| 1. |
- Ahlgren, Kerstin M, et al.
(författare)
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Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8, s. e105473-
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS:Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.METHODS:Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.RESULTS:None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.CONCLUSIONS/INTERPRETATIONS:Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.
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| 2. |
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| 3. |
- Borge, Kaja Sverdrup, et al.
(författare)
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The ESR1 gene is associated with risk for canine mammary tumours
- 2013
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Ingår i: BMC Veterinary Research. - : Springer Science and Business Media LLC. - 1746-6148. ; 9, s. 69-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The limited within-breed genetic heterogeneity and an enrichment of disease-predisposing alleles have made the dog a very suitable model for the identification of genes associated with risk for specific diseases. Canine mammary cancer is an example of such a disease. However, the underlying inherited risk factors for canine mammary tumours (CMTs) are still largely unknown. In this study, 52 single nucleotide polymorphisms (SNPs) in ten human cancer-associated genes were genotyped in two different datasets in order to identify genes/alleles associated with the development of CMTs. The first dataset consisted of English Springer Spaniel (ESS) CMT cases and controls. ESS is a dog breed known to be at increased risk of developing CMTs. In the second dataset, dogs from breeds known to have a high frequency of CMTs were compared to dogs from breeds with a lower occurrence of these tumours. Results: We found significant associations to CMT for SNPs and haplotypes in the estrogen receptor 1 (ESR1) gene in the ESS material (best P-Bonf = 0.021). A large number of SNPs, among them several SNPs in ESR1, showed significantly different allele frequencies between the high and low risk breed groups (best P-Bonf = 8.8E-32, best P-BPerm = 0.076). Conclusions: The identification of CMT-associated SNPs in ESR1 in two independent datasets suggests that this gene might be involved in CMT development. These findings also support that CMT may serve as a good model for human breast cancer research.
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| 4. |
- Karlsson, Elinor K, et al.
(författare)
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Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B
- 2013
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X .- 1474-7596. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible.RESULTS: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors.CONCLUSIONS: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.
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| 5. |
- Rivera, Patricio, et al.
(författare)
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Mammary tumor development in dogs is associated with BRCA1 and BRCA2
- 2009
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 69:22, s. 8770-8774
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a major contributor to overall morbidity and mortality in women. Several genes predisposing to breast cancer have been identified, but the majority of risk factors remain unknown. Even less is known about the inherited risk factors underlying canine mammary tumors (CMT). Clear breed predispositions exist, with 36% of English springer spaniels (ESS) in Sweden being affected. Here, we evaluate 10 human breast cancer genes (BRCA1, BRCA2, CHEK2, ERBB2, FGFR2, LSP1, MAP3K1, RCAS1, TOX3, and TP53) for association with CMTs. Sixty-three single-nucleotide polymorphisms (SNPs; four to nine SNPs per gene) were genotyped by iPLEX in female ESS dogs, 212 CMT cases and 143 controls. Two genes, BRCA1 and BRCA2, were significantly associated with CMT (Bonferroni corrected P = 0.005 and P = 0.0001, respectively). Borderline association was seen for FGFR2. Benign and malignant cases were also analyzed separately. Those findings supported the association to BRCA1 and BRCA2 but with a stronger association to BRCA1 in malignant cases. Both BRCA1 and BRCA2 showed odds ratios of approximately 4. In conclusion, this study indicates that BRCA1 and BRCA2 contribute to the risk of CMT in ESS, suggesting that dogs may serve as a good model for human breast cancer.
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| 6. |
- Stalhandske, Per, et al.
(författare)
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Homogeneous assay for real-time and simultaneous detection of thymidine kinase 1 and deoxycytidine kinase activities
- 2013
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 432:2, s. 155-164
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Tidskriftsartikel (refereegranskat)abstract
- Measurement of thymidine kinase-1 (TK1) and deoxycytidine kinase (dCK) activity may be useful in cancer disease management. Therefore, a one-step homogeneous assay for real-time determination of TK1 and dCK was developed by combining enzyme complementation with fluorescent signal generation using primer extension and a quenched probe oligodeoxyribonucleotide system at 37 degrees C. Complementation, for producing dCTP and TIP from nucleoside substrates, was carried out by dTMP kinase and/or UMP/CMP kinase and nucleoside diphosphate kinase. dNTP was continuously incorporated into a fixed oligodeoxyribonucleotide primer, template, and probe system, and the fluorescent signal was generated by using the combined actions of primer extension and 5' exonuclease activity of Thermophilus aquaticus (Taq) DNA polymerase for specific relief of fluorescent quenching. Fluorescence was captured at 1-min intervals using a real-time polymerase chain reaction (PCR) instrument. A horizontal threshold line, crossing all sample relative fluorescent units (RFU) values at the level of the RFU of the blank sample at the end of the assay (i.e., 90 min), was drawn, obtaining RFU measurement data in minutes for each sample. Duplex proof of principle was demonstrated by the independent determination of different amounts of dCK and TK1 in combination. R-2 values of 0.90 were demonstrated with Prolifigen TK-REA U/L reference values obtained from pathological canine and human serum samples.
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| 7. |
- Westberg, Sara, et al.
(författare)
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Treatment Efficacy and Immune Stimulation by AdCD40L Gene Therapy of Spontaneous Canine Malignant Melanoma
- 2013
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Ingår i: Journal of immunotherapy (1997). - 1524-9557 .- 1537-4513. ; 36:6, s. 350-358
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Tidskriftsartikel (refereegranskat)abstract
- Malignant melanoma is a serious disease in both humans and dogs, and the high metastatic potential results in poor prognosis for many patients. Its similarities with human melanoma make spontaneous canine melanoma an excellent model for comparative studies of novel therapies and tumor biology. We report a pilot study of local adenovector CD40L (AdCD40L) immunogene treatment in 19 cases of canine melanoma (14 oral, 4 cutaneous, and 1 conjunctival). Three patients were World Health Organization stage I, 2 were stage II, 10 stage III, and 4 stage IV. One to 6 intratumoral injections of AdCD40L were given every 7 days, followed by cytoreductive surgery in 9 cases and only immunotherapy in 10 cases. Tumor tissue was infiltrated with T and B lymphocytes after treatment, suggesting immune stimulation. The best overall response included 5 complete responses, 8 partial responses, and 4 stable and 2 progressive disease statuses according to the World Health Organization response criteria. Median survival was 160 days (range, 20-1141 d), with 3 dogs still alive at submission. Our results suggest that local AdCD40L therapy is safe and could have beneficial effects in dogs, supporting further treatment development. Clinical translation to human patients is in progress.
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| 8. |
- Arendt, Maja Louise, et al.
