor behavior and patient prognosis. Isocitrate dehydrogenase (IDH)-wildtype glioblastoma is the most common primary malignant brain tumor. It is associated with a particularly poor prognosis, as reflected by an overall median survival of only 15 months in patients who undergo a supramarginal surgical reduction of the tumor mass followed by combined chemoradiotherapy. The highly malignant nature of IDH-wildtype glioblastoma is thought to be driven by glioblastoma stem-like cells (GSCs) that harbor the ability of self-renewal, survival, and adaptability to challenging environmental conditions. The wingless (WNT) signaling pathway is a phylogenetically highly conserved stemness pathway, which promotes metabolic plasticity and adaptation to a nutrient-limited tumor microenvironment. To unravel the reciprocal regulation of the WNT pathway and the nutrient-limited microenvironment, glioblastoma cancer stem-like cells were cultured in a medium with either standard or reduced glucose concentrations for various time points (24, 48, and 72 h). Glucose depletion reduced cell viability and facilitated the survival of a small population of starvation-resistant tumor cells. The surviving cells demonstrated increased clonogenic and invasive properties as well as enhanced chemosensitivity to pharmacological inhibitors of the WNT pathway (LGK974, berberine). Glucose depletion partially led to the upregulation of WNT target genes such as CTNNB1, ZEB1, and AXIN2 at the mRNA and corresponding protein levels. LGK974 treatment alone or in combination with glucose depletion also altered the metabolite concentration in intracellular compartments, suggesting WNT-mediated metabolic regulation. Taken together, our findings suggest that WNT-mediated metabolic plasticity modulates the survival of GSCs under nutrient-restricted environmental conditions. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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- View/download PDF
19. Responses of Escherichia coli bacteria to two opposing chemoattractant gradients depend on the chemoreceptor ratio
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Kalinin, Yevgeniy, Neumann, Silke, Sourjik, Victor, and Wu, Mingming
- Subjects
Escherichia coli -- Physiological aspects ,Chemical senses -- Research ,Biological sciences - Abstract
Escherichia coli chemotaxis has long served as a simple model of environmental signal processing, and bacterial responses to single chemical gradients are relatively well understood. Less is known about the chemotactic behavior of E. coli in multiple chemical gradients. In their native environment, cells are often exposed to multiple chemical stimuli. Using a recently developed microfluidic chemotaxis device, we exposed E. coli cells to two opposing but equally potent gradients of major attractants, methyl-aspartate and serine. The responses of E. coli cells demonstrated that chemotactic decisions depended on the ratio of the respective receptor number of Tar/Tsr. In addition, the ratio of Tar to Tsr was found to vary with cells' growth conditions, whereby it depended on the culture density but not on the growth duration. These results provide biological insights into the decision-making processes of chemotactic bacteria that are subjected to multiple chemical stimuli and demonstrate the importance of the cellular microenvironment in determining phenotypic behavior. doi:10.1128/JB.01507-09
- Published
- 2010
20. Activation of the NLRP3 inflammasome is not a feature of all particulate vaccine adjuvants
- Author
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Neumann, Silke, Burkert, Kristina, Kemp, Roslyn, Rades, Thomas, Dunbar, Rod P, and Hook, Sarah
- Published
- 2014
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21. Crosstalk between β-Catenin and CCL2 Drives Migration of Monocytes towards Glioblastoma Cells.
- Author
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Aretz, Philippe, Maciaczyk, Donata, Yusuf, Suad, Sorg, Rüdiger V., Hänggi, Daniel, Liu, Hongjia, Liu, Hongde, Dakal, Tikam Chand, Sharma, Amit, Bethanabatla, Ramakrishna, Neumann, Silke, and Maciaczyk, Jarek
- Subjects
MONONUCLEAR leukocytes ,MONOCYTES ,CATENINS ,ISOCITRATE dehydrogenase ,GLIOBLASTOMA multiforme - Abstract
Isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) is a fast growing and highly heterogeneous tumor, often characterized by the presence of glioblastoma stem cells (GSCs). The plasticity of GSCs results in therapy resistance and impairs anti-tumor immune response by influencing immune cells in the tumor microenvironment (TME). Previously, β-catenin was associated with stemness in GBM as well as with immune escape mechanisms. Here, we investigated the effect of β-catenin on attracting monocytes towards GBM cells. In addition, we evaluated whether CCL2 is involved in β-catenin crosstalk between monocytes and tumor cells. Our analysis revealed that shRNA targeting β-catenin in GBMs reduces monocytes attraction and impacts CCL2 secretion. The addition of recombinant CCL2 restores peripheral blood mononuclear cells (PBMC) migration towards medium (TCM) conditioned by shβ-catenin GBM cells. CCL2 knockdown in GBM cells shows similar effects and reduces monocyte migration to a similar extent as β-catenin knockdown. When investigating the effect of CCL2 on β-catenin activity, we found that CCL2 modulates components of the Wnt/β-catenin pathway and alters the clonogenicity of GBM cells. In addition, the pharmacological β-catenin inhibitor MSAB reduces active β-catenin, downregulates the expression of associated genes and alters CCL2 secretion. Taken together, we showed that β-catenin plays an important role in attracting monocytes towards GBM cells in vitro. We hypothesize that the interactions between β-catenin and CCL2 contribute to maintenance of GSCs via modulating immune cell interaction and promoting GBM growth and recurrence. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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22. Influence of host and pathogen variables on the efficacy of Phoma herbarum, a potential biological control agent of Taraxacum officinale
- Author
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Neumann, Silke and Boland, Greg J
- Published
- 2002
23. Pleural malakoplakia caused by Rhodoccocus equi infection in a patient after stem cell transplantation
- Author
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Behnes Carl, Neumann Silke, Schweyer Stefan, and Radzun Heinz-Joachim
- Subjects
Malakoplakia ,Pleura ,Rhodococcus equi ,Michaelis-Gutmann-Bodies ,Pathology ,RB1-214 - Abstract
Abstract Malakoplakia is a disease especially of the urinary tract with typical plaques most frequently observed in the urinary bladder's mucosa. In the context of immunosuppression malakoplakia can also occur in other organs. Some of these extravesical malakoplakias are associated with an infection by Rhodococcus equi, a rare human pathogen well known from veterinary medicine. Here we present the first case of a pleural malakoplakia without lung involvement caused by a proved Rhodococcus equi infection.
