| 1. |
- Hofving, Tobias, 1989, et al.
(författare)
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The Microenvironment of Small Intestinal Neuroendocrine Tumours Contains Lymphocytes Capable of Recognition and Activation after Expansion
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:17
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The body's immune system can recognize tumors because they often contain proteins that are either different from or more abundant than in normal cells. Here, we characterised the immune cells of a rare tumor type called small-intestinal neuroendocrine tumors (SINET). We find that so called tumour-infiltrating lymphocytes (TILs) can be grown in the laboratory and activated by challenging them with digested tumor. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET. Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
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| 2. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 3. |
- Andersson, Anders, et al.
(författare)
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A transcriptional timetable of autumn senescence
- 2004
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 5:4, s. R24-
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Tidskriftsartikel (refereegranskat)abstract
- Background We have developed genomic tools to allow the genus Populus (aspens and cottonwoods) to be exploited as a full-featured model for investigating fundamental aspects of tree biology. We have undertaken large-scale expressed sequence tag (EST) sequencing programs and created Populus microarrays with significant gene coverage. One of the important aspects of plant biology that cannot be studied in annual plants is the gene activity involved in the induction of autumn leaf senescence. Results On the basis of 36,354 Populus ESTs, obtained from seven cDNA libraries, we have created a DNA microarray consisting of 13,490 clones, spotted in duplicate. Of these clones, 12,376 (92%) were confirmed by resequencing and all sequences were annotated and functionally classified. Here we have used the microarray to study transcript abundance in leaves of a free-growing aspen tree (Populus tremula) in northern Sweden during natural autumn senescence. Of the 13,490 spotted clones, 3,792 represented genes with significant expression in all leaf samples from the seven studied dates. Conclusions We observed a major shift in gene expression, coinciding with massive chlorophyll degradation, that reflected a shift from photosynthetic competence to energy generation by mitochondrial respiration, oxidation of fatty acids and nutrient mobilization. Autumn senescence had much in common with senescence in annual plants; for example many proteases were induced. We also found evidence for increased transcriptional activity before the appearance of visible signs of senescence, presumably preparing the leaf for degradation of its components.
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| 4. |
- Andersson, Kristoffer, 1976, et al.
(författare)
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Fabrication and characterization of field-plated buried-gate SiC MESFETs
- 2006
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Ingår i: IEEE Electron Device Letters. - 0741-3106 .- 1558-0563. ; 27:7, s. 573-575
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Tidskriftsartikel (refereegranskat)abstract
- Silicon carbide (SiC) MESFETs were fabricated using a standard SiC MESFET structure with the application of the "buried-channel" and field-plate (FP) techniques in the process. FPs combined with a buried-gate are shown to be favorable concerning output power density and power-added efficiency (PAE), due to higher breakdown voltage and decreased output conductance. A very high power density of 7.8 W/mm was measured on-wafer at 3 GHz for a two-finger 400-/spl mu/m gate periphery SiC MESFET. The PAE for this device was 70% at class AB bias. Two-tone measurements at 3 GHz /spl plusmn/ 100 kHz indicate an optimum FP length for high linearity operation.
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| 5. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma
- 2018
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- Karonudib (TH1579) is a novel compound that exerts anti-tumor activities and has recently entered phase I clinical testing. The aim of this study was to conduct a pre-clinical trial in patient-derived xenografts to identify the possible biomarkers of response or resistance that could guide inclusion of patients suffering from metastatic melanoma in phase II clinical trials. Patient-derived xenografts from 31 melanoma patients with metastatic disease were treated with karonudib or a vehicle for 18 days. Treatment responses were followed by measuring tumor sizes, and the models were categorized in the response groups. Tumors were harvested and processed for RNA sequencing and protein analysis. To investigate the effect of karonudib on T-cell-mediated anti-tumor activities, tumor-infiltrating T cells were injected in mice carrying autologous tumors and the mice treated with karonudib. We show that karonudib has heterogeneous anti-tumor effect on metastatic melanoma. Thus, based on the treatment responses, we could divide the 31 patient-derived xenografts in three treatment groups: progression group (32%), suppression group (42%), and regression group (26%). Furthermore, we show that karonudib has anti-tumor effect, irrespective of major melanoma driver mutations. Also, we identify high expression of ABCB1, which codes for p-gp pumps as a resistance biomarker. Finally, we show that karonudib treatment does not hamper T-cell-mediated anti-tumor responses. These findings can be used to guide future use of karonudib in clinical use with a potential approach as precision medicine.
