| 1. |
- Einarsdottir, Berglind Osk, 1979, et al.
(författare)
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Melanoma patient-derived xenografts accurately model the disease and develop fast enough to guide treatment decisions.
- 2014
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 5:20, s. 9609-18
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Tidskriftsartikel (refereegranskat)abstract
- The development of novel therapies against melanoma would benefit from individualized tumor models to ensure the rapid and accurate identification of biomarkers of therapy response. Previous studies have suggested that patient-derived xenografts (PDXes) could be useful. However, the utility of PDXes in guiding real-time treatment decisions has only been reported in anecdotal forms. Here tumor biopsies from patients with stage III and IV metastatic malignant melanoma were transplanted into immunocompromised mice to generate PDXes. 23/26 melanoma biopsies generated serially transplantable PDX models, and their histology, mutation status and expression profile resembled their corresponding patient biopsy. The potential treatment for one patient was revealed by an in vitro drug screen and treating PDXes with the MEK inhibitor trametinib. In another patient, the BRAF mutation predicted the response of both the patient and its corresponding PDXes to MAPK-targeted therapy. Importantly, in this unselected group of patients, the time from biopsy for generation of PDXes until death was significantly longer than the time required to reach the treatment phase of the PDXes. Thus, it could be clinically meaningful to use this type of platform for melanoma patients as a pre-selection tool in clinical trials.
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| 2. |
- Heddini, Ulrika, et al.
(författare)
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A118G polymorphism in the μ-opioid receptor gene and levels of β-endorphin are associated with provoked vestibulodynia and pressure pain sensitivity
- 2014
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Ingår i: Scandinavian Journal of Pain. - : Elsevier. - 1877-8860 .- 1877-8879. ; 5:1, s. 10-16
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Tidskriftsartikel (refereegranskat)abstract
- Background and aimsProvoked vestibulodynia (PVD) is the most common cause of dyspareunia among young women. The aetiology is largely unknown and treatment is often extensive and longstanding with varying outcomes. Patients display general pain hypersensitivity and there are correlations with other chronic pain syndromes such as fibromyalgia later in life. The A118G polymorphism in the μ-opioid receptor (OPRM1) gene influences endogenous pain regulation and pain sensitivity, but has not been studied in this patient group before. We aimed to investigate a possible association between A118G polymorphism and PVD, with correlation to plasma levels of β-endorphin, and to explore relationships between this polymorphism and pain sensitivity among women with PVD and healthy controls.MethodsThis case–control study included 98 women with PVD and 103 controls. Participants filled out study-specific questionnaires and underwent quantitative sensory testing of pressure pain thresholds on the arm, leg and in the vestibular area. Levels of β-endorphin were analyzed by radioimmunoassay using the EURIA-beta-endorphin kit, and the A118G single-nucleotide polymorphism (SNP; rs1799971) in the OPRM1 gene was analyzed using the TaqMan SNP genotyping assay.ResultsThe 118G allele was more common in controls (44%) than in patients (30%) (p = 0.042). The odds ratio of having PVD was 1.8 in participants carrying the 118A allele compared to participants hetero- or homozygous for the 118G allele (OR = 1.846, CI: 1.03–3.31, p = 0.039). Pressure pain thresholds on the leg were higher for participants carrying the 118G allele (mean 480 kPa, SD 167.5) than for those carrying the 118A allele (mean 419, SD 150.4, p = 0.008). Levels of β-endorphin were higher in patients (mean 17.9 fmol/ml, SD 4.71) than in controls (mean 15.8 fmol/ml, SD 4.03) (p < 0.001).ConclusionWe found an association between the A118G polymorphism in the OPRM1 gene and an increased risk of PVD and increased pain sensitivity among participants carrying the 118A allele. PVD patients were more sensitive to pressure pain and had higher levels of plasma β-endorphin than controls. The results indicate that differences in endogenous pain modulation involving the opioid system could contribute to the pathophysiology of PVD and the general pain hypersensitivity seen in these women.ImplicationsThe data support the conceptualization of PVD as part of a general pain disorder with a possible genetic predisposition. The age of onset of PVD is usually between 18 and 25 years and already at this age general pain hypersensitivity is present but rarely causing disability. We believe that early recognition and treatment, with the risk of further development of chronic pain taken into consideration, might prevent future aggravated pain problems in this patient group.
