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1.	Dorling, L, et al. (author) Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women 2021 In: The New England journal of medicine. - 1533-4406 .- 0028-4793. ; 384:5, s. 428-439 Journal article (peer-reviewed)
2.	Fredriksson, Anders, et al. (author) Running wheel activity restores MPTP-induced functional deficits 2011 In: Journal of neural transmission. - Wien : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 118:3, s. 407-420 Journal article (peer-reviewed)abstract Wheel-running and treadmill running physical exercise have been shown to alleviate parkinsonism in both laboratory and clinical studies. MPTP was administered to C57/BL6 mice using two different procedures: (a) administration of a double-dose regime (MPTP 2 × 20 or 2 × 40 mg/kg, separated by a 24-h interval), vehicle (saline 5 ml/kg) or saline (vehicle 2 × 5 ml/kg), and (b) administration of a single-dose weekly regime (MPTP 1 × 40 mg/kg) or saline (vehicle 1 × 5 ml/kg) repeated over 4 consecutive weeks. For each procedure, two different physical exercise regimes were followed: (a) after the double-dose MPTP regime, mice were given daily 30-min periods of wheel-running exercise over 5 consecutive days/week or placed in a cage in close proximity to the running wheels for 3 weeks. (b) Mice were either given wheel-running activity on 4 consecutive days (30-min periods) or placed in a cage nearby for 14 weeks. Behavioral testing was as follows: (a) after 3 weeks of exercise/no exercise, mice were tested for spontaneous motor activity (60 min) and subthreshold l-Dopa (5 mg/kg)-induced activity. (b) Spontaneous motor activity was measured on the fifth day during each of the each of the first 5 weeks (Tests 1–5), about 1 h before injections (first 4 weeks), and continued on the 5th days of the 6th to the 14th weeks (Tests 6–14). Subthreshold l-Dopa (5 mg/kg)-induced activity was tested on the 6th, 8th, 10th, 12th and 14th weeks. (b) Mice from the single-dose MPTP weekly regime were killed during the 15th week and striatal regions taken for dopamine analysis, whereas frontal and parietal cortex and hippocampus were taken for analysis of brain-derived neurotrophic factor (BDNF). It was shown that in both experiments, i.e., the double-dose regime and single-dose weekly regime of MPTP administration, physical activity attenuated markedly the MPTP-induced akinesia/hypokinesia in both the spontaneous motor activity and restored motor activity completely in subthreshold l-Dopa tests. Running wheel activity attenuated markedly the loss of dopamine due to repeated administrations of MPTP. BDNF protein level in the parietal cortex was elevated by the MPTP insult and increased further by physical exercise. Physical running wheel exercise alleviated both the functional and biomarker expressions of MPTP-induced parkinsonism.
3.	Öfverholm, Anna, et al. (author) Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer 2023 In: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1 Journal article (peer-reviewed)abstract BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.
4.	Abrahamsson, Per, 1985, et al. (author) Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics–population balance coupled compartment model 2018 In: Particuology. - : Elsevier BV. - 2210-4291 .- 1674-2001. ; 36, s. 1-12 Journal article (peer-reviewed)abstract There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that compartmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent powder mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space.
5.	Balboa, Diego, et al. (author) Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells. 2022 In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:7, s. 1042-1055 Journal article (peer-reviewed)abstract Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.
6.	Bergenholtz, Gunnar, 1939, et al. (author) Treatment of pulps in teeth affected by deep caries - A systematic review of the literature. 2013 In: Singapore dental journal. - : World Scientific Pub Co Pte Lt. - 0377-5291. ; 34:1, s. 1-12 Journal article (peer-reviewed)abstract BACKGROUND: This systematic review assesses the effect of methods commonly used to manage the pulp in cases of deep caries lesions, and the extent the pulp chamber remains uninfected and does not cause pulpal or periapical inflammatory lesions and associated tooth-ache over time.STUDY DESIGN: An electronic literature search included the databases PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and Cochrane Reviews from January 1950 to March 2013. In addition, hand searches were carried out. Two reviewers independently evaluated abstracts and full-text articles. An article was read in full if at least one of the two reviewers considered the abstract potentially relevant. Altogether, 161 articles were read in full text. Of these, 24 studies fulfilled established inclusion criteria. Based on studies of at least moderate quality, the quality of evidence of each procedure was rated in four levels according to GRADE.RESULTS: No study reached the high quality level. Twelve were of moderate quality. The overall evidence was insufficient to assess which of indirect pulp capping, stepwise excavation, direct excavation and pulp capping/partial pulpotomy, pulpotomy or pulpectomy is the most effective treatment approach for teeth with deep caries.CONCLUSIONS: Because of the lack of good studies it is not possible to determine whether an injured pulp by deep caries can be maintained or whether it should be removed and replaced with a root canal filling. Both randomized studies and prospective observational studies are needed to investigate whether a pulp exposed to deep caries is best treated by measures intended to preserve it or by pulpectomy and root filling.
7.	Bergentholtz, Gunnar, et al. (author) Rotfyllning : en systematisk litteraturöversikt 2010 Reports (other academic/artistic)
8.	Bergman, Petra, et al. (author) Genome-wide profiling of micro RNAS that associate with susceptibility to experimental neuroinflammation 2010 In: Journal of Neuroimmunology. - 0165-5728 .- 1872-8421. ; 228:1-2, s. 82-82 Journal article (other academic/artistic)
9.	Bergman, Petra, et al. (author) Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats. 2013 In: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:8, s. 4066-75 Journal article (peer-reviewed)abstract MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
10.	Brandão, Rita D., et al. (author) Targeted RNA-seq successfully identifies normal and pathogenic splicing events in breast/ovarian cancer susceptibility and Lynch syndrome genes 2019 In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 145:2, s. 401-414 Journal article (peer-reviewed)abstract A subset of genetic variants found through screening of patients with hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome impact RNA splicing. Through target enrichment of the transcriptome, it is possible to perform deep-sequencing and to identify the different and even rare mRNA isoforms. A targeted RNA-seq approach was used to analyse the naturally-occurring splicing events for a panel of 8 breast and/or ovarian cancer susceptibility genes (BRCA1, BRCA2, RAD51C, RAD51D, PTEN, STK11, CDH1, TP53), 3 Lynch syndrome genes (MLH1, MSH2, MSH6) and the fanconi anaemia SLX4 gene, in which monoallelic mutations were found in non-BRCA families. For BRCA1, BRCA2, RAD51C and RAD51D the results were validated by capillary electrophoresis and were compared to a non-targeted RNA-seq approach. We also compared splicing events from lymphoblastoid cell-lines with those from breast and ovarian fimbriae tissues. The potential of targeted RNA-seq to detect pathogenic changes in RNA-splicing was validated by the inclusion of samples with previously well characterized BRCA1/2 genetic variants. In our study, we update the catalogue of normal splicing events for BRCA1/2, provide an extensive catalogue of normal RAD51C and RAD51D alternative splicing, and list splicing events found for eight other genes. Additionally, we show that our approach allowed the identification of aberrant splicing events due to the presence of BRCA1/2 genetic variants and distinguished between complete and partial splicing events. In conclusion, targeted-RNA-seq can be very useful to classify variants based on their putative pathogenic impact on splicing.