(författare)
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PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia
- 2023
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Ingår i: Scientific Reports. - : Springer Nature. - 2045-2322. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Biological features of neoplastic disease affecting mammary gland tissue are shared between canines and humans. Research performed in either species has translational value and early phase clinical trials performed in canines with spontaneous disease could be informative for human trials. The purpose of this study was to investigate the somatic genetic aberrations occurring in canine mammary neoplasia by exome capture and next generation sequencing. Based on 55 tumor-normal pairs we identified the PIK3CA gene as the most commonly mutated gene in canine mammary tumors, with 25% of samples carrying mutations in this gene. A recurrent missense mutation was identified, p.H1047R, which is homologous to the human PIK3CA hotspot mutation found in different types of breast neoplasia. Mutations homologous to other known human mutation hotspots such as the PIK3CA p.E545K and the KRAS p.G12V/D were also identified. We identified copy number aberrations affecting important tumor suppressor and oncogenic pathways including deletions affecting the PTEN tumor suppressor gene. We suggest that activation of the KRAS or PIK3CA oncogenes or loss of the PTEN suppressor gene may be important for mammary tumor development in dogs. This data endorses the conservation of cancer across species and the validity of studying cancer in non-human species.
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| 9. |
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| 10. |
- Berlin Kolm, Sofia, et al.
(författare)
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Genetic diversity, population structure and phenotypic variation in European Salix viminalis L. (Salicaceae)
- 2014
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Ingår i: Tree Genetics & Genomes. - : Springer Science and Business Media LLC. - 1614-2942 .- 1614-2950. ; 10:6, s. 1595-1610
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the potential of association genetics for willow breeding, Salix viminalis germplasm was assembled from UK and Swedish collections (comprising accessions from several European countries) and new samples collected from nature. A subset of the germplasm was planted at two sites (UK and Sweden), genotyped using 38 SSR markers and assessed for phenological and biomass traits. Population structure, genetic differentiation (F-ST) and quantitative trait differentiation (Q(ST)) were investigated. The extent and patterns of trait adaptation were assessed by comparing F-ST and Q(ST) parameters. Of the 505 genotyped diploid accessions, 27 % were not unique. Genetic diversity was high: 471 alleles was amplified; the mean number of alleles per locus was 13.46, mean observed heterozygosity was 0.55 and mean expected heterozygosity was 0.62. Bayesian clustering identified four subpopulations which generally corresponded to Western Russia, Western Europe, Eastern Europe and Sweden. All pairwise F-ST values were highly significant (p<0.001) with the greatest genetic differentiation detected between the Western Russian and the Western European subpopulations (F-ST = 0.12), and the smallest between the Swedish and Eastern European populations (F-ST = 0.04). The Swedish population also had the highest number of identical accessions, supporting the view that S. viminalis was introduced into this country and has been heavily influenced by humans. Q(ST) values were high for growth cessation and leaf senescence, and to some extent stem diameter, but low for bud burst time and shoot number. Overall negative clines between longitudinal coordinates and leaf senescence, bud burst and stem diameter were also found.
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| 11. |
- Berlin Kolm, Sofia, et al.
(författare)
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Genetics of phenotypic plasticity and biomass traits in hybrid willows across contrasting environments and years
- 2017
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Ingår i: Annals of Botany. - : Oxford University Press (OUP). - 0305-7364 .- 1095-8290. ; 120, s. 87-100
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Phenotypic plasticity can affect the geographical distribution of taxa and greatly impact the productivity of crops across contrasting and variable environments. The main objectives of this study were to identify genotype-phenotype associations in key biomass and phenology traits and the strength of phenotypic plasticity of these traits in a short-rotation coppice willow population across multiple years and contrasting environments to facilitate marker-assisted selection for these traits.Methods A hybrid Salix viminalis x (S. viminalis x Salix schwerinii) population with 463 individuals was clonally propagated and planted in three common garden experiments comprising one climatic contrast between Sweden and Italy and one water availability contrast in Italy. Several key phenotypic traits were measured and phenotypic plasticity was estimated as the trait value difference between experiments. Quantitative trait locus (QTL) mapping analyses were conducted using a dense linkage map and phenotypic effects of S. schwerinii haplotypes derived from detected QTL were assessed.Key Results Across the climatic contrast, clone predictor correlations for biomass traits were low and few common biomass QTL were detected. This indicates that the genetic regulation of biomass traits was sensitive to environmental variation. Biomass QTL were, however, frequently shared across years and across the water availability contrast. Phenology QTL were generally shared between all experiments. Substantial phenotypic plasticity was found among the hybrid offspring, that to a large extent had a genetic origin. Individuals carrying influential S. schwerinii haplotypes generally performed well in Sweden but less well in Italy in terms of biomass production.Conclusions The results indicate that specific genetic elements of S. schwerinii are more suited to Swedish conditions than to those of Italy. Therefore, selection should preferably be conducted separately for such environments in order to maximize biomass production in admixed S. viminalis x S. schwerinii populations.
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| 12. |
- Bernstein, Joshua G, et al.
(författare)
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Spectrotemporal modulation sensitivity as a predictor of speech intelligibility in noise with hearing aids
- 2014
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Ingår i: Spectrotemporal modulation sensitivity as a predictor of speech intelligibility in noise with hearing aids.
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Konferensbidrag (refereegranskat)abstract
- The audiogram predicts less than a third of the variance in speech reception thresholds (SRTs) for hearing-impaired (HI) listeners properly fit with individualized frequency-dependent gain. The remaining variance is often attributed to a combination of su-prathreshold distortion in the auditory pathway and non-auditory factors such as cogni-tive processing. Distinguishing between these factors requires a measure of suprathresh-old auditory processing to account for the non-cognitive contributions. Preliminary re-sults in 12 HI listeners identified a correlation between spectrotemporal modulation (STM) sensitivity and speech intelligibility in noise presented over headphones. The cur-IHCON 2014 27 August 13-17, 2014rent study assessed the effectiveness of STM sensitivity as a measure of suprathreshold auditory function to predict free-field SRTs in noise for a larger group of 47 HI listeners with hearing aids.SRTs were measured for Hagerman sentences presented at 65 dB SPL in stationary speech-weighted noise or four-talker babble. Pre-recorded speech and masker stimuli were played through a small anechoic chamber equipped with a master hearing aid pro-grammed with individualized gain. The output from an IEC711 Ear Simulator was played binaurally through insert earphones. Three processing algorithms were examined: linear gain, linear gain plus noise reduction, or fast-acting compressive gain.STM stimuli consist of spectrally-rippled noise with spectral-peak frequencies that shift over time. STM with a 2-cycle/octave spectral-ripple density and a 4-Hz modulation rate was applied to a 2-kHz lowpass-filtered pink-noise carrier. Stimuli were presented over headphones at 80 dB SPL (±5-dB roving). The threshold modulation depth was estimated adaptively in a two-alternative forced-choice task.STM sensitivity was strongly correlated (R2=0.48) with the global SRT (i.e., the SRTs averaged across masker and processing conditions). The high-frequency pure-tone aver-age (3-8 kHz) and age together accounted for 23% of the variance in global SRT. STM sensitivity accounted for an additional 28% of the variance in global SRT (total R2=0.51) when combined with these two other metrics in a multiple-regression analysis. Correla-tions between STM sensitivity and SRTs for individual conditions were weaker for noise reduction than for the other algorithms, and marginally stronger for babble than for sta-tionary noise.The results are discussed in the context of previous work suggesting that STM sensitivity for low rates and low carrier frequencies is impaired by a reduced ability to use temporal fine-structure information to detect slowly shifting spectral peaks. STM detection is a fast, simple test of suprathreshold auditory function that accounts for a substantial pro-portion of variability in hearing-aid outcomes for speech perception in noise.
