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- Rasmussen, Maria, et al.
(författare)
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Lynch syndrome-associated epithelial ovarian cancer and its immunological profile
- 2021
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258. ; 162:3, s. 686-693
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Lynch syndrome is a multi-tumor syndrome characterized by mismatch repair deficiency (MMR-d), microsatellite instability (MSI), and increased tumor-infiltrating lymphocytes (TILs) making these tumors candidates for treatment with immune checkpoint inhibitors. However, response may depend on tumor-induced immune evasion mechanisms, e.g. loss of Beta-2-Microglobulin (B2M) or upregulation of programmed death protein ligand 1 (PD-L1). We investigated the immune response and B2M and PD-L1 expression in Lynch syndrome-associated ovarian cancers. Methods: We successfully analyzed 30 Lynch syndrome-associated epithelial ovarian cancers collected through the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) register. MMR-d, MSI, immune response (CD3, CD8, and CD68), and immune evasion mechanisms (B2M and PD-L1) were investigated. Statistical associations between these markers were evaluated in addition to survival in relation to B2M/PD-L1. Results: Of the 29 evaluable tumors, 27 were MMR-d (93.1%). Likewise of 26 evaluable tumors, 14 were MSI (53.8%). MMR-d/MMR-proficiency associated with MSI/MSS in 60.0%. Half of the ovarian tumors presented with high levels of TILs. Loss of B2M expression was observed in 46.7% of the tumors, while expression of PD-L1 was seen in 28.0% of the cases. There was no association between B2M/PD-L1 and MSI/TILs/survival. Loss of B2M was often seen in tumors with low TILs (p = 0.056 or p = 0.059 for CD3 and CD8 positive cells, respectively). Conclusion: MMR-d, MSI, and TILs are also seen in Lynch syndrome-associated ovarian cancers making these potential candidates for checkpoint-based immunotherapy. The clinical impact from immune evasion through loss of B2M needs to be investigated further in larger cohorts.
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| 2. |
- Walkowska, Joanna, et al.
(författare)
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Immunoprofiles of colorectal cancer from Lynch syndrome
- 2019
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Ingår i: OncoImmunology. - 2162-4011. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancers associated with Lynch syndrome are characterized by defective mismatch repair, microsatellite instability, high mutation rates, and a highly immunogenic environment. These features define a subset of cancer with a favorable prognosis and high likelihood to respond to treatment with anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) drugs. With the aim to define immune-evasive mechanisms and a potential impact hereof in colorectal cancers from Lynch syndrome versus hereditary cases with retained mismatch repair function, we immunohistochemically and transcriptionally profiled 270 tumors. Lynch syndrome-associated tumors showed an overrepresentation of tumor-infiltrating CD3, CD8 and CD68 positive cells, loss of beta-2-microglobulin (B2M) and up-regulation of PD-L1 on tumor cells. The gene expression signature of Lynch syndrome tumors was characterized by upregulation of genes related to antigen processing and presentation, apoptosis, natural killer cell-mediated cytotoxicity, and T cell activation. Tumors with loss of B2M and up-regulation of PD-L1 showed distinctive immunogenic profiles. In summary, our data demonstrate a complex tumor-host interplay where B2M loss and PD-L1 up-regulation influence immunological pathways and clinical outcome in Lynch syndrome tumors. Immunological classification may thus aid in the preselection of colorectal cancers relevant for treatment with anti-PD-1/PD-L1 therapies.
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| 5. |
- Chiotis, Konstantinos, et al.
(författare)
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Imaging in-vivo tau pathology in Alzheimer's disease with THK5317 PET in a multimodal paradigm
- 2016
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 43:9, s. 1686-1699
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [F-18]THK5317 (also known as (S)-[F-18]THK5117) retention in different stages of Alzheimer's disease; and study any associations with markers of hypometabolism and amyloid-beta deposition. Methods Thirty-three individuals were enrolled, including nine patients with Alzheimer's disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer's disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [F-18]THK5317, [C-11] Pittsburgh compound B ([C-11]PIB), and [F-18]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [C-11]PIB-positive (n=11) and MCI [C-11]PIB-negative (n=2) groups. Results Test-retest variability for [F-18]THK5317-PET was very low (1.17-3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [C-11]PIB-positive) and dementia-stage Alzheimer's disease had significantly higher [F-18]THK5317 retention than healthy controls (p=0.002 and p=0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [F-18]THK5317 retention and [F-18]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [F-18]THK5317 and [C-11] PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [C-11]PIB but high [F-18]THK5317 retentions with a different regional distribution from that in Alzheimer's disease patients. Conclusions The tau-specific PET tracer [F-18]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.
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| 6. |
- Farid, Karim, et al.
(författare)
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Case Report of Complex Amyotrophic Lateral Sclerosis with Cognitive Impairment and Cortical Amyloid Deposition.