11.	Brofelth, Mattias, et al. (author) Multiplex profiling of serum proteins in solution using barcoded antibody fragments and next generation sequencing 2020 In: Communications Biology. - : NATURE PUBLISHING GROUP. - 2399-3642. ; 3:1 Journal article (peer-reviewed)abstract The composition of serum proteins is reflecting the current health status and can, with the right tools, be used to detect early signs of disease, such as an emerging cancer. An earlier diagnosis of cancer would greatly increase the chance of an improved outcome for the patients. However, there is still an unmet need for proficient tools to decipher the information in the blood proteome, which calls for further technological development. Here, we present a proof-of-concept study that demonstrates an alternative approach for multiplexed protein profiling of serum samples in solution, using DNA barcoded scFv antibody fragments and next generation sequencing. The outcome shows high accuracy when discriminating samples derived from pancreatic cancer patients and healthy controls and represents a scalable alternative for serum analysis. Brofelth, Ekstrand et al use DNA barcoded scFv antibody fragments and next generation sequencing for multiplex profiling of proteins in serum from pancreatic cancer patients with high accuracy. This approach can potentially be used in high throughput precision diagnosis.
12.	Catucci, Irene, et al. (author) Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility 2018 In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:4, s. 452-457 Journal article (peer-reviewed)abstract PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.Genetics in Medicine advance online publication, 24 August 2017; doi:10.1038/gim.2017.123.
13.	Cirenajwis, Helena, et al. (author) Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy. 2015 In: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309 Journal article (peer-reviewed)abstract Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
14.	Cirenajwis, Helena, et al. (author) NF1-mutated melanoma tumors harbor distinct clinical and biological characteristics 2017 In: Molecular Oncology. - : Wiley. - 1574-7891. ; 11:4, s. 438-451 Journal article (peer-reviewed)abstract In general, melanoma can be considered as a UV-driven disease with an aggressive metastatic course and high mutational load, with only few tumors (acral, mucosal, and uveal melanomas) not induced by sunlight and possessing a lower mutational load. The most commonly activated pathway in melanoma is the mitogen-activated protein kinase (MAPK) pathway. However, the prognostic significance of mutational stratification is unclear and needs further investigation. Here, in silico we combined mutation data from 162 melanomas subjected to targeted deep sequencing with mutation data from three published studies. Tumors from 870 patients were grouped according to BRAF, RAS, NF1 mutation or triple-wild-type status and correlated with tumor and patient characteristics. We found that the NF1-mutated subtype had a higher mutational burden and strongest UV mutation signature. Searching for co-occurring mutated genes revealed the RASopathy genes PTPN11 and RASA2, as well as another RAS domain-containing gene RASSF2 enriched in the NF1 subtype after adjustment for mutational burden. We found that a larger proportion of the NF1-mutant tumors were from males and with older age at diagnosis. Importantly, we found an increased risk of death from melanoma (disease-specific survival, DSS; HR, 1.9; 95% CI, 1.21-3.10; P = 0.046) and poor overall survival (OS; HR, 2.0; 95% CI, 1.28-2.98; P = 0.01) in the NF1 subtype, which remained significant after adjustment for age, gender, and lesion type (DSS P = 0.03, OS P = 0.06, respectively). Melanoma genomic subtypes display different biological and clinical characteristics. The poor outcome observed in the NF1 subtype highlights the need for improved characterization of this group.
15.	Cristiani, Riccardo, et al. (author) High prevalence of associated injuries in anterior cruciate ligament tears: A detailed magnetic resonance imaging analysis of 254 patients 2024 In: Skeletal Radiology. - : SPRINGER. - 0364-2348 .- 1432-2161. Journal article (peer-reviewed)abstract Objectives To evaluate the type and prevalence of associated injuries by using magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) tears.Methods Data from the Natural Corollaries and Recovery after ACL injury multicenter longitudinal cohort study were analyzed. Between May 2016 and October 2018, patients aged between 15 and 40 years, who had experienced an ACL tear within the last 6 weeks and sought medical attention at one of seven healthcare clinics in Sweden, were invited to participate. The mean time from injury to MRI was 19.6 +/- 15.2 days. An orthopedic knee surgeon and a musculoskeletal radiologist reviewed all the MRI scans. The following structures were assessed: posterior cruciate ligament (PCL), medial collateral ligament (MCL) complex, lateral collateral ligament (LCL), popliteus tendon, medial meniscus (MM), lateral meniscus (LM), and cartilage. In addition, the presence of bone bruising, impaction fractures in the lateral femoral condyle (LFC) or posterolateral tibia (PLT), and Segond fractures were also assessed. Results A total of 254 patients (48.4% males) with a mean age of 25.4 +/- 7.1 years were included. The prevalence of associated injuries was as follows: PCL (0.4%), MCL {41.3% [superficial MCL and deep MCL (dMCL) 16.5%; isolated dMCL 24.8%]}, LCL (2.4%), MM (57.4%), LM (25.2%), cartilage (15.0%), bone bruising (92.9%), impaction fracture in the LFC (45.7%) and PLT (4.7%), and Segond fracture (7.5%).Conclusions The prevalence of associated injuries in patients with ACL tears was high. The findings reported in this study may serve as a reference tool for orthopedic surgeons and radiologists in the diagnosis of associated injuries using MRI in patients with ACL tears.
16.	Cristiani, Riccardo, et al. (author) High prevalence of meniscal ramp lesions in anterior cruciate ligament injuries 2023 In: Knee Surgery, Sports Traumatology, Arthroscopy. - : Springer. - 0942-2056 .- 1433-7347. ; 31:1, s. 316-324 Journal article (peer-reviewed)abstract Purpose To evaluate the prevalence of and factors associated with meniscal ramp lesions on magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) injuries. Methods Data from the Natural Corollaries and Recovery after ACL injury multicentre longitudinal cohort study (NACOX) were analysed. Only patients who underwent MRI were included in this study. All MRI scans were reviewed by an orthopaedic knee surgeon and a musculoskeletal radiologist. The patients were divided into two groups, those with and without ramp lesions according to MRI findings. Univariable and stepwise forward multiple logistic regression analyses were used to evaluate patient characteristics (age, gender, body mass index, pre-injury Tegner activity level, activity at injury) and concomitant injuries on MRI (lateral meniscus, medial collateral ligament [MCL], isolated deep MCL, lateral collateral ligament, pivot-shift-type bone bruising, posteromedial tibial [PMT] bone bruising, medial femoral condyle bone bruising, lateral femoral condyle [LFC] impaction and a Segond fracture) associated with the presence of meniscal ramp lesions. Results A total of 253 patients (52.2% males) with a mean age of 25.4 +/- 7.1 years were included. The overall prevalence of meniscal ramp lesions was 39.5% (100/253). Univariate analyses showed that contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising, LFC impaction and the presence of a Segond fracture increased the odds of having a meniscal ramp lesion. Stepwise forward multiple logistic regression analysis revealed that the presence of a meniscal ramp lesion was associated with contact sports at ACL injury [odds ratio (OR) 2.50; 95% confidence intervals (CI) 1.32-4.72; P = 0.005], pivot-shift-type bone bruising (OR 1.29; 95% CI 1.01-1.67; P = 0.04), PMT bone bruising (OR 4.62; 95% CI 2.61-8.19; P < 0.001) and the presence of a Segond fracture (OR 4.38; 95% CI 1.40-13.68; P = 0.001). Conclusion The overall prevalence of meniscal ramp lesions in patients with ACL injuries was high (39.5%). Contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising and the presence of a Segond fracture on MRI were associated with meniscal ramp lesions. Given their high prevalence, meniscal ramp lesions should be systematically searched for on MRI in patients with ACL injuries. Knowledge of the factors associated with meniscal ramp lesions may facilitate their diagnosis, raising surgeons and radiologists suspicion of these tears.