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| 13. |
- Bernstein, Joshua G. W., et al.
(författare)
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Spectrotemporal Modulation Sensitivity as a Predictor of Speech-Reception Performance in Noise With Hearing Aids
- 2016
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Ingår i: TRENDS IN HEARING. - : SAGE PUBLICATIONS INC. - 2331-2165. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- The audiogram predicts amp;lt;30% of the variance in speech-reception thresholds (SRTs) for hearing-impaired (HI) listeners fitted with individualized frequency-dependent gain. The remaining variance could reflect suprathreshold distortion in the auditory pathways or nonauditory factors such as cognitive processing. The relationship between a measure of suprathreshold auditory function-spectrotemporal modulation (STM) sensitivity-and SRTs in noise was examined for 154 HI listeners fitted with individualized frequency-specific gain. SRTs were measured for 65-dB SPL sentences presented in speech-weighted noise or four-talker babble to an individually programmed master hearing aid, with the output of an ear-simulating coupler played through insert earphones. Modulation-depth detection thresholds were measured over headphones for STM (2cycles/octave density, 4-Hz rate) applied to an 85-dB SPL, 2-kHz lowpass-filtered pink-noise carrier. SRTs were correlated with both the high-frequency (2-6 kHz) pure-tone average (HFA; R-2 = .31) and STM sensitivity (R-2 = .28). Combined with the HFA, STM sensitivity significantly improved the SRT prediction (Delta R-2 = .13; total R-2 = .44). The remaining unaccounted variance might be attributable to variability in cognitive function and other dimensions of suprathreshold distortion. STM sensitivity was most critical in predicting SRTs for listenersamp;lt;65 years old or with HFA amp;lt;53 dB HL. Results are discussed in the context of previous work suggesting that STM sensitivity for low rates and low-frequency carriers is impaired by a reduced ability to use temporal fine-structure information to detect dynamic spectra. STM detection is a fast test of suprathreshold auditory function for frequencies amp;lt;2 kHz that complements the HFA to predict variability in hearing-aid outcomes for speech perception in noise.
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| 14. |
- Blomberg, Rina, et al.
(författare)
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Aberrant resting-state connectivity of auditory, ventral attention/salience and default-mode networks in adults with attention deficit hyperactivity disorder
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background Numerous resting-state studies on attention deficit hyperactivity disorder (ADHD) have reported aberrant functional connectivity (FC) between the default-mode network (DMN) and the ventral attention/salience network (VA/SN). This finding has commonly been interpreted as an index of poorer DMN regulation associated with symptoms of mind wandering in ADHD literature. However, a competing perspective suggests that dysfunctional organization of the DMN and VA/SN may additionally index increased sensitivity to the external environment. The goal of the current study was to test this latter perspective in relation to auditory distraction by investigating whether ADHD-adults exhibit aberrant FC between DMN, VA/SN, and auditory networks. Methods Twelve minutes of resting-state fMRI data was collected from two adult groups: ADHD (n = 17) and controls (n = 17); from which the FC between predefined regions comprising the DMN, VA/SN, and auditory networks were analyzed. Results A weaker anticorrelation between the VA/SN and DMN was observed in ADHD. DMN and VA/SN hubs also exhibited aberrant FC with the auditory network in ADHD. Additionally, participants who displayed a stronger anticorrelation between the VA/SN and auditory network at rest, also performed better on a cognitively demanding behavioral task that involved ignoring a distracting auditory stimulus. Conclusion Results are consistent with the hypothesis that auditory distraction in ADHD is linked to aberrant interactions between DMN, VA/SN, and auditory systems. Our findings support models that implicate dysfunctional organization of the DMN and VA/SN in the disorder and encourage more research into sensory interactions with these major networks.
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| 15. |
- Blomberg, Rina, 1974-
(författare)
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Auditory Distraction in ADHD : From Behaviour to the Brain
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- ADHD is a heterogenous disorder encompassing neurodevelopmental deficits in cognitive control. Auditory distraction is a common clinically reported symptom in ADHD, yet empirical research investigating the manifestation of auditory distraction in the disorder is remarkably scarce. Findings from cognitive hearing science highlight the crucial role cognitive control plays in an individual’s ability to gate, attenuate and/or compensate for auditory distraction. However the field is yet to extensively test hypotheses in normal hearing populations with neurodevelopmental deficits in cognitive control such as ADHD. This thesis contributes to narrowing the gap within these two fields of research by studying auditory distraction in this clinical population to a greater extent than previous reports in the literature.Using a combination of both behavioural and neuroimaging methods, the research presented here was able to show that adults and adolescents with ADHD are inherently more susceptible to auditory distraction than their non-ADHD counterparts. At the behavioural level, impaired task performance due to auditory distraction was more likely to manifest in ADHD participants when the working memory system was under high processing load. At the neural level, functional aberrancy in auditory attention was evident at early stages of sensory processing in a variety of tasks, implicating both exogenous and endogenous control systems in ADHD. Furthermore, the distribution of ADHD-symptom severity across participants was shown to correlate with increases in both cortical activity to auditory distractors and intrinsic functional connectivity between auditory and exogenous attention networks.In line with evidence from cognitive hearing science, the general findings of this thesis demonstrate that cognitive control plays an important role in the ability to perceive sound under suboptimal listening conditions and hamper distraction. In addition, findings challenge theories of ADHD that question the extent in which sensory-related attentional control is impaired. More empirical research on the auditory modality in ADHD is therefore encouraged in order to revise models, improve diagnostic tools, and develop evidence-based interventions targeting study/work environments.
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| 16. |
- Blomberg, Rina, et al.