- Published
- 2012
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24. Whole-Grain Processing and Glycemic Control in Type 2 Diabetes: A Randomized Crossover Trial.
- Author
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Åberg, Sebastian, Mann, Jim, Neumann, Silke, Ross, Alastair B., and Reynolds, Andrew N.
- Abstract
Objective: To consider the effects of whole-grain processing, specifically milling, on glycemic control in free-living adults with type 2 diabetes.Research Design and Methods: Participants of this crossover trial were randomized to two interventions of 2 weeks, separated by washout. They were advised to replace the grain foods they normally consumed with intervention foods. Intervention foods were nutrient-matched whole-grain products of wheat, oats, and brown rice that differed in their degree of processing. No other lifestyle advice was given. Continuous glucose monitoring systems were worn. Other cardiometabolic risk factors and alkylresorcinols (a biomarker of whole-grain intake) were measured pre- and postintervention.Results: Thirty-one adults with type 2 diabetes (63 ± 13 years old, BMI 32.4 ± 7 kg/m2, HbA1c 7.5 ± 3.4% [59 ± 14 mmol/mol]) commenced the trial; 28 (90%) completed both interventions. The increase in alkylresorcinols did not differ between interventions, and there was no difference in reported energy intake. Postprandial responses were 9% (95% CI 3-15) lower following breakfast and 6% (1-10) lower following all meals of less-processed whole grains when compared with finely milled grains. Day-long glycemic variability also was reduced when measured by 24-h SD (-0.16 mmol/L [95% CI -0.25 to -0.06]) and mean amplitude of glycemic excursion (-0.36 [95% CI -0.65 to -0.08]). Mean change in body weight differed by 0.81 kg (95% CI 0.62-1.05) between interventions, increasing during the finely milled intervention and decreasing during the less-processed whole-grain intervention. This was not a mediating factor for the glycemic variables considered.Conclusions: Consuming less-processed whole-grain foods over 2 weeks improved measures of glycemia in free-living adults with type 2 diabetes compared with an equivalent amount of whole-grain foods that were finely milled. Dietary advice should promote the consumption of minimally processed whole grains. [ABSTRACT FROM AUTHOR]- Published
- 2020
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- View/download PDF
25. The Delta-Subunit Selective GABA A Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism.
- Author
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Neumann, Silke, Boothman-Burrell, Lily, Gowing, Emma K., Jacobsen, Thomas A., Ahring, Philip K., Young, Sarah L., Sandager-Nielsen, Karin, and Clarkson, Andrew N.
- Subjects
TUMOR necrosis factors ,STROKE ,CENTRAL nervous system ,BUTYRIC acid ,CELL receptors - Abstract
Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABA
A receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro. Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABAA receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment. [ABSTRACT FROM AUTHOR]- Published
- 2019
- Full Text
- View/download PDF
26. Effects of an Exergame Software for Older Adults on Fitness, Activities of Daily Living Performance, and Quality of Life.
- Author
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Neumann, Silke, Meidert, Ursula, Barberà-Guillem, Ricard, Poveda-Puente, Rakel, and Becker, Heidrun
- Published
- 2018
- Full Text
- View/download PDF
27. Improved Antitumor Activity of a Therapeutic Melanoma Vaccine through the Use of the Dual COX-2/5-LO Inhibitor Licofelone.
- Author
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Neumann, Silke, Shirley, Simon A., Kemp, Roslyn A., Hook, Sarah M., Kozlowska, Anna, and Van Hall, Thorbald
- Subjects
MELANOMA ,CYCLOOXYGENASE 2 inhibitors ,NONSTEROIDAL anti-inflammatory agents ,VACCINATION ,THERAPEUTICS - Abstract
Immune-suppressive cell populations impair antitumor immunity and can contribute to the failure of immune therapeutic approaches. We hypothesized that the nonsteroidal anti-inflammatory drug licofelone, a dual cyclooxygenase-2/5-LO inhibitor, would improve therapeutic melanoma vaccination by reducing immune-suppressive cell populations. Therefore, licofelone was administered after tumor implantation, either alone or in combination with a peptide vaccine containing a long tyrosinase-related protein 2-peptide and the adjuvant α-galactosylceramide, all formulated into cationic liposomes. Mice immunized with the long-peptide vaccine and licofelone showed delayed tumor growth compared to mice given the vaccine alone. This protection was associated with a lower frequency of immature myeloid cells (IMCs) in the bone marrow (BM) and spleen of tumor-inoculated mice. When investigating the effect of licofelone on IMCs in vitro, we found that the prostaglandin E
2 -induced generation of IMCs was decreased in the presence of licofelone. Furthermore, pre-incubation of BM cells differentiated under IMC-inducing conditions with licofelone reduced the secretion of cytokines interleukin (IL)-10 and -6 upon lipopolysaccharides (LPS) stimulation as compared to untreated cells. Interestingly, licofelone increased IL-6 and IL-10 secretion when administered after the LPS stimulus, demonstrating an environment-dependent effect of licofelone. Our findings support the use of licofelone to reduce tumor-promoting cell populations. [ABSTRACT FROM AUTHOR]- Published
- 2016
- Full Text
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28. Innate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective.
