| 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. |
- Tomic, Tajana Tesan, et al.
(författare)
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MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
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| 3. |
- Bronge, Mattias, et al.
(författare)
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Identification of four novel T cell autoantigens and personal autoreactive profiles in multiple sclerosis
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), in which pathological T cells, likely autoimmune, play a key role. Despite its central importance, the autoantigen repertoire remains largely uncharacterized. Using a novel in vitro antigen delivery method combined with the Human Protein Atlas library, we screened for T cell autoreactivity against 63 CNS-expressed proteins. We identified four previously unreported autoantigens in MS: fatty acid-binding protein 7, prokineticin-2, reticulon-3, and synaptosomal-associated protein 91, which were verified to induce interferon-gamma responses in MS in two cohorts. Autoreactive profiles were heterogeneous, and reactivity to several autoantigens was MS-selective. Autoreactive T cells were predominantly CD4(+) and human leukocyte antigen-DR restricted. Mouse immunization induced antigen-specific responses and CNS leukocyte infiltration. This represents one of the largest systematic efforts to date in the search for MS autoantigens, demonstrates the heterogeneity of autoreactive profiles, and highlights promising targets for future diagnostic tools and immunomodulatory therapies in MS.
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| 4. |
- Ilkhanizadeh, Shirin, et al.
(författare)
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Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative
- 2023
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Ingår i: ACS Applied Bio Materials. - : American Chemical Society (ACS). - 2576-6422. ; 6:9, s. 3790-3797
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.
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| 5. |
- Kvist, Ola, et al.
(författare)
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A cross-sectional magnetic resonance imaging study of factors influencing growth plate closure in adolescents and young adults
- 2021
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 110:4, s. 1249-1256
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Tidskriftsartikel (refereegranskat)abstract
- Aim To assess growth plate fusion by magnetic resonance imaging (MRI) and evaluate the correlation with sex, age, pubertal development, physical activity and BMI. Methods Wrist, knee and ankle of 958 healthy subjects aged 14.0-21.5 years old were examined using MRI and graded by two radiologists. Correlations of growth plate fusion score with age, pubertal development, physical activity and BMI were assessed. Results Complete growth plate fusion occurred in 75%, 85%, 97%, 98%, 98% and 90%, 97%, 95%, 97%, 98% (radius, femur, proximal- and distal tibia and calcaneus) in 17-year-old females and 19-year-old males, respectively. Complete fusion occurs approximately 2 years earlier in girls than in boys. Pubertal development correlated with growth plate fusion score (rho = 0.514-0.598 for the different growth plate sites) but regular physical activity did not. BMI also correlated with growth plate fusion (rho = 0.186-0.384). Stratified logistic regression showed increased odds ratio (OR F: 2.65-8.71; M: 1.71-4.03) for growth plate fusion of obese or overweight subects versus normal-weight subjects. Inter-observer agreement was high (Kappa = 0.87-0.94). Conclusion Growth plate fusion can be assessed by MRI; occurs in an ascending order, from the foot to the wrist; and is significantly influenced by sex, pubertal development and BMI, but not by physical activity.
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| 6. |
- Kvist, Ola, et al.
(författare)
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DTI assessment of the maturing growth plate of the knee in adolescents and young adults
- 2023
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Ingår i: European Journal of Radiology. - : Elsevier. - 0720-048X .- 1872-7727. ; 162
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the growth plates of the knee in a healthy population of young adults and adolescents using DTI, and to correlate the findings with chronological age and skeletal maturation.METHODS: A prospective, cross-sectional study to assess the tibial and femoral growth plates with DTI in 155 healthy volunteers aged between 14.0 and 21 years old. Echo-planar DTI with 15 directions and b value of 0 and 600 s/mm2 was performed on a 3 T whole-body scanner.RESULTS: A relationship was observed between chronological age and most DTI metrics (fractional anisotropy, mean diffusivity, and radial diffusivity), tract length and volume. (No significant relationship could be seen for axonal diffusivity and tract length.) Subdivision according to skeletal maturation showed the greatest tract lengths and volumes seen in stage 4b and not 4a. The intra-observer agreement was significant (P = 0.01) for all the measured variables, but agreement varied (femur 0.53 - 0.98; tibia 0.58 - 0.98). Spearman's correlation showed a significant correlation for age (P = 0.05; P = 0.01) as well as for the fractional anisotropy value within all variables in both femur and tibia. Tract number and volume had a similar correlation with most variables, especially the DTI metrics, and would seem to be interchangeable.CONCLUSION: The current study indicates that DTI metrics could be a tool to assess the skeletal maturation process of the growth plate and its activity. Tractography seems promising to assess the activity of the growth plate in a younger population but must be used with caution in the more mature growth plate.
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| 7. |
- Kvist, Ola F. T., et al.