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| 3. |
- Heddini, Ulrika, et al.
(författare)
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GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia
- 2012
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 8, s. 68-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Provoked vestibulodynia (PVD) is a pain disorder localized in the vestibular mucosa. It is the most common cause of dyspareunia among young women and it is associated with general pain hypersensitivity and other chronic pain conditions. Polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene has been found to influence general pain sensitivity and the risk of developing a longstanding pain condition. The aim of this study was to investigate GCH1-polymorphism in women with PVD and healthy controls, in correlation to pain sensitivity. Results: We found no correlation between the previously defined pain-protective GCH1-SNP combination and the diagnosis of PVD. Nor any correlation with pain sensitivity measured as pressure pain thresholds on the arm, leg and in the vestibule, coital pain scored on a visual analog scale and prevalence of other bodily pain conditions among women with PVD (n = 98) and healthy controls (n = 102). However, among patients with current treatment (n = 36), there was a significant interaction effect of GCH1-gene polymorphism and hormonal contraceptive (HC) therapy on coital pain (p = 0.04) as well as on pressure pain thresholds on the arm (p = 0.04). PVD patients carrying the specified SNP combination and using HCs had higher pain sensitivity compared to non-carriers. In non-HC-users, carriers had lower pain sensitivity. Conclusions: The results of this study gave no support to the hypothesis that polymorphism in the GCH1-gene contributes to the etiology of PVD. However, among patients currently receiving treatment an interaction effect of the defined SNP combination and use of hormonal contraceptives on pain sensitivity was found. This finding offers a possible explanation to the clinically known fact that some PVD patients improve after cessation of hormonal contraceptives, indicating that PVD patients carrying the defined SNP combination of GCH1 would benefit from this intervention.
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| 4. |
- Heddini, Ulrika, et al.
(författare)
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Provoked Vestibulodynia-Medical Factors and Comorbidity Associated with Treatment Outcome
- 2012
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Ingår i: Journal of Sexual Medicine. - : Oxford University Press (OUP). - 1743-6095 .- 1743-6109. ; 9:5, s. 1400-1406
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. Provoked vestibulodynia (PVD) is the most common cause of dyspareunia in young women. The etiology is unclear, and there is little knowledge of how to predict treatment outcome. Aim. The aim of this study was to identify medical factors associated with treatment outcome and coital pain in women with PVD. Methods. Seventy women previously treated for PVD at a vulvar open care unit completed questionnaires and a quantitative sensory testing session. Main Outcome Measures. Concomitant bodily pain and treatment outcome were surveyed using a study specific questionnaire. Coital pain was rated on a visual analog scale (VAS), range 0100. Psychometric screening was carried out using the Hospital Anxiety and Depression Scale. Pressure pain thresholds on the arm, leg, and in the vestibulum were measured using pressure algometers. Results. Major improvement/complete recovery was more likely in PVD patients with a maximum of one other concomitant pain disorder compared with patients with four or more (odds ratio = 7.8, confidence interval: 1.249.4, P = 0.03). In a multiple linear regression model, the number of other pain disorders (P < 0.01) and a diagnosis of primary PVD (P = 0.04) were positively associated with the coital VAS pain score. Women with secondary PVD reported major improvement/complete recovery to a higher extent than women with primary PVD (z = 2.11, P = 0.04). Conclusion. A successful treatment outcome was more likely in PVD patients with fewer other concomitant pain conditions. The number of other bodily pain conditions was also associated to the intensity of the coital pain. Additionally, the results indicate higher incomplete response rates to treatment in women with primary PVD compared with secondary PVD.
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| 5. |
- Heddini, Ulrika, et al.