- Author
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Neumann, Silke, Shields, Nicholas J., Balle, Thomas, Chebib, Mary, and Clarkson, Andrew N.
- Subjects
- *
STROKE , *INFLAMMATION , *CENTRAL nervous system diseases , *ALZHEIMER'S disease , *SCHIZOPHRENIA , *IMMUNE response - Abstract
Stroke is one of the leading causes of death and long-term disability, with limited treatment options available. Inflammation contributes to damage tissue in the central nervous system across a broad range of neuropathologies, including Alzheimer's disease, pain, Schizophrenia, and stroke. While the immune system plays an important role in contributing to brain damage produced by ischemia, the damaged brain, in turn, can exert a powerful immune-suppressive effect that promotes infections and threatens the survival of stroke patients. Recently the cholinergic anti-inflammatory pathway, in particular its modulation using α7-nicotinic acetylcholine receptor (α7-nAChR) ligands, has shown potential as a strategy to dampen the inflammatory response and facilitate functional recovery in stroke patients. Here we discuss the current literature on stroke-induced inflammation and the effects of α7-nAChR modulators on innate immune cells. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
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29. Example of the application of the PERSONA methodology in the definition of needs and requirements for the WeTakeCare system.
- Author
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BARBERA-GUILLEM, Ricard, POVEDA-PUENTE, Rakel, NEUMANN, Silke, BECKER, Heidrun, RAMÍREZ, Miguel, WIENHOLTZ, Arno, and SCHAEDLER, Inge
- Abstract
In user-centred design and marketing, personas are fictional characters created to represent the different user types that might use a site, brand, or product in a similar way[1]. As in other projects, the main application and use value of the persona approach in WeTakeCare project has been to depict and thus make "vivid" the characters and the milieus created and selected. It has helped to better understand and communicate the differences among the potential users. It has also helped to understand the heterogeneity and diversity of the users' lives and to focus on how to meet their actual needs [2]. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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30. Universal Response-Adaptation Relation in Bacterial Chemotaxis.
- Author
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Krembel, Anna K., Neumann, Silke, and Sourjik, Victor
- Subjects
- *
CHEMOTAXIS , *BACTERIAL physiology , *ESCHERICHIA coli , *METHYLATION , *LIGAND binding (Biochemistry) , *BACTERIA - Abstract
The bacterial strategy of chemotaxis relies on temporal comparisons of chemical concentrations, where the probability of maintaining the current direction of swimming is modulated by changes in stimulation experienced during the recent past. A shortterm memory required for such comparisons is provided by the adaptation system, which operates through the activity-dependent methylation of chemotaxis receptors. Previous theoretical studies have suggested that efficient navigation in gradients requires a well-defined adaptation rate, because the memory time scale needs to match the duration of straight runs made by bacteria. Here we demonstrate that the chemotaxis pathway of Escherichia coli does indeed exhibit a universal relation between the response magnitude and adaptation time which does not depend on the type of chemical ligand. Our results suggest that this alignment of adaptation rates for different ligands is achieved through cooperative interactions among chemoreceptors rather than through fine-tuning of methylation rates for individual receptors. This observation illustrates a yet-unrecognized function of receptor clustering in bacterial chemotaxis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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- View/download PDF
31. Predicting Chemical Environments of Bacteria from Receptor Signaling.
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Clausznitzer, Diana, Micali, Gabriele, Neumann, Silke, Sourjik, Victor, and Endres, Robert G.
- Subjects
SENSE organs ,AVERSIVE stimuli ,BIOCHEMICAL genetics ,CELLS ,FLUORESCENCE resonance energy transfer - Abstract
Sensory systems have evolved to respond to input stimuli of certain statistical properties, and to reliably transmit this information through biochemical pathways. Hence, for an experimentally well-characterized sensory system, one ought to be able to extract valuable information about the statistics of the stimuli. Based on dose-response curves from in vivo fluorescence resonance energy transfer (FRET) experiments of the bacterial chemotaxis sensory system, we predict the chemical gradients chemotactic Escherichia coli cells typically encounter in their natural environment. To predict average gradients cells experience, we revaluate the phenomenological Weber's law and its generalizations to the Weber-Fechner law and fold-change detection. To obtain full distributions of gradients we use information theory and simulations, considering limitations of information transmission from both cell-external and internal noise. We identify broad distributions of exponential gradients, which lead to log-normal stimuli and maximal drift velocity. Our results thus provide a first step towards deciphering the chemical nature of complex, experimentally inaccessible cellular microenvironments, such as the human intestine. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
