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- Paivandy, Aida, et al.
(författare)
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Induction of Human Lung Mast Cell Apoptosis by Granule Permeabilization : A Novel Approach for Targeting Mast Cells
- 2017
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells are implicated as detrimental players in inflammatory lung diseases, particularly asthma. Mast cells respond to activating stimuli by releasing a wide panel of pro-inflammatory compounds that can contribute profoundly to the pathology, and there is currently an unmet need for strategies that efficiently ameliorate harmful effects of mast cells under such conditions. Here, we sought to evaluate a novel concept for targeting human lung mast cells, by assessing the possibility of selectively depleting the lung mast cells by induction of apoptosis. For this purpose, we used lysosomotropic agents, i.e., compounds that are known to permeabilize the secretory granules of mast cells, thereby releasing the contents of the granules into the cytosol. Either intact human lung tissue, purified human lung mast cells or mixed populations of human lung cells were incubated with the lysosomotropic agents mefloquine or siramesine, followed by measurement of apoptosis, reactive oxygen species (ROS) production, and release of cytokines. We show that human lung mast cells were highly susceptible to apoptosis induced by this strategy, whereas other cell populations of the lung were largely refractory. Moreover, we demonstrate that apoptosis induced by this mode is dependent on the production of ROS and that the treatment of lung tissue with lysosomotropic agents causes a decrease in the release of pathogenic cytokines. We conclude that selective apoptosis of human lung mast cells can be accomplished by administration of lysosomotropic agents, thus introducing the possibility of using such drugs as novel therapeutics in the treatment of inflammatory lung disorders such as asthma.
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| 4. |
- Ekström, Magnus Pär, et al.
(författare)
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The association of body mass index, weight gain and central obesity with activity-related breathlessness : the Swedish Cardiopulmonary Bioimage Study
- 2019
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Ingår i: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 74:10, s. 958-964
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m(2)) is rapidly increasing globally and its impact on breathlessness is unclear.Methods: This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score >= 1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex.Results: We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m(2); and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness.Conclusion: Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.
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| 5. |
- Grudén, Stefan, et al.
(författare)
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Antitumoral effect and reduced systemic toxicity in mice after intra-tumoral injection of an in vivo solidifying calcium sulfate formulation with docetaxel
- 2017
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Ingår i: European journal of pharmaceutics and biopharmaceutics. - : Elsevier BV. - 0939-6411 .- 1873-3441. ; 114, s. 186-193
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDocetaxel is a cytostatic agent approved for treatment of non-small cell lung cancer as well as other cancers. Although docetaxel is an effective cytostatic agent, its effectiveness in clinical practice is associated with a variety of acute and long term side-effects. To overcome systemic side-effects, a slow release formulation based on calcium sulfate with docetaxel for intra-tumoral administration was developed.MethodsTwo formulations with the calcium sulfate NanoZolid technology were generated with a twofold difference in docetaxel drug load. The formulations were injected intra-tumorally as a paste which solidified within the tumor. The effects of the two intra-tumoral injection formulations were tested in female mice (n = 60) inoculated with subcutaneous Lewis lung carcinoma cells. The two formulations were compared to systemic intraperitoneal injection of docetaxel and a placebo formulation without docetaxel. Tumor volumes were measured and systemic side-effects were evaluated using body weight and cell counts from whole blood as well as plasma concentrations.ResultsBoth docetaxel formulations showed a significantly higher antitumor efficacy compared to placebo, which was comparable to that of systemic administration of docetaxel. Moreover, the intra-tumoral formulations with docetaxel showed reduced systemic toxicity compared to systemic treatment, including less weight loss and no decrease in blood cell counts.ConclusionsThe results suggest that intra-tumoral slow release calcium sulfate based formulations with docetaxel can be an alternative strategy as an efficient local antitumoral treatment with reduced systemic toxicity.
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| 6. |
- Horie, Masafumi, et al.
(författare)
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An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer
- 2018
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 246:2, s. 154-165
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Tidskriftsartikel (refereegranskat)abstract
- Small cell lung cancer (SCLC) is a neuroendocrine tumour that exhibits rapid growth and metastatic spread. Although SCLC represents a prototypically undifferentiated cancer type, thyroid transcription factor-1 (TTF-1, gene symbol NKX2-1), a master regulator for pulmonary epithelial cell differentiation and lung morphogenesis, is strongly upregulated in this aggressive cancer type. The aim of this study was to evaluate a functional role for TTF-1 in SCLC. We demonstrated that achaete-scute complex homolog 1 (ASCL1), an essential transcription factor for neuroendocrine differentiation, positively regulated TTF-1 in SCLC cell lines. Subsequently, we described genes and microRNAs (miRNAs) that were possibly controlled by TTF-1 and identified nuclear factor IB (NFIB), a recently characterised driver of SCLC progression, as a transcriptional target of TTF-1. Our findings shine light on a regulatory axis in SCLC consisting of ASCL1/TTF-1/NFIB that potentially contributes to the tumourigenesis of SCLC.
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- Sandelin, Erik, 1976-
(författare)
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Design and Grace : An Ahuman Odyssey
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Design is conventionally comprehended in terms of making new things; designers act through addition and intervention. But, in a world where human activities often violently constrict the lives of others, how can designers also cultivate creative acts of withdrawal, foreclosure and leaving be? This dissertation employs grace – actively not doing what you are able to do – to decouple action from force and passivity from resignation in design. To explore the friction between design and grace I conduct practical design experiments, and use theoretical tools from Michel Serres, Patricia MacCormack, Simone Weil, and from critical animal studies. The dissertation operates in the nexus of two emerging design landscapes: design and animals, and design and negation. Through recomposing situations where humans consume other animals (eating, angling and shopping) the experiments seek to populate a growing palette of affirmative nos and nots in design. The design experiments are fuelled by operative prototypes, multitemporal events in which life and representation, activism and investigation, bleed into each other. Four ahuman operators activate and communicate the experiments. Bully goes fishwatching to capture fish on camera instead of on a hook. Addict attends meat addiction hypnotherapy to stop eating animals. Allergic becomes physically incompatible with consuming animals. Odysseus blocks themselves from buying animal products, petrol and plane tickets through binding pacts.By working towards more supple human-animal relations, the experiments critically interrogate and enrich key notions of contemporary more-than-human design: entanglement, proximity, hybridity and care. I argue that designers need to develop interdependent disentanglements, attentive hesitations, expressive incompatibilities and careful self-bindings, to be able to oscillate between standing with the other in solidarity and graciously leaving the other be.Design and Grace tends to a friction at the core of design, that between proposing and imposing. It seeks to provide designers and design researchers with confidence, precision and generative exemplars in envisioning and manifesting vital, effective and beautiful nos and nots.
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