(författare)
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Serotonin Receptor Gene (5HT-2A) Polymorphism is Associated with Provoked Vestibulodynia and Comorbid Symptoms of Pain
- 2014
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Ingår i: Journal of Sexual Medicine. - : ELSEVIER SCI LTD. - 1743-6095 .- 1743-6109. ; 11:12, s. 3064-3071
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionProvoked vestibulodynia (PVD) is a common type of dyspareunia among young women. The patho-physiology remains largely unclear. Women with PVD have general pain hypersensitivity and often report additional pain symptoms. Signs point towards PVD being a chronic pain disorder similar to other syndromes of longstanding pain, including a common comorbidity of anxiety and depression. Polymorphism in the serotonin receptor gene, 5HT-2A, has been associated with other chronic pain disorders such as fibromyalgia but has not been investigated in PVD patients. AimWe aimed to investigate a possible contribution of polymorphism in the 5HT-2A gene to the etiology of PVD as well as a potential influence on pain sensitivity. MethodsIn this case-control study 98 women with PVD and 103 healthy controls between 18 and 44 years and in the same menstrual cycle phase completed questionnaires and underwent quantitative sensory testing. Venous blood samples were collected for DNA isolation. Main Outcome MeasuresConcomitant pain was reported, a bodily pain score was created and pressure pain thresholds (PPTs) on the arm, leg, and in the vestibule were measured. Intensity of coital pain was rated on a visual analog scale, range 0-100. The T102C (rs6313) and A-1438G (rs6311) single nucleotide polymorphisms (SNPs) in the 5HT-2A gene were analyzed. ResultsThe probability of PVD was elevated in participants carrying the 1438G- and 102C-alleles of the 5HT-2A gene (OR 2.9). The G-/C- genotypes were also associated with more concomitant bodily pain in addition to the dyspareunia, but not with experimental PPTs or coital pain ratings. PVD patients reported more concomitant bodily pain and had lower PPTs compared with controls. ConclusionThe results indicate a contribution of alterations in the serotonergic system to the patho-genesis of PVD and gives further evidence of PVD being a general pain disorder similar to other chronic pain disorders. Heddini U, Bohm-Starke N, Gronbladh A, Nyberg F, Nilsson KW, and Johannesson U. Serotonin receptor gene (5HT-2A) polymorphism is associated with provoked vestibulodynia and comorbid symptoms of pain. J Sex Med 2014;11:3064-3071.
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| 6. |
- Lundh Snis, Ulrika, 1970-, et al.
(författare)
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Nordic Innovation Networks in Education : Dealing with Educational Challenges with Cross Boarder Collaboration and User Driven Design
- 2012
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Ingår i: Uddevalla Symposium 2012<em> </em>. - 9789197794343 ; , s. 553-571
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Konferensbidrag (refereegranskat)abstract
- This is an EU-funded project related to cross boarder collaboration for educational purposes supported by information and communication technologies between Danish, Norwegian and Swedish schools. The project started in 2011 and extends to 2014 so this empirically dominated paper reports on early findings related to cross-border collaboration challenges. The aim of the project is to develop innovative cross-border teaching models by the means of user-driven, practice-based co-design processes between practitioners and researchers. In the first year, 18 classes from 13 schools in Denmark, Norway and Sweden in the Öresund-Kattegatt-Skagerack region participated. Organized in so called Nordic class-match groups (consisting of students and teachers from one class in each country) new cross-border teaching models are co-created, tested and evaluated in an iterative process. Since teaching models are subject dependent, the project develop teaching models in several subject domains, i.e. math, language, science and social studies / history. Heretofore findings show, however, that organizational and technical issues have superseded and squeezed out subject-oriented discussions due to surprisingly many practical issues that needed to be handled first. We have identified three major thresholds to overcome. The first is related to technical difficulties in schools when diverse IT systems are to be synchronized. The second threshold concerns scheduling coordination difficulties in order to allow synchronous cross boarder collaboration. The third threshold concerns linguistic and communication difficulties rooted in participants communicating in their respective Nordic language. Being able to communicate within Nordic languages are explicit learning goals in all three schools systems, and therefore part of the project aim and consequently all participants are expected to use their native languages when communicating. The next phase of the project is therefore to find solutions to these technical, organizational and linguistic barriers, and already now we see some barrier breaking models taking shape in the active network of Nordic teachers, students, school leaders, IT support teams and researchers.
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| 7. |
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| 8. |
- Ahlén, Gustaf, et al.