32. Exponential Signaling Gain at the Receptor Level Enhances Signal-to-Noise Ratio in Bacterial Chemotaxis.
- Author
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Neumann, Silke, Løvdok, Linda, Bentele, Kajetan, Meisig, Johannes, Ullner, Ekkehard, Paldy, Ferencz S., Sourjik, Victor, and Kollmann, Markus
- Subjects
- *
SIGNAL-to-noise ratio , *BACTERIAL toxins , *CHEMOTAXIS , *CELLULAR signal transduction , *AVERSIVE stimuli , *ENVIRONMENTAL impact analysis , *BACTERIA - Abstract
Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly designed signaling architectures. Here, we report on a novel control mechanism that allows living cells to keep precision in their signaling characteristics – stationary pathway output, response amplitude, and relaxation time – in the presence of strong intracellular perturbations. The concept relies on the surprising fact that for systems showing perfect adaptation an exponential signal amplification at the receptor level suffices to eliminate slowly varying multiplicative noise. To show this mechanism at work in living systems, we quantified the response dynamics of the E. coli chemotaxis network after genetically perturbing the information flux between upstream and downstream signaling components. We give strong evidence that this signaling system results in dynamic invariance of the activated response regulator against multiplicative intracellular noise. We further demonstrate that for environmental conditions, for which precision in chemosensing is crucial, the invariant response behavior results in highest chemotactic efficiency. Our results resolve several puzzling features of the chemotaxis pathway that are widely conserved across prokaryotes but so far could not be attributed any functional role. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
33. Imprecision of Adaptation in Escherichia coli Chemotaxis.
- Author
-
Neumann, Silke, Vladimirov, Nikita, Krembel, Anna K., Wingreen, Ned S., and Sourjik, Victor
- Subjects
- *
ESCHERICHIA coli , *CHEMOTAXIS , *CHEMORECEPTORS , *BIOACCUMULATION , *CHEMOTACTIC factors , *METHYLATION , *SATURATION (Chemistry) - Abstract
Adaptability is an essential property of many sensory systems, enabling maintenance of a sensitive response over a range of background stimulus levels. In bacterial chemotaxis, adaptation to the preset level of pathway activity is achieved through an integral feedback mechanism based on activity-dependent methylation of chemoreceptors. It has been argued that this architecture ensures precise and robust adaptation regardless of the ambient ligand concentration, making perfect adaptation a celebrated property of the chemotaxis system. However, possible deviations from such ideal adaptive behavior and its consequences for chemotaxis have not been explored in detail. Here we show that the chemotaxis pathway in Escherichia coli shows increasingly imprecise adaptation to higher concentrations of attractants, with a clear correlation between the time of adaptation to a step-like stimulus and the extent of imprecision. Our analysis suggests that this imprecision results from a gradual saturation of receptor methylation sites at high levels of stimulation, which prevents full recovery of the pathway activity by violating the conditions required for precise adaptation. We further use computer simulations to show that limited imprecision of adaptation has little effect on the rate of chemotactic drift of a bacterial population in gradients, but hinders precise accumulation at the peak of the gradient. Finally, we show that for two major chemoeffectors, serine and cysteine, failure of adaptation at concentrations above 1 mM might prevent bacteria from accumulating at toxic concentrations of these amino acids. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
34. Pharmacokinetics of Meropenem in Critically Ill Patients With Severe Infections.
- Author
-
Binder, Lutz, Schwörer, Harald, Hoppe, Sebastian, Streit, Frank, Neumann, Silke, Beckmann, Annett, Wachter, Rolf, Oellerich, Michael, and Walson, Philip D.
- Published
- 2013
- Full Text
- View/download PDF
35. Einsatz der Slackline in der Neurorehabilitation.
- Author
-
Neumann, Silke and Stadelmann, Roger
- Published
- 2012
- Full Text
- View/download PDF
36. The energy-speed-accuracy trade-off in sensory adaptation.
- Author
-
Lan, Ganhui, Sartori, Pablo, Neumann, Silke, Sourjik, Victor, and Tu, Yuhai
- Subjects
BIOLOGICAL adaptation ,STOCHASTIC models ,PHYSIOLOGICAL control systems ,ESCHERICHIA coli ,ENERGY consumption ,CHEMORECEPTORS ,INFORMATION processing ,NEUROPLASTICITY - Abstract
Adaptation is the essential process by which an organism becomes better suited to its environment. The benefits of adaptation are well documented, but the cost it incurs remains poorly understood. Here, by analysing a stochastic model of a minimum feedback network underlying many sensory adaptation systems, we show that adaptive processes are necessarily dissipative, and continuous energy consumption is required to stabilize the adapted state. Our study reveals a general relation among energy dissipation rate, adaptation speed and the maximum adaptation accuracy. This energy-speed-accuracy relation is tested in the Escherichia coli chemosensory system, which exhibits near-perfect chemoreceptor adaptation. We identify key requirements for the underlying biochemical network to achieve accurate adaptation with a given energy budget. Moreover, direct measurements confirm the prediction that adaptation slows down as cells gradually de-energize in a nutrient-poor medium without compromising adaptation accuracy. Our work provides a general framework to study cost-performance trade-offs for cellular regulatory functions and information processing. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