17.	Cristiani, Riccardo, et al. (author) High Prevalence of Superficial and Deep Medial Collateral Ligament Injuries on Magnetic Resonance Imaging in Patients With Anterior Cruciate Ligament Tears 2024 In: Arthroscopy. - : W B SAUNDERS CO-ELSEVIER INC. - 0749-8063 .- 1526-3231. ; 40:1, s. 103-110 Journal article (peer-reviewed)abstract Purpose: To assess the prevalence of and factors associated with medial collateral ligament (MCL) complex injuries on magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) tears.Methods: Data were extracted from the Natural Corollaries and Recovery After ACL Injury (NACOX) multicenter longitudinal cohort study. Between May 2016 and October 2018, patients who presented to 1 of 7 health care clinics across Sweden with an ACL tear sustained no more than 6 weeks earlier and who were aged between 15 and 40 years at the time of injury were invited to participate. All the patients included in this study underwent MRI. The mean time from injury to MRI was 19.6 +/- 15.2 days. An orthopaedic surgeon specializing in knee surgery and a musculoskeletal radiologist reviewed all MRI scans. Injuries to the superficial MCL (sMCL), deep MCL (dMCL), and posterior oblique ligament were identified. Stepwise forward multiple binary logistic regression analyses were used to evaluate patient characteristics (age, sex, body mass index, preinjury Tegner activity level, and activity at injury) and injuries on MRI (lateral meniscus [LM] injury, medial meniscus [MM] injury, pivot shift-type bone bruising, medial femoral condyle [MFC] bone bruising, and lateral femoral condyle [LFC] impaction) associated with the presence of MCL complex tears.Results: In total, 254 patients (48.4% male patients) with a mean age of 25.4 +/- 7.1 years were included. The overall prevalence of MCL (sMCL and dMCL) injuries and isolated dMCL injuries was 16.5% (42 of 254) and 24.8% (63 of 254), respectively. No isolated sMCL injuries were found. Posterior oblique ligament injuries were found in 12 patients (4.7%) with MCL (sMCL and dMCL) injuries. An LM injury (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.73-8.94; P = .001) and LFC impaction (OR, 2.37; 95% CI, 1.11-5.07; P = .02) increased the odds of having an MCL injury, whereas an MM injury (OR, 0.26; 95% CI, 0.12-0.59; P = .001) reduced the odds. Isolated dMCL injuries were significantly associated with MFC bone bruising (OR, 4.21; 95% CI, 1.92-9.25; P < .001) and LFC impaction (OR, 3.86; 95% CI, 1.99-7.49; P < .001).Conclusions: The overall combined prevalence of MCL (sMCL and dMCL) injuries and isolated dMCL injuries in patients with ACL tears was high (16.5% + 24.8% = 41.3%). The presence of an LM injury and LFC impaction increased the odds of having an MCL injury, whereas the presence of an MM injury reduced the odds. MFC bone bruising and LFC impaction were associated with the presence of isolated dMCL injuries.Level of Evidence: Level III, retrospective cohort study.
18.	Esbjörnsson, Joakim, et al. (author) Effect of HIV-2 infection on HIV-1 disease progression and mortality. 2014 In: AIDS. - 1473-5571. ; 28:4, s. 614-615 Journal article (peer-reviewed)
19.	Esbjörnsson, Joakim, et al. (author) Increased survival among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals 2014 In: AIDS. - 1473-5571. ; 28:7, s. 949-957 Journal article (peer-reviewed)abstract Objective: To compare survival times of HIV-1 single and HIV-1 and HIV-2 dual-infected individuals. Design: Prospective open cohort study. Methods: We analysed data from 259 HIV-1-seroincident cases (either HIV-1 single or HIV-1 and HIV-2 dual-infected) from a cohort with long follow-up (similar to 20 years) in order to study the influence of type of infection and infection order on mortality. Sex and age at HIV-1 infection date was controlled for in a Cox proportional-hazards model. Results: Dual-infected individuals had a 42% longer time from HIV-1 infection to death compared with single-infected individuals, adjusting for age asymmetries between groups. Dual-infected individuals with an HIV-2 infection preceding the HIV-1 infection had a more than two-fold lower mortality risk during follow-up than HIV-1 single-infected individuals. Conclusion: Survival time is longer and the risk of progression to death is lower among HIV-1 and HIV-2 dual-infected individuals compared to HIV-1 single-infected individuals. This natural inhibition could have implications for the development of future HIV-1 vaccines and therapeutics.
20.	Esbjörnsson, Joakim, et al. (author) Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection. 2012 In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 367:3, s. 224-232 Journal article (peer-reviewed)abstract BACKGROUND: Progressive immune dysfunction and the acquired immunodeficiency syndrome (AIDS) develop in most persons with untreated infection with human immunodeficiency virus type 1 (HIV-1) but in only approximately 20 to 30% of persons infected with HIV type 2 (HIV-2); among persons infected with both types, the natural history of disease progression is poorly understood. METHODS: We analyzed data from 223 participants who were infected with HIV-1 after enrollment (with either HIV-1 infection alone or HIV-1 and HIV-2 infection) in a cohort with a long follow-up duration (approximately 20 years), according to whether HIV-2 infection occurred first, the time to the development of AIDS (time to AIDS), CD4+ and CD8+ T-cell counts, and measures of viral evolution. RESULTS: The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P=0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection. CONCLUSIONS: Our results suggest that HIV-1 disease progression is inhibited by concomitant HIV-2 infection and that dual infection is associated with slower disease progression. The slower rate of disease progression was most evident in participants with dual infection in whom HIV-2 infection preceded HIV-1 infection. These findings could have implications for the development of HIV-1 vaccines and therapeutics. (Funded by the Swedish International Development Cooperation Agency-Swedish Agency for Research Cooperation with Developing Countries and others.).