(författare)
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Mannosylated mucin-type immunoglobulin fusion proteins enhance antigen-specific antibody and T lymphocyte responses
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:10
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Tidskriftsartikel (refereegranskat)abstract
- Targeting antigens to antigen-presenting cells (APC) improve their immunogenicity and capacity to induce Th1 responses and cytotoxic T lymphocytes (CTL). We have generated a mucin-type immunoglobulin fusion protein (PSGL-1/mIgG2b), which upon expression in the yeast Pichia pastoris became multivalently substituted with O-linked oligomannose structures and bound the macrophage mannose receptor (MMR) and dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) with high affinity in vitro. Here, its effects on the humoral and cellular anti-ovalbumin (OVA) responses in C57BL/6 mice are presented.OVA antibody class and subclass responses were determined by ELISA, the generation of anti-OVA CTLs was assessed in 51Cr release assays using in vitro-stimulated immune spleen cells from the different groups of mice as effector cells and OVA peptide-fed RMA-S cells as targets, and evaluation of the type of Th cell response was done by IFN-γ, IL-2, IL-4 and IL-5 ELISpot assays.Immunizations with the OVA − mannosylated PSGL-1/mIgG2b conjugate, especially when combined with the AbISCO®-100 adjuvant, lead to faster, stronger and broader (with regard to IgG subclass) OVA IgG responses, a stronger OVA-specific CTL response and stronger Th1 and Th2 responses than if OVA was used alone or together with AbISCO®-100. Also non-covalent mixing of mannosylated PSGL-1/mIgG2b, OVA and AbISCO®-100 lead to relatively stronger humoral and cellular responses. The O-glycan oligomannoses were necessary because PSGL-1/mIgG2b with mono- and disialyl core 1 structures did not have this effect.Mannosylated mucin-type fusion proteins can be used as versatile APC-targeting molecules for vaccines and as such enhance both humoral and cellular immune responses.
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| 9. |
- Ali, Ashfaq, et al.
(författare)
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Paranoid potato : phytophthora-resistant genotype shows constitutively activated defense
- 2012
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Ingår i: Plant Signaling and Behavior. - : Informa UK Limited. - 1559-2316 .- 1559-2324. ; 7:3, s. 400-408
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Tidskriftsartikel (refereegranskat)abstract
- Phytophthora is the most devastating pathogen of dicot plants. There is a need for resistance sources with different modes of action to counteract the fast evolution of this pathogen. In order to better understand mechanisms of defense against P. infestans, we analyzed several clones of potato. Two of the genotypes tested, Sarpo Mira and SW93-1015, exhibited strong resistance against P. infestans in field trials, whole plant assays and detached leaf assays. The resistant genotypes developed different sizes of hypersensitive response (HR)-related lesions. HR lesions in SW93-1015 were restricted to very small areas, whereas those in Sarpo Mira were similar to those in Solanum demissum, the main source of classical resistance genes. SW93-1015 can be characterized as a cpr (constitutive expressor of PR genes) genotype without spontaneous microscopic or macroscopic HR lesions. This is indicated by constitutive hydrogen peroxide (H₂O₂) production and PR1 (pathogenesis-related protein 1) secretion. SW93-1015 is one of the first plants identified as having classical protein-based induced defense expressed constitutively without any obvious metabolic costs or spontaneous cell death lesions.
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| 10. |
- Andersson, Daniel, 1979, et al.
(författare)
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Plasticity Response in the Contralesional Hemisphere after Subtle Neurotrauma: Gene Expression Profiling after Partial Deafferentation of the Hippocampus
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL). The expression of selected genes was assessed by quantitative real-time PCR in the hippocampal tissue at the injured side and the contralesional side at day 4 and 14 after injury. We observed that expression of genes coding for synaptotagmin 1, ezrin, thrombospondin 4, and C1q proteins, that have all been implicated in the synapse formation, re-arrangement and plasticity, were upregulated both in the injured and the contralesional hippocampus, implying a plasticity response in the uninjured hemisphere. Several of the genes, the expression of which was altered in response to ECL, are known to be expressed in astrocytes. To test whether astrocyte activation plays a role in the observed plasticity response to ECL, we took advantage of mice deficient in two intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-) Vim(-/-)) and exhibiting attenuated astrocyte activation and reactive gliosis. The absence of GFAP and vimentin reduced the ECL-induced upregulation of thrombospondin 4, indicating that this response to ECL depends on astrocyte activation and reactive gliosis. We conclude that even a very limited focal neurotrauma triggers a distinct response at the contralesional side, which at least to some extent depends on astrocyte activation.
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