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| 6. |
- Eliasson, Jens, et al.
(författare)
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A Feasibility Study of SOA-enabled Networked Rock Bolts
- 2014
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Ingår i: Proceedings of 2014 IEEE 19th International Conference on Emerging Technologies & Factory Automation (ETFA 2014). - Piscataway, NJ : IEEE Communications Society. - 9781479948451 ; , s. 1-8
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Konferensbidrag (refereegranskat)abstract
- The use of rock bolts in the mining industry is a widely used approach for increasing mine stability. However, when compared to the automation industry, where the use of sensors and real-time monitoring of processes have evolved rapidly, the use rock bolts have not changed a lot during the last 100 years. What is missing are technologies for keeping installed rock bolts under real-time and online monitoring. One problem is that rock bolts can become damaged by seismic activities or movements within the rock, and thus lose their load bearing capacity. If that happens, the outer shell of a tunnel’s walls or ceiling can collapse, with disaster as a result. Therefore, there is a clear need for online and real-time monitoring solutions for strain and thereby stress, as well as seismic activity. In this paper, the current state of art in research around intelligent rock bolts is presented. An intelligent rock bolt is the combination of a traditional rock bolt with an Internet of Things device, i.e. a rock bolt with embedded sensors, actuators, processing capabilities and wireless communication. In the proposed architecture, every rock bolt has its own IPv6 address and can establish a wireless mesh network in an ad-hoc manner. Bymeasuring strain and seismic activity and exposing the sensors in the form of services, large gains in terms of safety and efficiently can be achieved. A number of mining related activities such as stress on the rock bolt can be detected, falling rocks and the presence of mobile machinery can be observed. Since the network is based on standard communication protocols such as IPv6, it is vital to add security mechanisms to prevent eavesdropping and tampering of data traffic. By utilizing the real-time monitoring capabilities of a network of Internet-connected intelligent rock bolt, it is possible to drastically improve monitoring of mining activities and thereby providing workers with a safer working environment.
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| 7. |
- Forsberg, Elin, et al.
(författare)
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Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary CAR-T cells are immune cells equipped with a claw that enable them to bind cancer cells. Usually, CAR-T cells are made using immune cells from blood. Here, we tested the hypothesis that also immune cells that reside in the tumor, so called tumor-infiltrating lymphocytes, can also be modified to carry the claw. This may mean that these cells, called CAR-TILs, will be able to attack cancer cells in two ways, using the claw or binding using its normal protein on the cell surface, the so-called T cell receptor. We show that CAR-TILs can be generated, and that they can kill melanoma cells in cell culture and in mice. Finally, to prepare for clinical trials, we also assess if CAR-TILs can be safe in a human cancer patient-like model, a companion dog suffering from cancer. Our data suggest that CAR-TILs may be a way to treat patients with melanoma but human clinical trials are needed. Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
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| 8. |
- Göktürk, Camilla, et al.
(författare)
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Semicarbazide-sensitive amine oxidase in transgenic mice with diabetes
- 2004
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 325:3, s. 1013-1020
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Tidskriftsartikel (refereegranskat)abstract
- Semicarbazide-sensitive amine oxidase (SSAO) activity in plasma is increased in diabetes, and in particular, in diabetic patients with vascular complications. It has been speculated that SSAO is involved in the development of such complications due to the production of cytotoxic compounds. In this work, we have induced diabetes in a previously described mouse-model, overexpressing SSAO in smooth muscle cells. SSAO activity was estimated as well as expression of the endogenous mouse gene and human transgene using real-time PCR. Diabetes induced an increase in SSAO activity in serum, kidney, and adipose tissue of transgenic animals. An inverse correlation between SSAO activity and mouse SSAO mRNA levels was observed in transgenic animals with diabetes. These results further support the suggestion of a negative feedback control of the SSAO gene expression. The increased SSAO activity in diabetes is most likely dependent on post-transcriptional modifications or activation of existing inactive enzyme molecules.