(författare)
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Speech Processing Difficulties in Attention Deficit Hyperactivity Disorder
- 2019
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Ingår i: Frontiers in Psychology. - : FRONTIERS MEDIA SA. - 1664-1078. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The large body of research that forms the ease of language understanding (ELU) model emphasizes the important contribution of cognitive processes when listening to speech in adverse conditions; however, speech-in-noise (SIN) processing is yet to be thoroughly tested in populations with cognitive deficits. The purpose of the current study was to contribute to the field in this regard by assessing SIN performance in a sample of adolescents with attention deficit hyperactivity disorder (ADHD) and comparing results with age-matched controls. This population was chosen because core symptoms of ADHD include developmental deficits in cognitive control and working memory capacity and because these top-down processes are thought to reach maturity during adolescence in individuals with typical development. The study utilized natural language sentence materials under experimental conditions that manipulated the dependency on cognitive mechanisms in varying degrees. In addition, participants were tested on cognitive capacity measures of complex working memory-span, selective attention, and lexical access. Primary findings were in support of the ELU-model. Age was shown to significantly covary with SIN performance, and after controlling for age, ADHD participants demonstrated greater difficulty than controls with the experimental manipulations. In addition, overall SIN performance was strongly predicted by individual differences in cognitive capacity. Taken together, the results highlight the general disadvantage persons with deficient cognitive capacity have when attending to speech in typically noisy listening environments. Furthermore, the consistently poorer performance observed in the ADHD group suggests that auditory processing tasks designed to tax attention and working memory capacity may prove to be beneficial clinical instruments when diagnosing ADHD.
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| 17. |
- Blomberg, Rina, et al.
(författare)
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The Effects of Working Memory Load on Auditory Distraction in Adults With Attention Deficit Hyperactivity Disorder
- 2021
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Ingår i: Frontiers in Human Neuroscience. - : Frontiers Media SA. - 1662-5161. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Cognitive control provides us with the ability to inter alia, regulate the locus of attention and ignore environmental distractions in accordance with our goals. Auditory distraction is a frequently cited symptom in adults with attention deficit hyperactivity disorder (aADHD)-yet few task-based fMRI studies have explored whether deficits in cognitive control (associated with the disorder) impedes on the ability to suppress/compensate for exogenously evoked cortical responses to noise in this population. In the current study, we explored the effects of auditory distraction as function of working memory (WM) load. Participants completed two tasks: an auditory target detection (ATD) task in which the goal was to actively detect salient oddball tones amidst a stream of standard tones in noise, and a visual n-back task consisting of 0-, 1-, and 2-back WM conditions whilst concurrently ignoring the same tonal signal from the ATD task. Results indicated that our sample of young aADHD (n = 17), compared to typically developed controls (n = 17), had difficulty attenuating auditory cortical responses to the task-irrelevant sound when WM demands were high (2-back). Heightened auditory activity to task-irrelevant sound was associated with both poorer WM performance and symptomatic inattentiveness. In the ATD task, we observed a significant increase in functional communications between auditory and salience networks in aADHD. Because performance outcomes were on par with controls for this task, we suggest that this increased functional connectivity in aADHD was likely an adaptive mechanism for suboptimal listening conditions. Taken together, our results indicate that aADHD are more susceptible to noise interference when they are engaged in a primary task. The ability to cope with auditory distraction appears to be related to the WM demands of the task and thus the capacity to deploy cognitive control.
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| 18. |
- Carney, Daniel P. J., et al.
(författare)
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Using developmental trajectories to examine verbal and visuospatial short-term memory development in children and adolescents with Williams and Down syndromes
- 2013
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Ingår i: Research in Developmental Disabilities. - : Elsevier. - 0891-4222 .- 1873-3379. ; 34:10, s. 3421-3432
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Tidskriftsartikel (refereegranskat)abstract
- Williams (WS) and Down (DS) syndromes have been associated with specifically compromised short-term memory (STM) subsystems. Individuals with WS have shown impairments in visuospatial STM, while individuals with DS have often shown problems with the recall of verbal material. However, studies have not usually compared the development of STM skills in these domains, in these populations. The present study employed a cross-sectional developmental trajectories approach, plotting verbal and visuospatial STM performance against more general cognitive and chronological development, to investigate how the domain-specific skills of individuals with WS and DS may change as development progresses, as well as whether the difference between STM skill domains increases, in either group, as development progresses. Typically developing children, of broadly similar cognitive ability to the clinical groups, were also included. Planned between- and within-group comparisons were carried out. Individuals with WS and DS both showed the domain-specific STM weaknesses in overall performance that were expected based on the respective cognitive profiles. However, skills in both groups developed, according to general cognitive development, at similar rates to those of the TD group. In addition, no significant developmental divergence between STM domains was observed in either clinical group according to mental age or chronological age, although the general pattern of findings indicated that the influence of the latter variable across STM domains, particularly in WS, might merit further investigation.
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| 19. |
- Cunningham, Janet, et al.
(författare)
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Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in the Serum and Cerebrospinal Fluid of Patients With Coronavirus Disease 2019 and Neurological Symptoms
- 2022
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 225:6, s. 965-970
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Tidskriftsartikel (refereegranskat)abstract
- Antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in serum and cerebrospinal fluid (CSF) samples from 16 patients with coronavirus disease 2019 and neurological symptoms were assessed using 2 independent methods. Immunoglobulin G (IgG) specific for the virus spike protein was found in 81% of patients in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in 2 patients with negative serological findings. Levels of IgG in both serum and CSF were associated with disease severity (P < .05). All patients with elevated markers of central nervous system damage in CSF also had CSF antibodies (P = .002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 20. |
- Cunningham, Janet L, et al.
(författare)
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Anti-SARS-CoV2 antibody responses in serum and cerebrospinal fluid of COVID-19 patients with neurological symptoms.
- 2022
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Ingår i: The Journal of infectious diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 225:6, s. 965-970
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Tidskriftsartikel (refereegranskat)abstract
- Antibody responses to SARS-CoV-2 in serum and CSF from 16 COVID-19 patients with neurological symptoms were assessed using two independent methods. IgG specific for the virus spike protein was found in 81% of cases in serum and in 56% in CSF. SARS-CoV-2 IgG in CSF was observed in two cases with negative serology. Levels of IgG in both serum and CSF were associated with disease severity (p<0.05). All patients with elevated markers of CNS damage in CSF also had CSF antibodies (p=0.002), and CSF antibodies had the highest predictive value for neuronal damage markers of all tested clinical variables.
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| 21. |
- Dahlström, Örjan, 1973-, et al.
(författare)
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The applied value of collaborative memory research in aging – Some critical comments
- 2013
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Ingår i: Journal of Applied Research in Memory and Cognition. - : Elsevier. - 2211-3681 .- 2211-369X. ; 2:2, s. 122-123
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The article by Blumen, Rajaram, and Henkel (2013) raises some very interesting research topics. Using the aging population as the prime example, they also provide general recommendations for future research in the area of collaborative memory; ‘it's time to become more applied’, and we appreciate such a suggestion.The article spans many subfields and for obvious reasons, it is not possible to consider every potential issue in this field in one single article. In addition, there are several issues that could be either extended or added. We will in this commentary focus on issues we consider important for the understanding of the current literature, and we will add some from our own research.
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| 22. |
- Danielsson, Henrik, et al.