- 2015
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 47:3, s. 661-7
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS), a fatal disease of unknown origin, affects motor neurons in the primary motor cortex, brainstem, and spinal cord. Cognitive impairment may occur before the motor symptoms. We present a patient who was initially diagnosed with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) but who developed ALS-like symptoms during follow-up and died shortly thereafter. A 60-year-old subject with cognitive impairment underwent neuropsychological testing, cerebrospinal fluid (CSF) analysis, structural imaging (computed tomography and magnetic resonance imaging) and functional imaging [11C]-Pittsburgh compound B (PIB) positron emission tomography (PET), [18F]-fluorodeoxyglucose (FDG) PET, and [11C]-deuterium-L-deprenyl (DED) PET. Neuropsychological testing showed episodic memory impairment. CSF P-tau and T-tau levels were elevated. CSF amyloid-β (Aβ)42 levels were initially normal but became pathological during follow-up. MCI was diagnosed. [18F]-FDG PET showed hypometabolism in the left temporal and prefrontal cortices and [11C]-PIB PET demonstrated amyloid plaque deposition in the prefrontal, posterior cingulate, and parietal cortices. [11C]-DED PET showed high brain accumulation consistent with astrocytosis. The memory impairment progressed and AD was diagnosed. Motor impairments developed subsequently and, following additional neurological evaluation, ALS was diagnosed. The disease progressed rapidly and the patient died with pronounced motor symptoms three years after the initial cognitive assessment. Since relatives refused autopsy, postmortem analysis was not possible.
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| 7. |
- Friis, Elisabeth, et al.
(författare)
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Fishy business : kolonialiseringens dilemmaer i The Tempest
- 2013. - 1
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Ingår i: Europæisk litteratur 1500-1800 : Bind 1. Verden. Fra Columbus til Napoleon - Bind 1. Verden. Fra Columbus til Napoleon. - 9788771242201 ; 1, s. 119-143
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Bokkapitel (refereegranskat)
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| 8. |
- Garcia, Ignacio, et al.
(författare)
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Kel1 is a phosphorylation-regulated noise suppressor of the pheromone signaling pathway
- 2021
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Ingår i: Cell Reports. - : Elsevier. - 2211-1247. ; 37:13
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms have evolved that allow cells to detect signals and generate an appropriate response. The accuracy of these responses relies on the ability of cells to discriminate between signal and noise. How cells filter noise in signaling pathways is not well understood. Here, we analyze noise suppression in the yeast pheromone signaling pathway and show that the poorly characterized protein Kel1 serves as a major noise suppressor and prevents cell death. At the molecular level, Kel1 prevents spontaneous activation of the pheromone response by inhibiting membrane recruitment of Ste5 and Far1. Only a hypophosphorylated form of Kel1 suppresses signaling, reduces noise, and prevents pheromone-associated cell death, and our data indicate that the MAPK Fus3 contributes to Kel1 phosphorylation. Taken together, Kel1 serves as a phosphoregulated suppressor of the pheromone pathway to reduce noise, inhibit spontaneous activation of the pathway, regulate mating efficiency, and prevent pheromone-associated cell death.
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| 9. |
- Heybroek, Kim, 1981-
(författare)
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On Energy Efficient Mobile Hydraulic Systems : with Focus on Linear Actuation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this dissertation, energy efficient hydraulic systems are studied. The research focuses on solutions for linear actuators in mobile applications, with emphasis on construction machines. Alongside the aspect of energy efficiency, the thesis deals with competing aspects in hydraulic system design found in the development of construction machines. Simulation models and controls for different concepts are developed, taking the whole machine into account. In line with this work, several proof of concept demonstrators are developed.First, pump controlled systems are studied and a novel concept based on an open-circuit pump configuration is conceived. Special consideration is paid to multi-mode capabilities that allow for a broadened operating range and potential downsizing of components. Simulation models and controls are developed and the system is experimentally validated in a wheel loader application.Second, the possibility for energy recuperation in valve controlled systems is investigated. In such solutions, a hydraulic motor, added to the meter-out port, is used for energy recovery during load lowering and in multi-function operation. Recuperated energy is either be used momentarily or is stored in a hydraulic accumulator. The proposed solution means an incremental improvement to conventional systems, which is sometimes attractive to machine manufacturers due to fewer uncertainties in reliability, safety and development cost. The energy recovery system is studied on a conceptual level where several alternative systems are proposed and a concept based on a two-machine hydraulic pressure transformer is selected for a deeper control study followed by experimental validation.Third, so-called `common pressure rail' systems are suggested. This technique is well established for rotary drives, at least for the industrial sector. However, in applying this technique to mobile hydraulics, feasible solutions for linear actuators are needed. In this dissertation, two approaches to this problem are presented. The first one is the hydraulic pressure transformer, studied in simulation as the key-component of a `series hybrid' topology for wheel loaders. In the second approach variable displacement linear actuators (VDLA) based on a 4-chamber cylinder and multi-mode control is applied. In a theoretical study a model predictive control approach is suggested and new insights to the trade-off between controllability and energy efficiency of a multi-chamber cylinder are presented. Finally, a fullscale hydraulic hybrid system based on secondary controlled hydraulic motors and VDLAs is designed and experimentally validated on a large excavator.
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