37. Lateral density of receptor arrays in the membrane plane influences sensitivity of the E. coli chemotaxis response.
- Author
-
Khursigara, Cezar M, Lan, Ganhui, Neumann, Silke, Wu, Xiongwu, Ravindran, Suchie, Borgnia, Mario J, Sourjik, Victor, Milne, Jacqueline, Tu, Yuhai, and Subramaniam, Sriram
- Subjects
CELL receptors ,CHEMOTAXIS ,CELL membranes ,LIGANDS (Biochemistry) ,GENE amplification ,ENERGY transfer ,TOMOGRAPHY - Abstract
In chemotactic bacteria, transmembrane chemoreceptors, CheA and CheW form the core signalling complex of the chemotaxis sensory apparatus. These complexes are organized in extended arrays in the cytoplasmic membrane that allow bacteria to respond to changes in concentration of extracellular ligands via a cooperative, allosteric response that leads to substantial amplification of the signal induced by ligand binding. Here, we have combined cryo-electron tomographic studies of the 3D spatial architecture of chemoreceptor arrays in intact E. coli cells with computational modelling to develop a predictive model for the cooperativity and sensitivity of the chemotaxis response. The predictions were tested experimentally using fluorescence resonance energy transfer (FRET) microscopy. Our results demonstrate that changes in lateral packing densities of the partially ordered, spatially extended chemoreceptor arrays can modulate the bacterial chemotaxis response, and that information about the molecular organization of the arrays derived by cryo-electron tomography of intact cells can be translated into testable, predictive computational models of the chemotaxis response. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
38. Differences in signalling by directly and indirectly binding ligands in bacterial chemotaxis.
- Author
-
Neumann, Silke, Hansen, Clinton H., Wingreen, Ned S., and Sourjik, Victor
- Subjects
- *
CHEMOTAXIS , *BIOCHEMISTRY , *ESCHERICHIA coli , *CARRIER proteins , *ENTEROBACTERIACEAE - Abstract
In chemotaxis of Escherichia coli and other bacteria, extracellular stimuli are perceived by transmembrane receptors that bind their ligands either directly, or indirectly through periplasmic-binding proteins (BPs). As BPs are also involved in ligand uptake, they provide a link between chemotaxis and nutrient utilization by cells. However, signalling by indirectly binding ligands remains much less understood than signalling by directly binding ligands. Here, we compared intracellular responses mediated by both types of ligands and developed a new mathematical model for signalling by indirectly binding ligands. We show that indirect binding allows cells to better control sensitivity to specific ligands in response to their nutrient environment and to coordinate chemotaxis with ligand transport, but at the cost of the dynamic range being much narrower than for directly binding ligands. We further demonstrate that signal integration by the chemosensory complexes does not depend on the type of ligand. Overall, our data suggest that the distinction between signalling by directly and indirectly binding ligands is more physiologically important than the traditional distinction between high- and low-abundance receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
39. Obesity Has a Systemic Effect on Immune Cells in Naïve and Cancer-Bearing Mice.
- Author
-
Neumann, Silke, Campbell, Katrin, Woodall, Matthew J., Evans, Meghan, Clarkson, Andrew N., and Young, Sarah L.
- Subjects
- *
MYELOID cells , *COLORECTAL cancer , *TUMOR-infiltrating immune cells , *BONE marrow cells , *CANCER invasiveness , *BREAST - Abstract
Obesity is a major risk factor for developing cancer, with obesity-induced immune changes and inflammation in breast (BC) and colorectal cancer (CRC) providing a potential link between the two. This study investigates systemic effects of obesity on adaptive and innate immune cells in healthy and tumour-bearing mice. Immune cells from lean and obese mice were phenotyped prior to implantation of either BC (C57mg and EO771.LMB) or CRC (MC38) cells as tumour models. Tumour growth rate, tumour-infiltrating lymphocytes (TIL) and peripheral blood immune cell populations were compared between obese and lean mice. In vitro studies showed that naïve obese mice had higher levels of myeloid cells in the bone marrow and bone marrow-derived dendritic cells expressed lower levels of activation markers compared to cells from their lean counterparts. In the tumour setting, BC tumours grew faster in obese mice than in lean mice and lower numbers of TILs as well as higher frequency of exhausted T cells were observed. Data from peripheral blood showed lower levels of myeloid cells in tumour-bearing obese mice. This study highlights that systemic changes to the immune system are relevant for tumour burden and provides a potential mechanism behind the effects of obesity on cancer development and progression in patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
40. Achtsamkeitstraining in der ergotherapeutischen Behandlung bei Menschen nach Schlaganfall und ihren Angehörigen (Achtsamkeit bei Schlaganfall).
- Author
-
Neumann, Silke and Gantschnig, Brigitte
- Published
- 2018
41. Enzymatic Activity of CD73 Modulates Invasion of Gliomas via Epithelial–Mesenchymal Transition-Like Reprogramming.
- Author
-
Tsiampali, Julia, Neumann, Silke, Giesen, Beatriz, Koch, Katharina, Maciaczyk, Donata, Janiak, Christoph, Hänggi, Daniel, and Maciaczyk, Jaroslaw
- Subjects
- *
GLIOMAS , *GLIOBLASTOMA multiforme , *PHOSPHODIESTERASE inhibitors , *CELL death , *EPITHELIAL-mesenchymal transition , *METHYLGUANINE - Abstract
Glioblastoma (GBM) is the most aggressive malignant primary brain tumour in adulthood. Despite strong research efforts current treatment options have a limited impact on glioma stem-like cells (GSCs) which contribute to GBM formation, progression and chemoresistance. Invasive growth of GSCs is in part associated with epithelial–mesenchymal-like transition (EMT), a mechanism associated with CD73 in several cancers. Here, we show that CD73 regulates the EMT activator SNAIL1 and further investigate the role of enzymatic and non-enzymatic CD73 activity in GBM progression. Reduction of CD73 protein resulted in significant suppression of GSC viability, proliferation and clonogenicity, whereas CD73 enzymatic activity exhibited negative effects only on GSC invasion involving impaired downstream adenosine (ADO) signalling. Furthermore, application of phosphodiesterase inhibitor pentoxifylline, a potent immunomodulator, effectively inhibited ZEB1 and CD73 expression and significantly decreased viability, clonogenicity, and invasion of GSC in vitro cultures. Given the involvement of adenosine and A3 adenosine receptor in GSC invasion, we investigated the effect of the pharmacological inhibition of A3AR on GSC maintenance. Direct A3AR inhibition promoted apoptotic cell death and impaired the clonogenicity of GSC cultures. Taken together, our data indicate that CD73 is an exciting novel target in GBM therapy. Moreover, pharmacological interference, resulting in disturbed ADO signalling, provides new opportunities to innovate GBM therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