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| 9. |
- Hall, Johan, et al.
(författare)
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Single Malt or Blended? A Study in Multilingual Parser Optimization
- 2007
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Ingår i: Proceedings of the CoNLL Shared Task Session of EMNLP-CoNLL 2007. - : Association for Computational Linguistics. ; , s. 933–939-
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Konferensbidrag (refereegranskat)abstract
- We describe a two-stage optimization of the MaltParser system for the ten languages in the multilingual track of the CoNLL 2007 shared task on dependency parsing. The first stage consists in tuning a single-parser system for each language by optimizing parameters of the parsing algorithm, the feature model, and the learning algorithm. The second stage consists in building an ensemble system that combines six different parsing strategies, extrapolating from the optimal parameters settings for each language. When evaluated on the official test sets, the ensemble system significantly outperforms the single-parser system and achieves the highest average labeled attachment score.
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| 10. |
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| 11. |
- Henricson, Joakim, et al.
(författare)
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Tissue viability imaging : Microvascular response to vasoactive drugs induced by iontophoresis
- 2009
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Ingår i: Microvascular Research. - : Elsevier BV. - 0026-2862. ; 78:2, s. 199-205
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Tidskriftsartikel (refereegranskat)abstract
- When one is studying the physiology of the cutaneous microcirculation there is a need for relevant non-invasive and versatile techniques. In this study we used a new optical device, the tissue viability imager (TiVi), to map changes in cutaneous microvascular concentrations of red blood cells during iontophoresis of vasoactive substances (noradrenaline (NA) and phenylephrine (Phe) for vasoconstriction and acetylcholine (ACh) and sodium nitroprusside (SNP) for vasodilatation). We aimed to present data both individually and pooled, using a four-variable logistic dose response model that is commonly used in similar in vitro vascular studies. The accuracy of the TiVi was also investigated by calculating the coefficient of variation and comparing it with similar tests previously done using laser Doppler imaging. Tests were also performed using the TiVi and LDPI simultaneously to further compare the two methods. Results showed that the TiVi is capable of quantifying vascular responses to iontophorised noradrenaline and phenylephrine without the need to increase background flow first. Fitting the TiVi data to the dose response model resulted in ED50-values with narrow confidence intervals and acceptable r2 values. Mean ED50-values for the TiVi did not differ significantly from similar values obtained using laser Doppler. Results further seem to suggest that when the blood perfusion increases during vasodilatation in skin the initial phase relies mainly on an increase in red blood cell concentration whereas the further perfusion increase is due to an increase in red blood cell velocity.
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| 12. |
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| 13. |
- Janelidze, Shorena, et al.
(författare)
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Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 104-112
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF bio-markers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. (C) 2016 The Authors. Published by Elsevier Inc.
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| 14. |
- Karlsson, Joakim, et al.
(författare)
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Molecular profiling of driver events in metastatic uveal melanoma
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic uveal melanoma is less well understood than its primary counterpart, has a distinct biology compared to skin melanoma, and lacks effective treatments. Here we genomically profile metastatic tumors and infiltrating lymphocytes. BAP1 alterations are overrepresented and found in 29/32 of cases. Reintroducing a functional BAP1 allele into a deficient patient-derived cell line, reveals a broad shift towards a transcriptomic subtype previously associated with better prognosis of the primary disease. One outlier tumor has ahigh mutational burden associated with UV-damage. CDKN2A deletions also occur, which are rarely present in primaries. A focused knockdown screen is used to investigate overexpressed genesassociated withcopy number gains. Tumor-infiltrating lymphocytes are in several cases found tumor-reactive, but expression of the immune checkpoint receptors TIM-3, TIGIT and LAG3 is also abundant. This study represents the largest whole-genome analysis of uveal melanoma to date, and presents an updated view of the metastatic disease. © 2020, The Author(s).