21.	Esbjörnsson, Joakim, et al. (author) Long-term follow-up of HIV-2-related AIDS and mortality in Guinea-Bissau : a prospective open cohort study 2019 In: The Lancet HIV. - : The Lancet Publishing Group. - 2405-4704 .- 2352-3018. ; 6:1, s. E25-E31 Journal article (peer-reviewed)abstract BACKGROUND: HIV type 2 (HIV-2) is considered more benign and has fewer pathogenic consequences than HIV type 1 (HIV-1) for most infected individuals. However, reliable estimates of time to AIDS and mortality among those with HIV-2 infection are absent. We therefore aimed to compare the time to AIDS and mortality, and the CD4 T-cell dynamics between those infected with HIV-1 and HIV-2.METHODS: We did a prospective open cohort study. We included all police officers with regular employment from police stations in both urban and rural areas of Guinea-Bissau since Feb 6, 1990. We continued to include participants until Sept 28, 2009, and follow-up of HIV-1-positive and HIV-2-positive individuals continued until Sept 28, 2013. We collected blood samples at enrolment and at scheduled annual follow-up visits at police stations. We analysed longitudinal data from individuals infected with HIV-1 and HIV-2 according to time to AIDS, time to death, and T-cell dynamics. Time of HIV infection was estimated as the mid-timepoint between last HIV-seronegative and first HIV-seropositive sample. Data from an additional 2984 HIV-uninfected individuals from the same population were analysed to assess the effect of natural mortality on HIV-related mortality.FINDINGS: 872 participants tested HIV positive during the 23-year study period: 408 were infected with HIV-1 (183 infected before and 225 infected after enrolment) and 464 were infected with HIV-2 (377 before and 87 after enrolment). The median time from HIV infection to development of AIDS was 6·2 years (95% CI 5·4-7·1) for HIV-1 infection and 14·3 years (10·7-18·0) for HIV-2 infection (p<0·0001). The median survival time after HIV infection was 8·2 years (95% CI 7·5-8·9) for HIV-1 infection and 15·6 years (12·0-19·2) for HIV-2 infection (p<0·0001). Individuals who were infected with HIV-1 or HIV-2 before enrolment showed similar results. Comparison with uninfected individuals indicated limited confounding contribution from natural mortality. Mean CD4 percentages were higher in individuals with HIV-2 than in those with HIV-1 during early infection (28·0% [SE 1·3] vs 22·3% [1·7]; p=0·00094) and declined at a slower rate (0·4% [0·2] vs 0·9% [0·2] per year; p=0·028). HIV-2-infected individuals developed clinical AIDS at higher mean CD4 percentages (18·2%, IQR 7·2-25·4) than HIV-1-infected individuals (8·2%, 3·0-13·8; p<0·0001).INTERPRETATION: Our results show that both HIV-1-infected and HIV-2-infected individuals have a high probability of developing and dying from AIDS without antiretroviral treatment.
22.	Frisk, Fredrik, 1971, et al. (author) Is apical periodontitis in root filled teeth associated with the type of restoration? 2015 In: Acta Odontologica Scandinavica. - : Informa UK Limited. - 0001-6357 .- 1502-3850. ; 73:3, s. 169-75 Journal article (peer-reviewed)abstract OBJECTIVE: To study the association between type of restoration and apical periodontitis (AP) in root filled teeth. MATERIALS AND METHODS: The present study used data from surveys conducted in 1983, 1993 and 2003. In 1983, 130 randomly selected subjects aged 3-80 years in the city of Jönköping, Sweden, were invited for a clinical and radiological examination. The study was repeated in 1993 and 2003. New participants were, thus, recruited with the same sampling criteria and sample size in the same geographical area in 1993 and 2003, respectively. In the present study, only dentate individuals aged 20-70 years with ≥1 root filled tooth were included, yielding a sample of 788 subjects with 2634 root filled teeth. Apical periodontitis on the tooth level was the dependent variable. Periapical status was assessed according to Periapical Index (PAI). Independent variables were root filling quality, recurrent caries, type of restoration, number of teeth with apical periodontitis, age and gender. Root fillings appearing homogenous and ending within 2 mm from radiographic apex were regarded as adequate, otherwise inadequate. All radiographs were re-studied by one observer regarding periapical status and root filling quality. Risk was analyzed by means of a GEE model. RESULTS: Type of restoration, root filling quality, number of teeth with apical periodontitis within the individual and age were found to be predictors of AP in root filled teeth. Presence of recurrent caries and gender were not found to be associated with AP. CONCLUSIONS: According to the present study, root filling quality and type of restoration may be predictive of AP in root filled teeth.
23.	Frisk, Fredrik, 1971, et al. (author) Pulp exposures in adults--choice of treatment among Swedish dentists. 2013 In: Swedish dental journal. - : Sveriges tandläkarförbund. - 0347-9994. ; 37:3, s. 153-60 Journal article (peer-reviewed)abstract This study comprises a survey of Swedish dentists'treatment preferences in cases of carious exposure of the dental pulp in adults.The survey was conducted as part of a comprehensive report on methods of diagnosis and treatment in endodontics, published in 2010 by the Swedish Council on Health Technology Assessment. A questionnaire was mailed to a random subsample of 2012 dental offices where one dentist at each office was requested to answer all questions. Each questionnaire contained one of three sets of questions about endodontic practice routines.Thus around one-third of the subsample received case-specific questions about treating carious exposure. Only general practitioners aged below 70 years were included.The final study sample comprised 412 participants.The dentists were presented with two case scenarios. In Case 1 a 22-year old patient had a deep carious lesion in tooth 36 and in Case 2 a 50-year old patient had a deep carious lesion in tooth 14.The participants were asked to nominate their treatment of choice: pulp capping, partial pulpotomy or pulpectomy. For Case 1, 17 per cent of the respondents selected pulpectomy; the corresponding rate for Case 2 was 47 per cent. Female gender and age group 25-49 years were predictive of selection of less invasive treatment options. However, according to recent guidelines (2011) from the National Board of Health and Wellfare, Swedish dentists are recommended to elect pulpectomy prior to pulp capping/partial pulpotomy when confronted with a tooth having a cariously exposed pulp in adults.
24.	Galeev, Roman, et al. (author) Genome-wide RNAi Screen Identifies Cohesin Genes as Modifiers of Renewal and Differentiation in Human HSCs 2016 In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 14:12, s. 2988-3000 Journal article (peer-reviewed)abstract To gain insights into the regulatory mechanisms of hematopoietic stem cells (HSCs), we employed a genome-wide RNAi screen in human cord-blood derived cells and identified candidate genes whose knockdown maintained the HSC phenotype during culture. A striking finding was the identification of members of the cohesin complex (STAG2, RAD21, STAG1, and SMC3) among the top 20 genes from the screen. Upon individual validation of these cohesin genes, we found that their knockdown led to an immediate expansion of cells with an HSC phenotype in vitro. A similar expansion was observed in vivo following transplantation to immunodeficient mice. Transcriptome analysis of cohesin-deficient CD34(+) cells showed an upregulation of HSC-specific genes, demonstrating an immediate shift toward a more stem-cell-like gene expression signature upon cohesin deficiency. Our findings implicate cohesin as a major regulator of HSCs and illustrate the power of global RNAi screens to identify modifiers of cell fate.