(författare)
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Comparison of reliability of magnetic resonance imaging using cartilage and T1-weighted sequences in the assessment of the closure of the growth plates at the knee
- 2020
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Ingår i: Acta Radiologica Open. - London : Sage Publications. - 2058-4601. ; 9:9, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Growth development is traditionally evaluated with plain radiographs of the hand and wrist to visualize bone structures using ionizing radiation. Meanwhile, MRI visualizes bone and cartilaginous tissue without radiation exposure. Purpose: To determine the state of growth plate closure of the knee in healthy adolescents and young adults and compare the reliability of staging using cartilage sequences and T1-weighted (T1W) sequence between pediatric and general radiologists. Material and Methods: A prospective, cross-sectional study of MRI of the knee with both cartilage and T1W sequences was performed in 395 male and female healthy subjects aged between 14.0 and 21.5 years old. The growth plate of the femur and the tibia were graded using a modified staging scale by two pediatric and two general radiologists. Femur and tibia were graded separately with both sequences. Results: The intraclass correlation was overall excellent. The inter- and intra-observer agreement for pediatric radiologists on T1W was 82% (kappa = 0.73) and 77% (kappa = 0.65) for the femur and 90% (kappa = 0.82) and 87% (kappa = 0.75) for the tibia. The inter-observer agreement for general radiologists on T1W was 69% (kappa = 0.56) for the femur and 56% (kappa = 0.34) for the tibia. Cohen's kappa coefficient showed a higher inter- and intra-observer agreement for cartilage sequences than for T1W: 93% (kappa = 0.86) and 89% (kappa = 0.79) for the femur and 95% (kappa = 0.90) and 91% (kappa = 0.81) for the tibia. Conclusion: Cartilage sequences are more reliable than T1W sequence in the assessment of the growth plate in adolescents and young adults. Pediatric radiology experience is preferable.
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| 8. |
- Kvist, Ola, et al.
(författare)
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Magnetic resonance and diffusion tensor imaging of the adolescent rabbit growth plate of the knee
- 2023
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Ingår i: Magnetic Resonance in Medicine. - : John Wiley & Sons. - 0740-3194 .- 1522-2594. ; 89:1, s. 331-342
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To assess the ability of MRI-DTI to evaluate growth plate morphology and activity compared with that of histomorphometry and micro-CT in rabbits.METHODS: The hind limbs of female rabbits aged 16, 20, and 24 wk (n = 4 per age group) were studied using a 9.4T MRI scanner with a multi-gradient echo 3D sequence and DTI in 14 directions (b-value = 984 s/mm2 ). After MRI, the right and left hind limb were processed for histological analysis and micro-CT, respectively. The Wilcoxon signed-rank test was used to evaluate the height and volume of the growth plate. Intraclass correlation and Pearson correlation coefficient were used to evaluate the association between DTI metrics and age.RESULTS: The growth plate height and volume were similar for all modalities at each time point and age. Age was correlated with all tractography and DTI metrics in both the femur and tibia. A correlation was also observed between all the metrics at both sites. Tract number and volume declined with age; however, tract length did not show any changes. The fractional anisotropy color map showed lateral diffusion centrally in the growth plate and perpendicular diffusion in the hypertrophic zone, as verified by histology and micro-CT.CONCLUSION: MRI-DTI may be useful for evaluating the growth plates.
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| 9. |
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| 10. |
- Ain, Noor U., et al.
(författare)
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Biallelic TMEM251 variants in patients with severe skeletal dysplasia and extreme short stature
- 2020
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Ingår i: Human Mutation. - : John Wiley & Sons. - 1059-7794 .- 1098-1004. ; 42:1, s. 89-101
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Tidskriftsartikel (refereegranskat)abstract
- Skeletal dysplasias are a heterogeneous group of disorders ranging from mild to lethal skeletal defects. We investigated two unrelated families with individuals presenting with a severe skeletal disorder. In family NMD02, affected individuals had a dysostosis multiplex-like skeletal dysplasia and severe short stature (<-8.5 SD). They manifested increasingly coarse facial features, protruding abdomens, and progressive skeletal changes, reminiscent of mucopolysaccharidosis. The patients gradually lost mobility and the two oldest affected individuals died in their twenties. The affected child in family ID01 had coarse facial features and severe skeletal dysplasia with clinical features similar to mucopolysaccharidosis. She had short stature, craniosynostosis, kyphoscoliosis, and hip-joint subluxation. She died at the age of 5 years. Whole-exome sequencing identified two homozygous variants c.133C>T; p.(Arg45Trp) and c.215dupA; p.(Tyr72Ter), respectively, in the two families, affecting an evolutionary conserved gene TMEM251 (NM_001098621.1). Immunofluorescence and confocal studies using human osteosarcoma cells indicated that TMEM251 is localized to the Golgi complex. However, p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate. Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes. Our work implicates TMEM251 in the pathogenesis of a novel disorder and suggests its potential function in chondrocyte differentiation.
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