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| 15. |
- Kirvalidze, Mariam, et al.
(författare)
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Effectiveness of integrated person-centered interventions for older people's care : Review of Swedish experiences and experts' perspective
- 2024
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Ingår i: Journal of Internal Medicine. - : John Wiley & Sons. - 0954-6820 .- 1365-2796.
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Tidskriftsartikel (refereegranskat)abstract
- Older adults have multiple medical and social care needs, requiring a shift toward an integrated person-centered model of care. Our objective was to describe and summarize Swedish experiences of integrated person-centered care by reviewing studies published between 2000 and 2023, and to identify the main challenges and scientific gaps through expert discussions. Seventy-three publications were identified by searching MEDLINE and contacting experts. Interventions were categorized using two World Health Organization frameworks: (1) Integrated Care for Older People (ICOPE), and (2) Integrated People-Centered Health Services (IPCHS). The included 73 publications were derived from 31 unique and heterogeneous interventions pertaining mainly to the micro- and meso-levels. Among publications measuring mortality, 15% were effective. Subjective health outcomes showed improvement in 24% of publications, morbidity outcomes in 42%, disability outcomes in 48%, and service utilization outcomes in 58%. Workshop discussions in Stockholm (Sweden), March 2023, were recorded, transcribed, and summarized. Experts emphasized: (1) lack of rigorous evaluation methods, (2) need for participatory designs, (3) scarcity of macro-level interventions, and (4) importance of transitioning from person- to people-centered integrated care. These challenges could explain the unexpected weak beneficial effects of the interventions on health outcomes, whereas service utilization outcomes were more positively impacted. Finally, we derived a list of recommendations, including the need to engage care organizations in interventions from their inception and to leverage researchers' scientific expertise. Although this review provides a comprehensive snapshot of interventions in the context of Sweden, the findings offer transferable perspectives on the real-world challenges encountered in this field. image
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| 16. |
- Munkhammar, Joakim, 1982-, et al.
(författare)
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Photovoltaic self-consumption potential of alternative year-round daylight savings time
- 2013
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Ingår i: Proceedings of the 28th European Photovoltaic Solar Energy Conference (EU PVSEC), Paris, France, September 30 - October 4, 2013.. - 3936338337 ; , s. 4753-4757
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Konferensbidrag (refereegranskat)abstract
- In a mature photovoltaic (PV) market where feed-in tariffs have declined, managing of the hosting capacity of the distribution grid becomes essential by maximizing the utilization of PV. One way to increase hosting capacity is to increase self-consumption of the self-produced PV power. This paper investigates the effect of an alternative year-round daylight savings time (DST) – where the time of the entire society is changed relative to the sun - on the level of self-consumption in terms of solar fraction and load fraction of PV power both on household- and national level. Household electricity use was modeled with a Markov-chain model, PV power production was modeled from solar irradiance data, and the national level was simulated using national electricity data. Results show that one hour year-round DST shifted ahead might increase self-consumption by a fraction of one percentage point for a net-zero energy household. For a 30 GWp PV installation on a national scale with a 140 TWh annual electricity use one hour DST shift ahead had almost no effect on self-consumption. The optimal self-consumption of PV power on the national level was concluded to be the current DST setup.
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| 17. |
- Nilsson, Joakim, et al.