25.	Glodzik, Dominik, et al. (author) Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers 2020 In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1 Journal article (peer-reviewed)abstract Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.
26.	Harbst, Katja, et al. (author) Molecular and genetic diversity in the metastatic process of melanoma. 2014 In: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 233:1, s. 39-50 Journal article (peer-reviewed)abstract Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.
27.	Harbst, Katja, et al. (author) Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma 2016 In: Cancer Research. - 0008-5472. ; 76:16, s. 4765-4774 Journal article (peer-reviewed)abstract Cancer genome sequencing has shed light on the underlying genetic aberrations that drive tumorigenesis. However, current sequencing-based strategies, which focus on a single tumor biopsy, fail to take into account intratumoral heterogeneity. To address this challenge and elucidate the evolutionary history of melanoma, we performed whole-exome and transcriptome sequencing of 41 multiple melanoma biopsies from eight individual tumors. This approach revealed heterogeneous somatic mutations in the range of 3%-38% in individual tumors. Known mutations in melanoma drivers BRAF and NRAS were always ubiquitous events. Using RNA sequencing, we found that the majority of mutations were not expressed or were expressed at very low levels, and preferential expression of a particular mutated allele did not occur frequently. In addition, we found that the proportion of ultraviolet B (UVB) radiation-induced C>T transitions differed significantly (P <0.001) between early and late mutation acquisition, suggesting that different mutational processes operate during the evolution of metastatic melanoma. Finally, clinical history reports revealed that patients harboring a high degree of mutational heterogeneity were associated with more aggressive disease progression. In conclusion, our multiregion tumor-sequencing approach highlights the genetic evolution and non-UVB mutational signatures associated with melanoma development and progression, and may provide a more comprehensive perspective of patient outcome.
28.	Hellström, Peter, et al. (author) Experimental evaluation of decision support tools for train traffic control 2003 In: The World Congress on Railway Research. - Edinburgh. ; , s. 670-677 Conference paper (other academic/artistic)
29.	Ibrahim, Hazem, et al. (author) RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function In: Diabetologia. - 0012-186X. Journal article (peer-reviewed)abstract Aims/hypothesis: Regulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown. Methods: To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice. Results: Stem cell models of the homozygous variant RFX6−/− predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell–Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/− SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes. Conclusions/interpretation: Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes. Data availability: Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (https://data.mendeley.com/datasets/g75drr3mgw/2). Graphical Abstract: (Figure presented.).
30.	Jenni-Eiermann, Susanne, et al. (author) Fuel use and metabolic response to endurance exercise: a wind tunnel study of a long-distance migrant shorebird 2002 In: Journal of Experimental Biology. - 1477-9145. ; 205:16, s. 2453-2460 Journal article (peer-reviewed)abstract This study examines fuel use and metabolism in a group of long-distance migrating birds, red knots Calidris canutus (Scolopacidae), flying under controlled conditions in a wind tunnel for up to 10 h. Data are compared with values for resting birds fasting for the same time. Plasma levels of free fatty acids, glycerol and uric acid were elevated during flight, irrespective of flight duration (1-10h). Triglyceride levels, the estimated concentration of very-low-density lipoproteins (VLDLs) and beta-hydroxybutyrate levels were lower during flight, while glucose levels did not change. In flying birds, plasma levels of uric acid and lipid catabolites were positively correlated with the residual variation in body mass loss, and lipid catabolites with energy expenditure (as measured using the doubly labelled water method), after removing the effect of initial body mass. The plasma metabolite levels indicate: (i) that the rates of catabolism of lipids from adipose tissue and of protein are higher during flight; (H) that low ketone body concentrations probably facilitate fatty acid release from adipose tissue; (iii) that low triglyceride and VLDL levels do not indicate the use of an additional pathway of fatty acid delivery, as found in small birds; and (iv) that the relationships between energy expenditure, body mass loss and metabolic pattern suggest that a higher individual energy expenditure entails a higher rate of catabolism of both lipids and protein and not a shift in fuel substrate.
31.	Jenni, L, et al. (author) Effect of endurance flight on haematocrit in migrating birds 2006 In: Journal of Ornithology. - : Springer Science and Business Media LLC. - 2193-7192 .- 2193-7206. ; 147:4, s. 531-542 Journal article (other academic/artistic)abstract The effects of an endurance flight on the haematocrit, the percentage of packed red blood cells per blood volume, were examined within the framework of six possible factors explaining possible changes in the haematocrit. Two approaches were adopted: (1) the haematocrit was studied in four species of passerine birds which landed on an Italian island after having crossed the Mediterranean Sea on their spring migration in a non-stop flight; (2) the haematocrit was evaluated in six individual red knots after a flight of 1, 2, 4 and 10 h in a wind tunnel and the data thus obtained compared with data on resting birds with or without food. In the four passerine species, the haematocrit decreased from 51% in fat birds to 48% in lean birds. In lean birds, the haematocrit dropped from 48% in birds with well-developed breast muscles to 36% in birds with emaciated breast muscles. In the red knots, the haematocrit was dependent on body mass in flying and resting birds. The haematocrit decreased from about 51% pre-flight to about 49% within 1 h of flight and remained at this level for up to 10 h of flight. Taking the results from the passerines and the red knots together, it seems that the haematocrit drops by a few percentage points within 1 h after the onset of flight, decreases very slowly with decreasing body mass and decreases more steeply in very lean birds having entered stage III of fasting. This indicates that dehydration is not an underlying factor in decreased haematocrit because if this were the case we would expect an increase with endurance flight. We found no effect of the presence of blood parasites on haematocrit. With the onset of flight, haemodilution may be adaptive, because it reduces blood viscosity and, thereby, energy expenditure by the heart, or it may be a sign of water conservation as an insurance against the risk of dehydration during long non-stop flights. During endurance flight, a reduction in the haematocrit may be adaptive, in that oxygen delivery capacity is adjusted to the decreased oxygen needs as body mass decreases. A decreasing haematocrit would also allow birds to reduce heart beat frequency and/or heart size, because blood viscosity decreases disproportionally with decreasing haematocrit. However, when energy stores are about to come to an end and birds increase protein breakdown, the haematocrit decreases even further, and birds probably become anaemic due to a reduced erythropoiesis.