42. Gentherapie bei Niemann-Pick.
- Author
-
Bause, Alexandra, Neumann, Silke, Worlicek, Johannes, Dingermann, Theo, and Zündorf, Ilse
- Published
- 2007
- Full Text
- View/download PDF
43. The Effects of Obesity on Anti-Cancer Immunity and Cancer Immunotherapy.
- Author
-
Woodall, Matthew J., Neumann, Silke, Campbell, Katrin, Pattison, Sharon T., and Young, Sarah L.
- Subjects
- *
THERAPEUTIC use of monoclonal antibodies , *OBESITY complications , *IMMUNE system , *IMMUNOTHERAPY , *INFLAMMATORY mediators , *OBESITY , *SURVIVAL , *T cells , *TUMORS , *TREATMENT effectiveness - Abstract
Cancer is one of the leading causes of morbidity and mortality worldwide. Traditional treatments include surgery, chemotherapy and radiation therapy, and more recently targeted therapies including immunotherapy are becoming routine care for some cancers. Immunotherapy aims to upregulate the patient's own immune system, enabling it to destroy cancerous cells. Obesity is a metabolic disorder characterized by significant weight that is an important contributor to many different diseases, including cancers. Obesity impacts the immune system and causes, among other things, a state of chronic low-grade inflammation. This is hypothesized to impact the efficacy of the immunotherapies. This review discusses the effects of obesity on the immune system and cancer immunotherapy, including the current evidence on the effect of obesity on immune checkpoint blockade, something which currently published reviews on this topic have not delved into. Data from several studies show that even though obesity causes a state of chronic low-grade inflammation with reductions in effector immune populations, it has a beneficial effect on patient survival following anti-PD-1/PD-L1 and anti-CTLA-4 treatment. However, research in this field is just emerging and further work is needed to expand our understanding of which cancer patients are likely to benefit from immunotherapy. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
44. Healthy grocery delivery in the usual care for adults recovering from an acute coronary event: protocol for a three-arm randomised controlled trial.
- Author
-
Reynolds AN, Hood F, Wilson R, Ross A, Neumann S, Turner R, Iosua E, Katare R, Shahin A, Kok ZY, Chan H, Coffey S, and Mann J
- Subjects
- Adult, Humans, Cholesterol, Dietary Fiber, Fats, Unsaturated, Randomized Controlled Trials as Topic, Coronary Disease, Diet, Healthy
- Abstract
Introduction: Coronary heart disease is a major contributor to the global burden of disease. Appropriate nutrition is a cornerstone of the prevention and treatment of coronary heart disease; however, barriers including cost and access to recommended foods limits long-term adherence for many. We are conducting, in adults with coronary heart disease, a randomised controlled trial comparing usual care with two dietary interventions in which usual care is augmented by 12 weeks free delivered groceries., Methods and Analysis: Three hundred adults recovering from an acute coronary event will be recruited from outpatient cardiovascular services in three regions of Aotearoa New Zealand. Participants will be randomly allocated to three arms: usual care (control group), usual care and the free delivery of foods high in dietary fibre or usual care and the free delivery of foods high in unsaturated fats. Interventions duration is 12 weeks, with a further 12 months follow-up. The primary outcome measures are change in low-density lipoprotein (LDL) cholesterol concentration following the intervention, and a cost-effectiveness analysis of healthcare access and social costs in the year after the intervention. A broad range of secondary outcome measures include other blood lipids, anthropometry, glycaemia, inflammatory markers, gut microbiome, dietary biomarkers, food acceptability, dietary change and the facilitators and barriers to dietary change. The trial will determine whether the free provision of groceries known to reduce cardiovascular risk within usual care will be clinically beneficial and justify the cost of doing so. Results may also provide an indication of the relative benefit of foods rich in dietary fibre or unsaturated fats in coronary heart disease management., Ethics and Dissemination: This trial, The Healthy Heart Study, has Health and Disability Ethics Committee approval (20/NTB/121), underwent Māori consultation, and has locality authority to be conducted in Canterbury, Otago and Southland., Trial Registration Number: ACTRN12620000689976, U1111-1250-1499., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