(författare)
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Developmental delays in phonological recoding among children and adolescents with Down syndrome and Williams syndrome
- 2016
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Ingår i: Research in Developmental Disabilities. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0891-4222 .- 1873-3379. ; 55, s. 64-76
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Tidskriftsartikel (refereegranskat)abstract
- This study examined the development of phonological recoding in short-term memory (STM) span tasks among two clinical groups with contrasting STM and language profiles: those with Down syndrome (DS) and Williams syndrome (WS). Phonological recoding was assessed by comparing: (1) performance on phonologically similar and dissimilar items (phonological similarity effects, PSE); and (2) items with short and long names (word length effects, WLE). Participant groups included children and adolescents with DS (n = 29), WS (n = 25) and typical development (n = 51), all with average mental ages around 6 years. The group with WS, contrary to predictions based on their relatively strong verbal STM and language abilities, showed no evidence for phonological recoding. Those in the group with DS, with weaker verbal STM and language abilities, showed positive evidence for phonological recoding (PSE), but to a lesser degree than the typical group (who showed PSE and WLE). These findings provide new information about the memory systems of these groups of children and adolescents, and suggest that STM processes involving phonological recoding do not fit with the usual expectations of the abilities of children and adolescents with WS and DS. (c) 2016 Elsevier Ltd. All rights reserved.
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| 23. |
- Danielsson, Henrik, et al.
(författare)
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Different Associations between Auditory Function and Cognition Depending on Type of Auditory Function and Type of Cognition
- 2019
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Ingår i: Ear and Hearing. - : LIPPINCOTT WILLIAMS & WILKINS. - 0196-0202 .- 1538-4667. ; 40:5, s. 1210-1219
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Previous studies strongly suggest that declines in auditory threshold can lead to impaired cognition. The aim of this study was to expand that picture by investigating how the relationships between age, auditory function, and cognitive function vary with the types of auditory and cognitive function considered. Design: Three auditory constructs (threshold, temporal-order identification, and gap detection) were modeled to have an effect on four cognitive constructs (episodic long-term memory, semantic long-term memory, working memory, and cognitive processing speed) together with age that could have an effect on both cognitive and auditory constructs. The model was evaluated with structural equation modeling of the data from 213 adults ranging in age from 18 to 86 years. Results: The model provided good a fit to the data. Regarding the auditory measures, temporal-order identification had the strongest effect on the cognitive functions, followed by weaker indirect effects for gap detection and nonsignificant effects for threshold. Regarding the cognitive measures, the association with audition was strongest for semantic long-term memory and working memory but weaker for episodic long-term memory and cognitive speed. Age had a very strong effect on threshold and cognitive speed, a moderate effect on temporal-order identification, episodic long-term memory, and working memory, a weak effect on gap detection, and nonsignificant, close to zero effect on semantic long-term memory. Conclusions: The result shows that auditory temporal-order function has the strongest effect on cognition, which has implications both for which auditory concepts to include in cognitive hearing science experiments and for practitioners. The fact that the total effect of age was different for different aspects of cognition and partly mediated via auditory concepts is also discussed.
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| 24. |
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| 25. |
- Danielsson, Henrik, et al.
(författare)
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Executive Functions in Children with Intellectual Disabilities
- 2010
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Konferensbidrag (refereegranskat)abstract
- Executive functions have been assessed in children with intellectual disabilities (ID) in relatively few previous studies. Most have reported that children with ID perform on a par with mental age-matched controls, but there is at least one report of even greater impairment. However, no previous research has used a broad range of executive measures, systematically varying in terms of verbal and visuospatial demands. In the present study, tests of 5 different sub components of executive functions were included: updating, shifting, fluency, problem solving and inhibition. Each component was assessed with one verbal and one nonverbal test. Preliminary results from 17 children with ID, mental age- (MA) and chronological age-matched (CA) comparison groups revealed different levels of impairment on different tests. The performance for the ID group ranged from CA-appropriate, to below MA level. These results emphasize the importance of using a wide range of tests of executive function to better understand the extent of the difficulties in children with ID.
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| 26. |
- Danielsson, Henrik, et al.
(författare)
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Executive functions in individuals with intellectual disability
- 2010
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Ingår i: Research in Developmental Disabilities. - : Elsevier BV. - 0891-4222 .- 1873-3379. ; 31:6, s. 1299-1304
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of the present study was to investigate executive functions in adults with intellectual disability, and compare them to a closely matched control group longitudinally for 5 years. In the Betula database, a group of adults with intellectual disability (ID, n = 46) was defined from measures of verbal and non-verbal IQ. A control group, with two people for every person with intellectual disability (n = 92), was chosen by matching on the following criterion in order of priority: IQ higher than 85, age, sex, sample, level of education, and years of education. Three types of tasks of executive functions were included on two occasions, with 5 years between testing sessions: The Tower of Hanoi,. executively loaded dual task versions of word recall, and verbal fluency. Adults with ID showed significant impairments on verbal fluency and on the executively loaded dual task word recall task (at encoding but not at recall). There were no group differences on the Tower of Hanoi. No significant differences between the two test occasions were found. The results are interpreted in terms of individuals with ID having problems with speed of accessing lexical items and difficulties with working memory-related executive control at encoding, which includes shifting between tasks. There are, however, not necessarily problems with inhibition. The dual task results additionally imply that the adults with intellectual disability were more sensitive to strategy interruptions at encoding, but that dividing attention at recall did not have such detrimental effects.
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| 27. |
- Danielsson, Henrik, 1974-
(författare)
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Facing the Illusion Piece by Piece : Face Recognition for Persons with Learning Disability
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Avhandlingens övergripande syfte var att undersöka ansiktsigenkänning för personer med och utan utvecklingsstörning. Tre specifika forskningsfrågor undersöktes:1. Hur ser interaktionen ut mellan familjaritet med ansikten och familjaritet med miljöer när det gäller bildigenkänning för personer med utvecklingsstörning?2. Kan någon av de 2 teoretiska ansatserna till förklaring av falska minnen (sammanblandning av olika minnen), bindingsansatsen och dubbelprocessansatsen, förklara prestationen för både personer med och utan utvecklingsstörning?3. Hur förhåller sig arbetsminnesförmåga till prestation i studier av falska minnen?Resultaten i de 4 artiklarna som ingår i avhandlingen gav svar på frågorna:1. Interaktionen mellan familjaritet med personer och miljöer kan förklaras med förhållandet mellan personen och miljön, som antingen kan vara frånvarande, närvarande eller osannolikt. Dessa semantiska relationer bestämmer prestationen och en ”lat” semantisk strategi föreslogs.2. Beroende på uppgiftens svårighetsgrad framkom olika interaktionsmönster mellan grupp och typ av igenkänningsbild, och då särskilt olika antal sammanblandade bilder. Dessa mönster kunde inte förklaras av någon av de 2 teoretisk ansatserna. Därför föreslås ett nytt sätt att tolka resultaten som inkluderar arbetsminne.3. Hög arbetsminneskapacitet gav 2 effekter: för det första, igenkänning av fler ansiktsdelar, och för det andra, igenkänning av fler ansiktskonfigurationer. Vid höga arbetsminneskrav så används den första effekten mer på bekostnad av den andra.Det visade sig också att prestationen för personer med utvecklingsstörning på uppgifter med låga arbetsminneskrav liknade prestationen för åldermatchade kontrollpersoner utan utvecklingsstörning på uppgifter med höga arbetsminneskrav. Detta indikerar att utvecklingsstörning kan ”simuleras” genom högre arbetsminneskrav, åtminstone på denna typ av igenkänningsuppgifter. Resultatens implikationer för vittnespsykologi och användandet av fotografier som kognitivt stöd diskuteras.