32.	Kiiski, Johanna I., et al. (author) FANCM mutation c.5791C>T is a risk factor for triple-negative breast cancer in the Finnish population 2017 In: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 166:1, s. 217-226 Journal article (peer-reviewed)abstract Purpose: The FANCM c.5101C>T nonsense mutation was previously found to associate with breast cancer in the Finnish population, especially among triple-negative cases. Here, we studied the prevalence of three other FANCM variants: c.5791C>T, which has been reported to predispose to familial breast cancer, and the c.4025_4026delCT and c.5293dupA variants recently identified in Finnish cancer patients. Methods: We genotyped the FANCM c.5791C>T mutation in 4806 invasive breast cancer patients, including BRCA1/2 mutation negative familial cases and unselected cases, and in 2734 healthy population controls from four different geographical areas of Finland. The association of the mutation with breast cancer risk among patient subgroups was statistically evaluated. We further analyzed the combined risk associated with c.5101C>T and c.5791C>T mutations. We also genotyped 526 unselected ovarian cancer patients for the c.5791C>T mutation and 862 familial breast cancer patients for the c.4025_4026delCT and c.5293dupA variants. Results: The frequency of the FANCM c.5791C>T mutation was higher among breast cancer cases than in controls (OR 1.94, 95% CI 0.87–4.32, P = 0.11), with a statistically significant association with triple-negative breast cancer (OR 5.14, 95% CI 1.65–16.0, P = 0.005). The combined analysis for c.5101C>T and c.5791C>T carriers confirmed a strong association with breast cancer (OR 1.86, 95% CI 1.32–2.49, P = 0.0002), especially among the triple-negative patients (OR 3.08, 95% CI 1.77–5.35, P = 0.00007). For the other variants, only one additional c.4025_4026delCT carrier and no c.5293dupA carriers were observed. Conclusions: These results support the role of FANCM as a breast cancer susceptibility gene, particularly for triple-negative breast cancer.
33.	Klaassen, M, et al. (author) Flight costs and fuel composition of a bird migrating in a wind tunnel 2000 In: The Condor: ornithological applications. - 0010-5422. ; 102:2, s. 444-451 Journal article (peer-reviewed)abstract We studied the energy and protein balance of a Thrush Nightingale Luscinia luscinia, a small long-distance migrant, during repeated 12-hr long Eights in a wind tunnel and during subsequent two-day fueling periods. From the energy budgets we estimated the power requirements for migratory flight in this 26 g bird at 1.91 Watts. This is low compared to flight cost estimates in birds of similar mass and with similar wing shape. This suggests that power requirements for migratory flight are lower than the power requirements for nonmigratory Eight. From excreta production during Right, and nitrogen and energy balance during subsequent fueling, the dry protein proportion of stores was estimated to be around 10%. A net catabolism of protein during migratory flight along with that of fat may reflect a physiologically inevitable process, a means of providing extra water to counteract dehydration, a production of uric acid for anti-oxidative purposes, and adaptive changes in the size of Eight muscles and digestive organs in the exercising animal.
34.	Klaassen, Marcel, et al. (author) How body water and fuel stores affect long distance flight in migrating birds 1999 In: Proceedings of the 22nd International Ornithological Congress. ; , s. 1450-1467 Conference paper (peer-reviewed)
35.	Kvist, Anders, 1961 (author) Atom Probe Field Ion Microscopy of Surface Zones, Coatings and Interfaces 1995 Doctoral thesis (other academic/artistic)abstract This thesis is focused on developingmethods for high resolution microanalysis of coatings on a substrate, andsurface zones of a bulk sample using atom probe field ion microscopy,APFIM. The APFIM technique is described and some examples of its applications to semiconductors,cemented carbides and intermetallic compounds are given. The main part of the thesis is concerned with the formation of Schottky andohmic contacts on highly-doped GaAs. Three different metal coatings wereanalysed, gold, silver and gold-germanium, all of them formed on an APFIMspecimen of the semiconductor. The gold and silver coatings were studied on atomically clean as well asair exposed GaAs surfaces. Intermixing occurred for Au on a clean surfacewhereas Ag showed an atomically abrupt interface. Oxygen seemed to stopintermixing between Au and GaAs, but promoted diffusion of Ag into the semiconductor. Deposition of thegold-germanium alloy was only made on oxidised GaAs surfaces and the effectof heat treatment on this contact was studied. After heat treatment a thinlayer containing a few at.% of Ge in the GaAs was observed beneath an almost pure layer of Au. A technique for preparing APFIM specimens of the near surface zone of acemented carbide sample was developed, using a combination of dimplegrinding, electropolishing and ion milling. The first results obtained froma specimen prepared with this methodare presented. The possible applicability of this technique to metal/GaAsinterfaces and CVD-coated cemented carbides is discussed. APFIM analysis for the determination of the platinum distribution in anordered Cu3Au(4 at.% Pt) alloy is presented with a particularinterest in problems related to quantitative analysis near and at grainboundaries.
36.	Kvist, Anders, 1961 (author) Atom-probe microanalysis of the AuGe/GaAs interface 1993 Licentiate thesis (other academic/artistic)
37.	Kvist, Anders, et al. (author) Basal metabolic rate in migratory waders: intra-individual, intraspecific, interspecific and seasonal variation 2001 In: Functional Ecology. - : Wiley. - 1365-2435 .- 0269-8463. ; 15:4, s. 465-473 Journal article (peer-reviewed)abstract 1. Basal metabolic rates (BMR) were measured in 36 adult and 119 juvenile waders of 19 species on autumn migration in southern Sweden. 2. Ina comparison with literature data, it was found that juvenile BMR was generally lower than at the onset of migration in the Arctic and slightly higher than on African wintering grounds. 3. The seasonal differences may reflect local physiological adaptations or possibly a gradual decline from high premigratory levels due to growth. Our data contradict the idea that BMR is high during migration as an adaptation to generally high levels of energy expenditure. 4. The allometric exponent, scaling BMR to body mass, was significantly higher within individuals (1.19) and within species (1.82) than among species (0.62). 5. The high intra-individual exponent indicates that non-fat tissues, with a high metabolic activity, are involved in the mass changes during migratory stopover. 6. The high intraspecific exponent indicates that tissues with a high metabolic activity contributed disproportionately to variation in body mass among individuals or that larger individuals had elevated mass specific metabolic rates of some tissues.
38.	Kvist, Anders, et al. (author) Carrying large fuel loads during sustained bird flight is cheaper than expected 2001 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 413:6857, s. 730-732 Journal article (peer-reviewed)abstract Birds on migration alternate between consuming fuel stores during flights and accumulating fuel stores during stopovers. The optimal timing and length of flights and stopovers for successful migration depend heavily on the extra metabolic power input (fuel use) required to carry the fuel stores during flight(1,2). The effect of large fuel loads on metabolic power input has never been empirically determined. We measured the total metabolic power input of a long-distance migrant, the red knot (Calidris canutus), flying for 6 to 10 h in a wind tunnel, using the doubly labelled water technique(3). Here we show that total metabolic power input increased with fuel load, but proportionally less than the predicted mechanical power output from the flight muscles. The most likely explanation is that the efficiency with which metabolic power input is converted into mechanical output by the flight muscles increases with fuel load. This will influence current models of bird flight and bird migration. It may also help to explain why some shorebirds, despite the high metabolic power input required to fly, routinely make nonstop flights of 4,000 km longer(4).