- Full Text
- View/download PDF
45. Calpains Released from Necrotic Tumor Cells Enhance Antigen Cross-Presentation to Activate CD8 + T Cells In Vitro.
- Author
-
Shields NJ, Peyroux EM, Campbell K, Mehta S, Woolley AG, Counoupas C, Neumann S, and Young SL
- Subjects
- Antigen Presentation, CD8-Positive T-Lymphocytes, Calpain metabolism, Dendritic Cells, Humans, Necrosis metabolism, Cross-Priming, Neoplasms metabolism
- Abstract
The initiation of CD8
+ T cell responses against dead cell-associated Ags is tightly regulated, facilitating adaptive immunity against pathogens and tumors while preventing autoimmunity. It is now well established that dying cells actively regulate the generation of CD8+ T cell responses via the release or exposure of damage-associated molecular patterns. However, it is unclear whether nonproteasomal proteases (activated in stressed and dying cells) can influence the availability of Ags for cross-presentation. Using a mouse model of immunogenic necrosis, we investigated the role of tumor-derived proteases in the priming of CD8+ T cells. We demonstrate that proteases released from necrotic tumor cells can degrade whole-protein Ag, generating proteolytic intermediates that are efficiently cross-presented by dendritic cells and enhance CD8+ T cell cross-priming. We identify a dominant role for calpain proteases, which are activated during necrotic cell death induced by severe heat shock. Mechanistically, proteolytic intermediates generated by tumor-derived proteases associate with necrotic tumor cell debris, which acts as a vehicle for Ag transfer that facilitates highly efficient cross-presentation in dendritic cells. Our results suggest that proteolytic systems activated in Ag donor cells during cell death may influence the availability of antigenic substrates for cross-presentation, thereby regulating the antigenicity of cell death., (Copyright © 2022 by The American Association of Immunologists, Inc.)- Published
- 2022
- Full Text
- View/download PDF
46. The Delta-Subunit Selective GABA A Receptor Modulator, DS2, Improves Stroke Recovery via an Anti-inflammatory Mechanism.
- Author
-
Neumann S, Boothman-Burrell L, Gowing EK, Jacobsen TA, Ahring PK, Young SL, Sandager-Nielsen K, and Clarkson AN
- Abstract
Inflammatory processes are known to contribute to tissue damage in the central nervous system (CNS) across a broad range of neurological conditions, including stroke. Gamma amino butyric acid (GABA), the main inhibitory neurotransmitter in the CNS, has been implicated in modulating peripheral immune responses by acting on GABA
A receptors on antigen-presenting cells and lymphocytes. Here, we investigated the effects and mechanism of action of the delta-selective compound, DS2, to improve stroke recovery and modulate inflammation. We report a decrease in nuclear factor (NF)-κB activation in innate immune cells over a concentration range in vitro . Following a photochemically induced motor cortex stroke, treatment with DS2 at 0.1 mg/kg from 1 h post-stroke significantly decreased circulating tumor necrosis factor (TNF)-α, interleukin (IL)-17, and IL-6 levels, reduced infarct size and improved motor function in mice. Free brain concentrations of DS2 were found to be lower than needed for robust modulation of central GABAA receptors and were not affected by the presence and absence of elacridar, an inhibitor of both P-glycoprotein and breast cancer resistance protein (BCRP). Finally, as DS2 appears to dampen peripheral immune activation and only shows limited brain exposure, we assessed the role of DS2 to promote functional recovery after stroke when administered from 3-days after the stroke. Treatment with DS2 from 3-days post-stroke improved motor function on the grid-walking, but not on the cylinder task. These data highlight the need to further develop subunit-selective compounds to better understand change in GABA receptor signaling pathways both centrally and peripherally. Importantly, we show that GABA compounds such as DS2 that only shows limited brain exposure can still afford significant protection and promote functional recovery most likely via modulation of peripheral immune cells and could be given as an adjunct treatment., (Copyright © 2019 Neumann, Boothman-Burrell, Gowing, Jacobsen, Ahring, Young, Sandager-Nielsen and Clarkson.)- Published
- 2019
- Full Text
- View/download PDF
47. Combining dendritic cells and B cells for presentation of oxidised tumour antigens to CD8 + T cells.
- Author
-
Grant ML, Shields N, Neumann S, Kramer K, Bonato A, Jackson C, Baird MA, and Young SL
- Abstract
The dendritic cell (DC) is the foremost antigen-presenting cell (APC) for ex vivo expansion of tumour-specific patient T cells. Despite marked responses in some patients following reinfusion of DC-activated autologous or HLA-matched donor T cells, overall response rates remain modest in solid tumours. Furthermore, most studies aim to generate immune responses against defined tumour-associated antigens (TAA), however, meta-analysis reveals that those approaches have less clinical success than those using whole tumour cells or their components. Tumour lysate (TL) is used as a source of tumour antigen in clinical trials and potentially represents the full range of TAAs in an undefined state. Little is known about how different APCs cooperate to present TL antigens. We examined the effect of oxidised whole-cell lysate (ox-L) versus soluble fraction freeze-thaw lysate (s-L) on bone marrow-derived DCs and macrophages, and magnetic bead-isolated splenic B cells. The APCs were used individually, or in combination, to prime T cells. CD8
+ T cells produced interferon (IFN)-γ in response to both s-L and ox-L, but only proliferated in response to ox-L. IFN-γ production and proliferation was enhanced by priming with the DC+B cell combination. Compared to DC alone, a trend toward greater interleukin (IL)-12 production was observed when DC+B cell were loaded with s-L and ox-L antigens. CD8+ T-cell specific lysis in vivo was greatest in ox-L-primed groups and DC+B cell priming significantly increased in vivo cytotoxicity compared to DC alone. These improved T-cell responses with two APCs and stressed cell lysate has implications for APC-based adoptive cell therapies., Competing Interests: The authors declare no conflict of interest.- Published