(författare)
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FASTIGHETSNÄRA SÄSONGSLAGRING AV FJÄRRVÄRME
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Projektet bygger på en idé om att industriell spillvärme och annan tillgänglig basproduktion av värme under sommaren kan distribueras via befintliga fjärrvärmesystem och lagras lokalt i fastighetsnära säsongslager för att sedan användas under den kalla delen av året, utan att ytterligare energi tillförs. Projektets övergripande mål har varit att bedöma möjligheterna för fastighetsnära säsongslagring i kombination med lågenergi- och lågtemperaturbyggande i Sverige. Arbetet har genomförts i samarbete mellan Devcco och SP Sveriges Tekniska Forskningsinstitut. Till projektets förfogande har funnits en referensgrupp med representanter från Energiföretagen, Skanska, Akademiska hus, Göteborg Energi, Tekniska Verken i Linköping, Eon samt Umeå Energi. I ett systemperspektiv skulle fastighetsnära säsongslagring av fjärrvärme på marginalen betyda ökad produktion på sommaren och minskad på vintern under förutsättning att alternativet för en fastighet är en vanlig leverans av fjärrvärme. För att utvärdera lönsamheten har fastighetsnära säsongslagring av fjärrvärme jämförts med ”vanlig” fjärrvärme i ett LCC-perspektiv. Miljöpåverkan har beräknats baserat på ett antal olika alternativ för miljövärdering av el samt allokeringsprinciper för fjärrvärme. Lagren som simulerats består av standardmässiga borrhålslager som laddas med fjärrvärme under maj till och med september. I slutet på april antas lagret vara mer eller mindre tömt. Tre typbyggnader som representerar vanligt förekommande större byggnader och kvarter av olika storlek har ingått i studien. De tre typerna är 1) nybyggt energieffektivt kontor, 2) äldre energirenoverat kontor och 3) energirenoverat miljonprogram. Beräkningar av de miljömässiga samt de ekonomiska för- och nackdelarna baseras på vilka produktionsslag som används på marginalen under olika delar av året för ett givet fjärrvärmesystem. Analysen baseras huvudsakligen på två olika produktionsmixer inspirerade av systemen i Stockholm respektive Göteborg. Miljömässigt finns under vissa förutsättningar goda möjligheter att åstadkomma positiva resultat med fastighetsnära säsongslagring av fjärrvärme. Använder man kraftbonusmetoden i kombination med marginalel så resulterar säsongslagring i miljönytta både i göteborgs- och stockholmsfallet. Använder man energimetoden i kombination med nordisk elmix blir resultatet det motsatta. Ur ett ekonomiskt perspektiv kan fastighetsnära säsongslagring för två av tre typbyggnader konkurrera med konventionell fjärrvärme under förutsättning att man kan åstadkomma en marginalproduktionskostnad i storleksordning 50 kr/MWh. Resultaten är starkt beroende av lokala förutsättningar samt av vilken metod som används för att beräkna miljöpåverkan. Därför har som en del av projektet en modell utvecklats där användaren utifrån relativt grundläggande indata om fastighet och fjärrvärmesystem kan göra egna indikativa beräkningar av ekonomiska och miljömässiga aspekter av fastighetsnära säsongslagring av fjärrvärme.
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| 18. |
- Nilsson, Lisa M, 1976, et al.
(författare)
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Genetics and Therapeutic Responses to Tumor-Infiltrating Lymphocyte Therapy of Pancreatic Cancer Patient-Derived Xenograft Models
- 2022
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Ingår i: Gastro Hep Advances. - : Elsevier BV. - 2772-5723. ; 1:6, s. 1037-1048
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. Checkpoint immunotherapy has not yet shown encouraging results in pancreatic cancer possibly because of a poor immunogenicity and/or an immune suppressive microenvironment. The aim of this study was to develop patient-derived xenograft (PDX) models, compare their genetics to the original biopsies, and assess if autologous tumor-infiltrating lymphocytes (TILs) would have antitumoral activity in pancreatic cancer. Methods We subcutaneously transplanted tumors from 29 patients into NOG mice to generate PDX models. We established TIL cultures and injected them into PDX mice. We analyzed histology and genetics of biopsies and PDX tumors. Results Tumor growths were confirmed in 11 of 29 transplantations. The PDX tumors histologically resembled their original biopsies, but because stromal cells in the PDX model tumors were from mouse, their gene expression differed from the original biopsies. Immune checkpoint ligands other than programmed death ligand-1 (PD-L1) were expressed in pancreatic cancers, but PD-L1 was rarely expressed. When it was expressed, it correlated with tumor take in PDX models. One of the 3 tumors that expressed PD-L1 was an adenosquamous cancer, and another had a mismatch repair deficiency. TILs were expanded from 6 tumors and were injected into NOG or human interleukin-2 transgenic-NOG mice carrying PDX tumors. Regression of tumors could be verified in human interleukin-2 transgenic-NOG mice in 3 of the 6 PDX models treated with autologous TILs, including the adenosquamous PDX model. Conclusion PDX models of pancreatic cancer can be used to learn more about tumor characteristics and biomarkers and to evaluate responses to adoptive cell therapy and combination therapies. The major benefit of the model is that modifications of T cells can be tested in an autologous humanized mouse model to gain preclinical data to support the initiation of a clinical trial.