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| 28. |
- Danielsson, Henrik, et al.
(författare)
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Get better social skills : Computerized theory of mind training for children with intellectual disability
- 2008
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Ingår i: XXIX International Congress Of Psychology, Berlin, 2008. - : Taylor & Francis Group. - 9781841698601 ; , s. 490-490
-
Konferensbidrag (refereegranskat)abstract
- The effect of a computerized theory of mind training program was investigated in children with intellectual disability with a mean age of 12 years. The training time was 15 minutes every school day for 5 weeks and took place in the participant’s school. Compared to an age matched control group with intellectual disability, who performed computerized training not related to theory of mind, there were training effects for some theory of mind measures, but not for all. The results are promising and form a basis for further research.
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| 29. |
- Danielsson, Henrik, 1974-, et al.
(författare)
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Handikappvetenskap
- 2009
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Annan publikation (populärvet., debatt m.m.)
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| 30. |
- Danielsson, Henrik, et al.
(författare)
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Improved MindReading : The Relationship between Theory of Mind, Working Memory and Literacy.
- 2009
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The first aim of this study was to investigate the links between literacy, working memory and theory of mind in children with intellectual disability. Earlier studies have demonstrated these relationships in typically developing children.This was investigated in 48 children with intellectual disability (mental age = 6:7 years, chronological age = 12:4 years). Mental age was assessed with the block design test of the WISC-III, i.e. the Swedish version of the WISC-R. Working memory was tested with six tests (digit span forward and backward, listening span with and without dual task, clown span [visuospatial test where participants had to recall placement of dots put on a drawing of a clown. The test was an adaption of the “Mr Peanut”-test.] with and without dual task). Theory of mind was tested with 6 tests (Sally Anne test of 1st and 2nd order theory of mind, own developed tests to minimize working memory load on the theory of mind task for 1st and 2nd order theory of mind, irony, and social blunders). Literacy was tested with 3 tests (comprehension of written words, comprehension of written sentences, and comprehension of written stories).Factor analyses was made for the three concepts (working memory, theory of mind, and literacy) and the following factors were found: visuospatial working memory (loading on clown span with and without dual task), phonological working memory (loading on digit span and listening span both with and without dual task), Sally Anne theory of mind (loading on Sally Anne tests of 1st and 2nd order theory of mind), working memory free theory of mind (loading on own developed for 1st and 2nd order theory of mind), Advanced theory of mind (loading on own developed tests of irony, and social blunders), Literacy (loading on comprehension of written words and comprehension of written sentences. Comprehension of written stories did not load on the factor). There are intercorrelations between working memory, theory of mind, and Literacy, but not for all factors of all variables. All intercorrelations between the factors are shown in Table 1.Table 1. Intercorrelations between six variables of working memory (WM), theory of mind (ToM) and literacy: Visuospatial working memory, phonological working memory, Sally Anne theory of mind, working memory free theory of mind, advanced theory of mind and literacy. The six variables were created through factor analysis.* Correlation significant at the 0.05 level (onetailed). ** Correlation significant at the 0.01 level (onetailed).The second aim of this study was to examine if training of theory of mind also would improve literacy. A computerized theory of mind training program was developed. The program showed social situations (with pictures and speech) and the trainee had to chose from three given alternatives of what happened in the situation. Feedback (speech and instructions to choose another alternative) was given if the answer was wrong. The program adapted the level of difficulty according to performance.One group (n = 21, mental age = 6:6 years, chronological age = 12:5 years) got computerized theory of mind training 15 minutes a day for 5 weeks at school. They improved their theory of mind ability compared to a group (n = 27, mental age = 6:8 years, chronological age = 12:3 years) that got similar computerized mathematical training (Interaction effect in an analysis of variance, F(1, 44) = 4.97, p < .05, partial η2 = .10). Literacy improved equally in both groups, which means that there was no transfer effect to literacy. The same was true for working memory. It was investigated if the training effect was dependent on any initial skills, but no significant correlations could be found between training gain and initial working memory, theory of mind and literacy abilities in the theory of mind training group.The conclusion is that working memory, theory of mind and literacy correlates in children with intellectual disability, but improving theory of mind through training does not necessarily improve literacy or working memory.
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| 31. |
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| 32. |
- Danielsson, Henrik, et al.
(författare)
-
Modeling the effect of early age-related hearing loss on cognition and participation in social leisure activities
- 2015
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- There are well-known age-related declines in hearing, cognition and social participation. Furthermore, previous studies have shown that hearing loss is associated with both cognitive decline and increased risk for social isolation and that engagement in social leisure activities is related to cognitive decline. However, it is unclear how the three concepts and age relate to each other. In the current study, behavioral measures of hearing and memory were examined in relation to self-reported participation in social leisure activities. Data from two different samples were analyzed with structural equation modeling. The first consisted of 297 adults from Umeå, Sweden, who participated in the Betula longitudinal study. The second consisted of 273 older adults who volunteered for lab-based research on aging in Toronto, Canada. Structural equation modeling yielded two models with similar statistical properties for both samples. The first model suggests that age contributes to both hearing and memory performance, hearing contributes to memory performance, and memory (but not hearing) contributes to participation in social leisure activities. The second model also suggests that age contributes to hearing and memory performance and that hearing contributes to memory performance, but that age also contributes to participation in social leisure activities, which in turn contributes to memory performance. The models were confirmed in both samples, indicating robustness in the findings, especially since the samples differed on background variables such as years of education and marital status. Few participants in both samples were candidates for hearing aids, but most of those who were candidates used them. This suggests that even early stages of hearing loss can increase demands on cognitive processing that may deter participation in social leisure activities.
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| 33. |
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| 34. |
- Danielsson, Henrik, et al.