- 2017
- Full Text
- View/download PDF
48. Imprecision of adaptation in Escherichia coli chemotaxis.
- Author
-
Neumann S, Vladimirov N, Krembel AK, Wingreen NS, and Sourjik V
- Subjects
- Cell Proliferation, Escherichia coli metabolism, Ligands, Adaptation, Physiological, Chemotaxis, Escherichia coli cytology, Escherichia coli physiology
- Abstract
Adaptability is an essential property of many sensory systems, enabling maintenance of a sensitive response over a range of background stimulus levels. In bacterial chemotaxis, adaptation to the preset level of pathway activity is achieved through an integral feedback mechanism based on activity-dependent methylation of chemoreceptors. It has been argued that this architecture ensures precise and robust adaptation regardless of the ambient ligand concentration, making perfect adaptation a celebrated property of the chemotaxis system. However, possible deviations from such ideal adaptive behavior and its consequences for chemotaxis have not been explored in detail. Here we show that the chemotaxis pathway in Escherichia coli shows increasingly imprecise adaptation to higher concentrations of attractants, with a clear correlation between the time of adaptation to a step-like stimulus and the extent of imprecision. Our analysis suggests that this imprecision results from a gradual saturation of receptor methylation sites at high levels of stimulation, which prevents full recovery of the pathway activity by violating the conditions required for precise adaptation. We further use computer simulations to show that limited imprecision of adaptation has little effect on the rate of chemotactic drift of a bacterial population in gradients, but hinders precise accumulation at the peak of the gradient. Finally, we show that for two major chemoeffectors, serine and cysteine, failure of adaptation at concentrations above 1 mM might prevent bacteria from accumulating at toxic concentrations of these amino acids.
- Published
- 2014
- Full Text
- View/download PDF
49. The energy-speed-accuracy tradeoff in sensory adaptation.
- Author
-
Lan G, Sartori P, Neumann S, Sourjik V, and Tu Y
- Abstract
Adaptation is the essential process by which an organism becomes better suited to its environment. The benefits of adaptation are well documented, but the cost it incurs remains poorly understood. Here, by analysing a stochastic model of a minimum feedback network underlying many sensory adaptation systems, we show that adaptive processes are necessarily dissipative, and continuous energy consumption is required to stabilize the adapted state. Our study reveals a general relation among energy dissipation rate, adaptation speed and the maximum adaptation accuracy. This energy-speed-accuracy relation is tested in the Escherichia coli chemosensory system, which exhibits near-perfect chemoreceptor adaptation. We identify key requirements for the underlying biochemical network to achieve accurate adaptation with a given energy budget. Moreover, direct measurements confirm the prediction that adaptation slows down as cells gradually de-energize in a nutrient-poor medium without compromising adaptation accuracy. Our work provides a general framework to study cost-performance tradeoffs for cellular regulatory functions and information processing.
- Published
- 2012
- Full Text
- View/download PDF
50. Clinically defined chemotherapy-associated bowel syndrome predicts severe complications and death in cancer patients.
- Author
-
Vehreschild MJ, Meissner AM, Cornely OA, Maschmeyer G, Neumann S, von Lilienfeld-Toal M, Karthaus M, Wattad M, Staib P, Hellmich M, Christ H, and Vehreschild JJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents administration & dosage, Female, Humans, Incidence, Male, Middle Aged, Mitoxantrone administration & dosage, Neoplasms drug therapy, Neutropenia chemically induced, Neutropenia mortality, Risk Factors, Syndrome, Time Factors, Antineoplastic Agents adverse effects, Inflammatory Bowel Diseases chemically induced, Inflammatory Bowel Diseases mortality, Mitoxantrone adverse effects, Neoplasms mortality
- Abstract
Background: Neutropenic patients are at risk of abdominal complications and yet the incidence and impact of these complications on patients' morbidity and mortality have not been sufficiently evaluated. We aimed to assess a clinical rule for early detection of abdominal complications leading to death or transfer to intensive care in patients with chemotherapy-associated neutropenia., Design and Methods: This observational multicenter study was carried out in seven German hematology-oncology departments. For inclusion, neutropenia of at least 5 consecutive days was required. Risk factors for "transfer to intensive care" and "death" were assessed by backward-stepwise binary logistic regression analyses. Chemotherapy-associated bowel syndrome was defined as a combination of fever (T ≥37.8 °C) and abdominal pain and/or lack of bowel movement for 72 hours or more. Five hundred and twenty-one neutropenic episodes were documented in 359 patients., Results: The incidence of chemotherapy-associated bowel syndrome was 126/359 (35%) in first episodes of neutropenia. Transfer to intensive care occurred in 41/359 (11%) and death occurred in 17/359 (5%) first episodes. Chemotherapy-associated bowel syndrome and duration of neutropenia were identified as risk factors for transfer to intensive care (P<0.001; OR 4.753; 95% CI 2.297-9.833, and P=0.003; OR 1.061/d; 95% CI 1.021-1.103). Chemotherapy-associated bowel syndrome and mitoxantrone administration were identified as risk factors for death (P=0.005; OR 4.611; 95% CI 1.573-13.515 and P=0.026; OR 3.628; 95% CI 1.169-11.256)., Conclusions: The occurrence of chemotherapy-associated bowel syndrome has a significant impact on patients' outcome. In future interventional clinical trials, this definition might be used as a selection criterion for early treatment of patients at risk of severe complications.
- Published
- 2011
- Full Text
- View/download PDF
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