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| 19. |
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| 20. |
- Ny, Lars, 1967, et al.
(författare)
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The PEMDAC phase 2 study of pembrolizumab and entinostat in patients with metastatic uveal melanoma
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The authors report the results of the phase II PEMDAC clinical study testing the combination of the HDAC inhibitor entinostat with the anti- PD-1 antibody pembrolizumab in uveal melanoma. Low tumor burden, a wildtype BAP1 gene in the tumor or iris melanoma correlates with response and longer survival. Preclinical studies have suggested that epigenetic therapy could enhance immunogenicity of cancer cells. We report the results of the PEMDAC phase 2 clinical trial (n = 29; NCT02697630) where the HDAC inhibitor entinostat was combined with the PD-1 inhibitor pembrolizumab in patients with metastatic uveal melanoma (UM). The primary endpoint was objective response rate (ORR), and was met with an ORR of 14%. The clinical benefit rate at 18 weeks was 28%, median progression free survival was 2.1 months and the median overall survival was 13.4 months. Toxicities were manageable, and there were no treatment-related deaths. Objective responses and/or prolonged survival were seen in patients with BAP1 wildtype tumors, and in one patient with an iris melanoma that exhibited a UV signature. Longer survival also correlated with low baseline ctDNA levels or LDH. In conclusion, HDAC inhibition and anti-PD1 immunotherapy results in durable responses in a subset of patients with metastatic UM.
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| 21. |
- Sah, Vasu R., et al.
(författare)
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Chemokine Analysis in Patients with Metastatic Uveal Melanoma Suggests a Role for CCL21 Signaling in Combined Epigenetic Therapy and Checkpoint Immunotherapy
- 2023
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Ingår i: Cancer Research Communications. - : American Association For Cancer Research (AACR). - 2767-9764. ; 3:5, s. 884-895
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Patients with metastatic uveal melanoma have limited therapeutic options and high mortality rate so new treatment options are needed.Patients and Methods: We previously reported that patients treated with the PD-1 inhibitor pembrolizumab and the histone deacetylase inhibitor entinostat in the PEMDAC trial, experienced clinical benefits if their tu-mor originated from iris or was wildtype for BAP1 tumor suppressor gene. Here we present the 2-year follow-up of the patients in the PEMDAC trial and identify additional factors that correlate with response or survival.Results: Durable responses were observed in 4 patients, with additional 8 patients exhibiting a stable disease. The median overall survival was 13.7 months. Grade 3 adverse events were reported in 62% of the patients, but they were all manageable. No fatal toxicity was observed. Activity of thymidine kinase 1 in plasma was higher in patients with stable disease or who progressed on treatment, compared with those with partial response. Chemokines and cytokines were analyzed in plasma. Three chemokines were significantly different when comparing patients with and without response. One of the factors, CCL21, was higher in the plasma of respond-ing patients before treatment initiation but decreased in the same patients upon treatment. In tumors, CCL21 was expressed in areas resembling ter -tiar y lymphoid structures (TLS). High plasma levels of CCL21 and presence of TLS-like regions in the tumor correlated with longer survival.Conclusions: This study provides insight into durable responses in the PEMDAC trial, and describes dynamic changes of chemokines and cytokines in the blood of these patients.Significance: The most significant finding from the 2-year follow-up study of the PEMDAC trial was that high CCL21 levels in blood was associated with response and survival. CCL21 was also expressed in TLS-like regions and presence of these regions was associated with longer survival. These analyses of soluble and tumor markers can inform on predictive biomark-ers needing validation and become hypothesis generating for experimental research.