(författare)
-
Selective problems in executive function in adults with ID : The Betula Database
- 2010
-
Ingår i: Abstracts of the Third International Conference of IASSID-Europe, 20-22 October, 2010, Rome. - : Wiley. ; , s. 438-438
-
Konferensbidrag (refereegranskat)abstract
- Aim: To compare executive function in adults with ID to a group matched on chronological age, sex, type of education and years of education. Method: In the Betula database, a group of adults with ID (N = 46) was defined from measures of verbal and nonverbal IQ. A control group, with two people for every person with ID (N = 92), was chosen by matching on the following criteria in order of priority: IQ higher than 85, age, sex, sample, level of education and years of edu- cation. Three tasks of executive function were included on two occasions, with five years in between testing sessions: the Tower of Hanoi, dual task versions of word recall and verbal fluency. Results: Adults with ID showed significant impairments on verbal fluency and on the dual task word recall task (at encod- ing but not at recall). There were no group differences on the Tower of Hanoi. No significant differences between the two test occasions were found. Conclusion: The dual task results imply that the adults with ID were more sen- sitive to strategy interruptions at encoding, but that dividing attention at recall did not have such detrimental effects. The Tower of Hanoi is a complex task that is meant to assess planning, but has also been associated with inhibition. Adults with ID seem, therefore, not to have marked difficulties with planning and/or inhibition.
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| 35. |
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| 36. |
- Danielsson, Henrik, et al.
(författare)
-
Strengths and weaknesses in executive functioning in children with intellectual disability
- 2012
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Ingår i: Research in Developmental Disabilities. - : Elsevier. - 0891-4222 .- 1873-3379. ; 33:2, s. 600-607
-
Tidskriftsartikel (refereegranskat)abstract
- Children with intellectual disability (ID) were given a comprehensive range of executive functioning measures, which systematically varied in terms of verbal and non-verbal demands. Their performance was compared to the performance of groups matched on mental age (MA) and chronological age (CA), respectively. Twenty-two children were included in each group. Children with ID performed on par with the MA group on switching, verbal executive-loaded working memory and most fluency tasks, but below the MA group on inhibition, planning, and non-verbal executive-loaded working memory. Children with ID performed below CA comparisons on all the executive tasks. We suggest that children with ID have a specific profile of executive functioning, with MA appropriate abilities to generate new exemplars (fluency) and to switch attention between tasks, but difficulties with respect to inhibiting pre-potent responses, planning, and non-verbal executive-loaded working memory The development of different types of executive functioning skills may, to different degrees, be related to mental age and experience.
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| 37. |
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| 38. |
- Danielsson, Henrik, et al.
(författare)
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The face you recognize may not be the one you saw : Memory conjunction errors in individuals with or without learning disability
- 2006
-
Ingår i: Scandinavian Journal of Psychology. - : Wiley. - 0036-5564 .- 1467-9450. ; 47:3, s. 177-186
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Tidskriftsartikel (refereegranskat)abstract
- Memory conjunction errors, that is, when a combination of two previously presented stimuli is erroneously recognized as previously having been seen, were investigated in a face recognition task with drawings and photographs in 23 individuals with learning disability, and 18 chronologically age-matched controls without learning disability. Compared to the controls, individuals with learning disability committed significantly more conjunction errors, feature errors (one old and one new component), but had lower correct recognition, when the results were adjusted for different guessing levels. A dual-processing approach gained more support than a binding approach. However, neither of the approaches could explain all of the results. The results of the learning disability group were only partly related to non-verbal intelligence.
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| 39. |
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| 40. |
- Danielsson, Henrik, et al.
(författare)
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What am I doing in Timbuktu: Person–environment picture recognition for persons with intellectual disability
- 2006
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Ingår i: Journal of Intellectual Disability Research. - : Wiley. - 0964-2633 .- 1365-2788. ; 50:2, s. 127-138
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Tidskriftsartikel (refereegranskat)abstract
- Background The aim of this study was to examine the effects of familiarity of depicted persons and environments in recognition of photographs for pupils with different degrees of intellectual disability (ID). Method Forty-five pupils with ID participated. Results An interaction effect between the two variables, person and environment, was found in addition to main effects for both the variables. Pictures of the test person himself or herself in familiar environments were easier to recognize than in unfamiliar environments, whereas the opposite was found for pictures of other familiar persons. No interaction effects of degree of ID were found. Conclusions The interaction pattern is explained in terms of absent, present or implausible semantic associations between the person and the environmental context. The results are discussed in relation to augmentative and alternative communication with photographs.
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| 41. |
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| 42. |
- Danielsson, Henrik, et al.
(författare)
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Work your memory : Computerized working memory training for children with intellectual disability
- 2008
-
Ingår i: XXIX International Congress of Psychology, Berlin, 2008. - : Taylor & Francis Group. - 9781841698601 ; , s. 592-592
-
Konferensbidrag (refereegranskat)abstract
- The purpose of thepresent study was to investigate the effect of a computerizedworking memory training program for children with intellectualdisability. The participants had a mean age of 12 years. Thetraining took place in the child¿s school environment for 15minutes every school day for 5 weeks. There were training effectsfor some working memory measures, but not for all, compared to anage matched control group, also with intellectual disability, whoalso performed computerized training, but not related to workingmemory.
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| 43. |
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| 44. |
- Forsberg, Elin, et al.
(författare)
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Treatment with Anti-HER2 Chimeric Antigen Receptor Tumor-Infiltrating Lymphocytes (CAR-TILs) Is Safe and Associated with Antitumor Efficacy in Mice and Companion Dogs
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:3
-
Tidskriftsartikel (refereegranskat)abstract
- Simple Summary CAR-T cells are immune cells equipped with a claw that enable them to bind cancer cells. Usually, CAR-T cells are made using immune cells from blood. Here, we tested the hypothesis that also immune cells that reside in the tumor, so called tumor-infiltrating lymphocytes, can also be modified to carry the claw. This may mean that these cells, called CAR-TILs, will be able to attack cancer cells in two ways, using the claw or binding using its normal protein on the cell surface, the so-called T cell receptor. We show that CAR-TILs can be generated, and that they can kill melanoma cells in cell culture and in mice. Finally, to prepare for clinical trials, we also assess if CAR-TILs can be safe in a human cancer patient-like model, a companion dog suffering from cancer. Our data suggest that CAR-TILs may be a way to treat patients with melanoma but human clinical trials are needed. Patients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
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| 45. |
- Hajizadeh, Roghayeh, 1986-
(författare)
-
Optimization of Snow Removal in Cities
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Removing snow in a city is an unavoidable task in Nordic countries like Sweden. A number of streets in an area need to be cleared of snow by a limited number of vehicles and the tours for the vehicles must be planned in order to minimize the time and/or cost. Since the amount of snow can vary significantly from one year to another, the plans/tours of one year cannot be used for the next year. Hence, new tours need to be planned each time. Snow removal can be done in rural or urban areas and in addition during snowfall or after a snowfall. In this thesis, we study urban snow removal after a snowfall. There are different relevant specifics of the urban snow removal problem. For instance, there are different types of streets which need different numbers of sweeps in order to remove the snow. In addition, some tasks must be done before other tasks can be started. This leads to precedence constraints. Furthermore, each vehicle needs a certain time to switch from a task to another task. The problem can be formulated as a huge time-indexed mixed integer programming which often is not directly solvable in practice. The contributions of this thesis include the study of different relaxations and heuristics to find feasible solutions and improve the bounds on the optimal objective function values which are discussed in five papers. Paper I deals with single vehicle snow removal. A branch-and-dive heuristic based on branch-and-bound principles is given in order to improve the solutions and bounds. In Paper II, feasible solutions for the snow removal problem with a limited number of identical vehicles are obtained. First, the work is broken down into smaller parts, one for each vehicle. Based on the obtained allocation, a feasible tour for each single vehicle snow removal is obtained. Finally, combined solution approaches and co-ordination of the vehicles to find a feasible solution for the original problem are discussed. In order to improve the computational efficiency, one can take advantage of the tree structure, since modern real life city networks often contain parts that are trees. In Paper III, tree parts are studied and a tree elimination procedure is given for the snow removal problem, to be used before searching for optimal tours. Two variations encountered in practice for normal streets are compared in Paper IV. The first variant is doing a middle sweep before the two side sweeps and the second one is doing only side sweeps. Paper V studies the problem from modeling perspective. The problem is formulated as a mixed integer programming model and different relaxations of it are investigated. Finally, Lagrangian relaxation of the problem is studied in Paper VI. Different possibilities for Lagrangian relaxations are investigated and subgradient optimization is used to solve the Lagrangian dual.