39.	Kvist, Alexander, et al. (author) Chondroitin sulfate perlecan enhances collagen fibril formation - Implications for perlecan chondrodysplasias 2006 In: Journal of Biological Chemistry. - 1083-351X. ; 281:44, s. 33127-33139 Journal article (peer-reviewed)abstract Inactivation of the perlecan gene leads to perinatal lethal chondrodysplasia. The similarity to the phenotypes of the Col2A1 knock-out and the disproportionate micromelia mutation suggests perlecan involvement in cartilage collagen matrix assembly. We now present a mechanism for the defect in collagen type II fibril assembly by perlecan-null chondrocytes. Cartilage perlecan is a heparin sulfate or a mixed heparan sulfate/ chondroitin sulfate proteoglycan. The latter form binds collagen and accelerates fibril formation in vitro, with more defined fibril morphology and increased fibril diameters produced in the presence of perlecan. Interestingly, the enhancement of collagen fibril formation is independent on the core protein and is mimicked by chondroitin sulfate E but neither by chondroitin sulfate D nor dextran sulfate. Furthermore, perlecan chondroitin sulfate contains the 4,6-disulfated disaccharides typical for chondroitin sulfate E. Indeed, purified glycosaminoglycans from perlecan-enriched fractions of cartilage extracts contain elevated levels of 4,6-disulfated chondroitin sulfate disaccharides and enhance collagen fibril formation. The effect on collagen assembly is proportional to the content of the 4,6- disulfated disaccharide in the different cartilage extracts, with growth plate cartilage glycosaminoglycan being the most efficient enhancer. These findings demonstrate a role for perlecan chondroitin sulfate side chains in cartilage extracellular matrix assembly and provide an explanation for the perlecan-null chondrodysplasia.
40.	Kvist, Anders, et al. (author) Energy expenditure in relation to flight speed : what is the power of mass loss rate estimates? 1998 In: Journal of Avian Biology. - : JSTOR. - 0908-8857. ; 29:4, s. 485-498 Journal article (peer-reviewed)
41.	Kvist, Anders (author) Fuel and fly: adaptations to endurance exercise in migrating birds 2001 Doctoral thesis (other academic/artistic)abstract Birds on migration alternate between consuming fuel stores during flights and accumulating fuel stores during stopovers. This thesis highlights some of the ways in which migrating birds have adapted to the different demands of fuelling and flight. Most of the time on migration is spent at stopover sites accumulating fuel stores. To minimise the total time spent on migration, birds should fuel up as fast as possible. I show that migrating birds have an exceptional energy assimilation capacity, enabling rapid accumulation of fuel stores. Migrating birds can increase their daily energy assimilation, and fuel accumulation rates, by utilizing a larger part of the day for foraging. There is also evidence for an adaptive flexibility in this digestive capacity and that digestive capacity can be built up rapidly following depletion of fuel stores due to flight. Fuel economy is crucial during long distance migratory flights. I present the first estimates of metabolic power, or rate of fuel consumption, for migratory birds performing sustained flight in a windtunnel. The way metabolic power increases with body mass in the red knot (Calidris canutus) indicate that the flight muscles are adapted for fuel efficiency in long flights with heavy fuel loads. Metabolic power curves and minimum power speeds for a thrush nightingale (Luscinia luscinia) and a teal (Anas crecca), estimated from mass loss rate, indicate that the drag of the birds bodies in flight is lower than previously thought. Fat is the main fuel for long migratory flights. I show that protein makes a significant contribution to the energy metabolism during sustained flights in the thrush nightingale. Net protein catabolism may reflect physiologically inevitable processes, may provide extra water to counteract dehydration during flight, or may reflect adaptive changes in the size of organs. Intraindividual variation in BMR, protein catabolism during flight and protein deposition during fuelling all indicate that migrants flexibly adapt their morphology and physiology to the different demands of fuelling and flight. Changes in pectoral muscle size of red knots may be an adaptation to maintain optimal flight performance when body mass varies. Maintaining heat balance in flying birds, especially at high ambient temperatures, can create problems with water balance. Red knots flying at lower ambient temperatures regulated dry heat loss and maintained water loss at a constant low level. At higher temperatures evaporative heat loss increased sharply, resulting in a net water loss. Maximum flight range in migrating birds imposed by energy and water budgets are predicted using an updated physiological computer model. Comparing the outcome of this model with experimental data indicate that the model predictions appear to be realistic but are associated with considerable uncertainties.
42.	Kvist, Anders, et al. (author) Gluttony in migratory waders - unprecedented energy assimilation rates in vertebrates 2003 In: Oikos. - : Wiley. - 1600-0706 .- 0030-1299. ; 103:2, s. 397-402 Journal article (peer-reviewed)abstract Maximum energy assimilation rate has been implicated as a constraint on maximal sustained energy expenditure, on biomass production, and in various behavioural and life history models. Data on the upper limit to energy assimilation rate are scarce, and the factors that set the limit remain poorly known. We studied migratory waders in captivity, given unlimited food supply around the clock. Many of these waders assimilated energy at rates of seven to ten times basal metabolism, exceeding maximum rates reported for vertebrates during periods of high energy demand, for example during reproduction and in extreme cold. One factor allowing the high energy assimilation rates may be that much of the assimilated energy is stored and not concomitantly expended by muscles or other organs. The remarkable digestive capacity in waders is probably an adaptation to long and rapid migrations, putting a premium on high energy deposition rates. The upper limit to daily energy assimilation in vertebrates is clearly higher than hitherto believed, and food availability, total daily feeding time and, possibly, the fate of assimilated energy may be important factors to take into account when estimating limits to energy budgets in animals.
43.	Kvist, Anders, et al. (author) Maximum daily energy intake: It takes time to lift the metabolic ceiling 2000 In: Physiological and Biochemical Zoology. - 1522-2152. ; 73:1, s. 30-36 Journal article (peer-reviewed)abstract Conventionally, maximum capacities for energy assimilation are presented as daily averages. However, maximum daily energy intake is determined by the maximum metabolizable energy intake rate and the time available for assimilation of food energy Thrush nightingales (Luscinia luscinia) in migratory disposition were given limited food rations for 3 d to reduce their energy stores. Subsequently, groups of birds were fed ad lib. during fixed time periods varying between 7 and 23 h per day. Metabolizable energy intake rate, averaged over the available feeding time, was 1.9 W and showed no difference between groups on the first day of refueling. Total daily metabolizable energy intake increased linearly with available feeding time, and for the 23-h group, it was well above suggested maximum levels for animals. We conclude that both intake rate and available feeding time must be taken into account when interpreting potential constraints acting on animals' energy budgets. In the 7-h group, energy intake rates increased from 1.9 W on the first day to 3.1 W on the seventh day. This supports the idea that small birds can adaptively increase their energy intake rates on a short timescale.