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| 22. |
- Sah, Vasu R., et al.
(författare)
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Epigenetic therapy to enhance therapeutic effects of PD-1 inhibition in therapy-resistant melanoma
- 2022
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Ingår i: Melanoma Research. - : Ovid Technologies (Wolters Kluwer Health). - 0960-8931. ; 32:4, s. 241-248
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Tidskriftsartikel (refereegranskat)abstract
- Targeted therapy and immunotherapy have revolutionized the treatment of metastatic skin melanoma but around half of all patients develop resistance early or late during treatment. The situation is even worse for patients with metastatic uveal melanoma (UM). Here we hypothesized that the immunotherapy of therapy-resistant skin melanoma or UM can be enhanced by epigenetic inhibitors. Cultured B16F10 cells and human UM cells were treated with the histone deacetylase inhibitor (HDACi) entinostat or BETi JQ1. Entinostat-induced HLA expression and PD-L1, but JQ1 did not. A syngeneic mouse model carrying B16-F10 melanoma cells was treated with PD-1 and CTLA4 inhibitors, which was curative. Co-treatment with the bioavailable BETi iBET726 impaired the immunotherapy effect. Monotherapy of a B16-F10 mouse model with anti-PD-1 resulted in a moderate therapeutic effect that could be enhanced by entinostat. Mice carrying PD-L1 knockout B16-F10 cells were also sensitive to entinostat. This suggests HDAC inhibition and immunotherapy could work in concert. Indeed, co-cultures of UM with HLA-matched melanoma-specific tumor-infiltrating lymphocytes (TILs) resulted in higher TIL-mediated melanoma killing when entinostat was added. Further exploration of combined immunotherapy and epigenetic therapy in metastatic melanoma resistant to PD-1 inhibition is warranted.
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| 23. |
- Sterky, Fredrik, et al.
(författare)
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A Populus EST resource for plant functional genomics
- 2004
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 101:38, s. 13951-13956
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Tidskriftsartikel (refereegranskat)abstract
- Trees present a life form of paramount importance for terrestrial ecosystems and human societies because of their ecological structure and physiological function and provision of energy and industrial materials. The genus Populus is the internationally accepted model for molecular tree biology. We have analyzed 102,019 Populus ESTs that clustered into 11,885 clusters and 12,759 singletons. We also provide >4,000 assembled full clone sequences to serve as a basis for the upcoming annotation of the Populus genome sequence. A public web-based EST database (POPULUSDB) provides digital expression profiles for 18 tissues that comprise the majority of differentiated organs. The coding content of Populus and Arabidopsis genomes shows very high similarity, indicating that differences between these annual and perennial angiosperm life forms result primarily from differences in gene regulation. The high similarity between Populus and Arabidopsis will allow studies of Populus to directly benefit from the detailed functional genomic information generated for Arabidopsis, enabling detailed insights into tree development and adaptation. These data will also valuable for functional genomic efforts in Arabidopsis.
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| 24. |
- Sudow, Mattias, 1980, et al.
(författare)
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The Chalmers microstrip SiC MMIC Process
- 2005
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Ingår i: Conference Proceedings Gighahertz 2005.
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Konferensbidrag (refereegranskat)abstract
- A generic microstrip MMIC process targeted for SiC and GaN technology has beendeveloped. Passive components for high power operation were developed and verified. Circuit modelsfor both passive and active components have been formulated. Using the developed MMIC process anamplifier and a limiter have been manufactured.
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| 25. |
- Uhlén, Mathias, et al.
(författare)
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A human protein atlas for normal and cancer tissues based on antibody proteomics
- 2005
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 4:12, s. 1920-1932
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Tidskriftsartikel (refereegranskat)abstract
- Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, similar to 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.
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