44.	Kvist, Anders, et al. (author) Promoter usage of BRCA1-IRIS 2005 In: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 7:4, s. 325-326 Journal article (other academic/artistic)
45.	Kvist, Alexander, et al. (author) The major basement membrane components localize to the chondrocyte pericellular matrix - A cartilage basement membrane equivalent? 2008 In: Matrix Biology. - : Elsevier BV. - 1569-1802 .- 0945-053X. ; 27:1, s. 22-33 Journal article (peer-reviewed)abstract In this study, we demonstrate that articular cartilage chondrocytes are surrounded by the defining basement membrane proteins laminin, collagen type IV, nidogen and perlecan, and suggest that these form the functional equivalent of a basement membrane. We found by real-time PCR that mouse chondrocytes express these four cardinal components of basement membranes and demonstrated by immunohistochemistry that the proteins are present in bovine and mouse cartilage tissues and are deposited in a thin pericellular structure. Immunoelectron microscopy confirmed high laminin concentration in the pericellular matrix. In cartilage from newborn mice, basement membrane components are widespread in the territorial and interterritorial matrix, while in mature cartilage of adult mice the basement membrane components are localized mainly to a narrow pericellular zone. With progression into old age, this layer becomes less distinct, especially in areas of obvious mechanical attrition. Interestingly, individual laminin subunits were located in different zones of the cartilage, with laminin α1 showing preferential localization around a select population of superficial layer chondrocytes. We propose that the chondrocyte, like several other cell types of mesenchymal origin, is surrounded by the functional equivalent of a basement membrane. This structure is presumably involved in maintaining chondrocyte phenotype and viability and may well allow a new understanding of cartilage development and provide clues to the progression of degenerative joint disorders.
46.	Kvist, Joanna, 1967-, et al. (author) Natural corollaries and recovery after acute ACL injury : The NACOX cohort study protocol 2018 In: BMJ Open. - : BMJ. - 2044-6055. ; 8:6 Journal article (peer-reviewed)abstract Introduction Anterior cruciate ligament (ACL) injury can result in joint instability, decreased functional performance, reduced physical activity and quality of life and an increased risk for post-traumatic osteoarthritis. Despite the development of new treatment techniques and extensive research, the complex and multifaceted nature of ACL injury and its consequences are yet to be fully understood. The overall aim of the NACOX study is to evaluate the natural corollaries and recovery after an ACL injury. Methods and analysis The NACOX study is a multicentre prospective prognostic cohort study of patients with acute ACL injury. At seven sites in Sweden, we will include patients aged 15-40 years, within 6 weeks after primary ACL injury. Patients will complete questionnaires at multiple occasions over the 3 years following injury or the 3 years following ACL reconstruction (for participants who have surgical treatment). In addition, a subgroup of 130 patients will be followed with clinical examinations, several imaging modalities and biological samples. Data analyses will be specific to each aim. Ethics and dissemination This study has been approved by the regional Ethical committee in Linköping, Sweden (Dnr 2016/44-31 and 2017/221-32). We plan to present the results at national and international conferences and in peer-reviewed scientific journals. Participants will receive a short summary of the results following completion of the study. Trial registration number NCT02931084.
47.	Kvist, Patric, 1985, et al. (author) A multi-scale model for diffusion of large molecules in steam-exploded wood 2020 In: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 54:4, s. 821-835 Journal article (peer-reviewed)abstract In this paper, multi-scale modeling was used to resolve diffusion in steam-exploded wood at tracheid scales including sub-micrometer features of bordered pits. Simulations were performed using the lattice Boltzmann method with high-resolution X-ray tomography image data as the input for the microstructure. The results show an effective method for utilizing a variable diffusion coefficient to implement two length scales. This circumvents the need to resolve the bordered pits in detail, which requires massive computing power. Instead, the effective diffusion coefficient for one bordered pit is used as input for this model. Results based on the present model are comparable to experimental data. This methodology can be extended to more structural features at the microscale of wood, such as latewood and the cell wall. Obtaining a map of different diffusion coefficients based on features and scale gives a better overall understanding of diffusion and the importance of mass transport with regard to the pretreatment of wood.
48.	Kvist, Patric, 1985, et al. (author) Lattice Boltzmann simulations of diffusion in steam-exploded wood 2019 In: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 53:4, s. 855-871 Journal article (peer-reviewed)abstract Diffusion of large molecules throughout the porous microstructure of wood pretreated with steam explosion was investigated by using the lattice Boltzmann method for simulations. Wood samples were investigated with high-resolution X-ray tomography to effectively reconstruct an accurate geometry of the structural changes that ensue after pretreatment. Samples of approximately 1mm(3) with voxel sizes from 0.5 to 1 mu m were examined with X-ray imaging. These large volumes, relative to what reasonably can be simulated, were divided into sub-volumes and were further reconstructed into geometries suited for the LBM simulations. The transient development of the concentration was investigated, and the effective diffusion coefficient at steady state was computed. Diffusion rates were found to increase significantly in the transversal direction due to the steam explosion pretreatment. The increase was observed both in the time needed for solutes to diffuse throughout the pores and in the effective diffusion coefficient. A shorter diffusion pathway and a higher connectivity between pores were found for the pretreated samples, even though the porosity was similar and the pore size distribution narrower than the native sample. These results show that local mass transport depends not only on porosity but also, in a complex manner, on pore structure. Thus, a more detailed analysis of pore space structure using tomography data, in combination with simulations, enables a more general understanding of the diffusional process.
49.	Kvist, Patric, 1985, et al. (author) Lattice Boltzmann simulations of diffusion through native and steam-exploded softwood bordered pits 2017 In: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 51:6, s. 1261-1276 Journal article (peer-reviewed)abstract Bordered pits connect adjacent tracheid cells in softwoods and enable water transport between them. Knowledge of how large molecules, such as polysaccharides and enzymes, are transported through pits is important to understand the extraction process of valuable biopolymers from wood. The main mass transport mechanism for large dissolved molecules in wood is diffusion, and this is investigated through mathematical modeling in the lattice Boltzmann framework utilizing SEM images and 3D reconstruction of an actual bordered pit to compute an effective diffusion coefficient. Confocal laser scanning microscopy is used to find the unobstructed diffusion coefficients in a free aqueous solution using fluorescent diffusion probes of dextran. The effect of steam explosion on pit structure is explored through the use of a simplified model. The importance of different components of a bordered pit is investigated using simulation data, and results show that the most important structural features are the borders. Expressions for the effective diffusion coefficient as a function of the free diffusion coefficient are presented for a native and for a steam-exploded pit, respectively.
50.	Kvist, Patric, et al. (author) Using fluorescent probes and FRAP to investigate macromolecule diffusion in steam-exploded wood 2018 In: Wood Science and Technology. - : Springer Science and Business Media LLC. - 0043-7719 .- 1432-5225. ; 52:5, s. 1395-1410 Journal article (peer-reviewed)abstract Diffusion of fluorescently labeled dextran of varying molecular weight in wood pretreated by steam explosion was studied with a confocal microscope. The steam explosion experiments were conducted at relatively mild conditions relevant for materials biorefinery at a pressure of 14 bars for 10 min. The method of fluorescence recovery after photobleaching (FRAP) was used to perform diffusion measurements locally in the wood microstructure. It was found that the FRAP methodology can be used to observe differences in the diffusion coefficient based on localization in the microstructure, i.e., earlywood, latewood, and cell wall. Microscopic changes due to steam explosion were seen to increase diffusion of the smaller 3-kDa dextran diffusion probe in the earlywood, while the latewood structure was not affected in any significant way. Macroscopic changes to the structure in the form of ruptures due to the steam explosion pretreatment were observed to increase the rate of diffusion for the larger 40-kDa dextran probe.

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