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| 46. |
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| 47. |
- Hallingbäck, Henrik, et al.
(författare)
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Association mapping in Salix viminalis L. (Salicaceae) - identification of candidate genes associated with growth and phenology
- 2016
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Ingår i: Global Change Biology Bioenergy. - : Wiley. - 1757-1693 .- 1757-1707. ; 8:3, s. 670-685
-
Tidskriftsartikel (refereegranskat)abstract
- Willow species (Salix) are important as short-rotation biomass crops for bioenergy, which creates a demand for faster genetic improvement and breeding through deployment of molecular marker-assisted selection (MAS). To find markers associated with important adaptive traits, such as growth and phenology, for use in MAS, we genetically dissected the trait variation of a Salix viminalis (L.) population of 323 accessions. The accessions were sampled throughout northern Europe and were established at two field sites in Pustnas, Sweden, and at Woburn, UK, offering the opportunity to assess the impact of genotype-by-environment interactions (GxE) on trait-marker associations. Field measurements were recorded for growth and phenology traits. The accessions were genotyped using 1536 SNP markers developed from phenology candidate genes and from genes previously observed to be differentially expressed in contrasting environments. Association mapping between 1233 of these SNPs and the measured traits was performed taking into account population structure and threshold selection bias. At a false discovery rate (FDR) of 0.2, 29 SNPs were associated with bud burst, leaf senescence, number of shoots or shoot diameter. The percentage of accession variation explained by these associations ranged from 0.3% to 4.4%, suggesting that the studied traits are controlled by many loci of limited individual impact. Despite this, a SNP in the EARLY FLOWERING 3 gene was repeatedly associated (FDR<0.2) with bud burst. The rare homozygous genotype exhibited 0.4-1.0 lower bud burst scores than the other genotype classes on a five-grade scale. Consequently, this marker could be promising for use in MAS and the gene deserves further study. Otherwise, associations were less consistent across sites, likely due to their small estimates and to considerable GxE interactions indicated by multivariate association analyses and modest trait accession correlations across sites (0.32-0.61).
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| 48. |
- Hallingbäck, Henrik, et al.
(författare)
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Genome-wide association mapping uncovers sex-associated copy number variation markers and female hemizygous regions on the W chromosome in Salix viminalis
- 2021
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 22
-
Tidskriftsartikel (refereegranskat)abstract
- Background Sex chromosomes are in some species largely undifferentiated (homomorphic) with restricted sex determination regions. Homomorphic but different sex chromosomes are found in the closely related genera Populus and Salix indicating flexible sex determination systems, ideal for studies of processes involved in sex chromosome evolution. We have performed genome-wide association studies of sex and analysed sex chromosomes in a population of 265 wild collected Salix viminalis accessions and studied the sex determining locus. Results A total of 19,592 markers were used in association analyses using both Fisher's exact tests and a single-marker mixed linear model, which resulted in 48 and 41 sex-associated (SA) markers respectively. Across all 48 SA markers, females were much more often heterozygous than males, which is expected if females were the heterogametic sex. The majority of the SA markers were, based on positions in the S. purpurea genome, located on chromosome 15, previously demonstrated to be the sex chromosome. Interestingly, when mapping the genotyping-by-sequencing sequence tag harbouring the two SA markers with the highest significance to the S. viminalis genomic scaffolds, five regions of very high similarity were found: three on a scaffold that represents a part of chromosome 15, one on a scaffold that represents a part of chromosome 9 and one on a scaffold not anchored to the genome. Based on segregation differences of the alleles at the two marker positions and on differences in PCR amplification between females and males we conclude that females had multiple copies of this DNA fragment (chromosome 9 and 15), whereas males only had one (chromosome 9). We therefore postulate that the female specific sequences have been copied from chromosome 9 and inserted on chromosome 15, subsequently developing into a hemizygous W chromosome linked region. Conclusions Our results support that sex determination in S. viminalis is controlled by one locus on chromosome 15. The segregation patterns observed at the SA markers furthermore confirm that S. viminalis females are the heterogametic sex. We also identified a translocation from chromosome 9 to the W chromosome.
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| 49. |
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| 50. |
- Hallingbäck, Henrik, et al.
(författare)
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Genome Wide Associations of Growth, Phenology, and Plasticity Traits in Willow [Salix viminalis (L.)]
- 2019
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Ingår i: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The short rotation biomass crop willow (Salix genera) has been of interest for bioenergy but recently also for biofuel production. For a faster development of new varieties molecular markers could be used as selection tool in an early stage of the breeding cycle. To identify markers associated with growth traits, genome-wide association mapping was conducted using a population of 291 Salix viminalis accessions collected across Europe and Russia and a large set of genotyping-by-sequencing markers. The accessions were vegetatively propagated and planted in replicated field experiments, one in Southern Sweden and one in Central Sweden. Phenology data, including bud burst and leaf senescence, as well as different growth traits were collected and measured repeatedly between 2010 and 2017 at both field environments. A value of the plasticity for each accession was calculated for all traits that were measured the same year in both environments as the normalized accession value in one environment subtracted by the corresponding value in the other environment. Broad-sense accession heritabilities and narrow-sense chip heritabilities ranged from 0.68 to 0.95 and 0.45 to 0.99, respectively for phenology traits and from 0.56 to 0.85 and 0.24 to 0.97 for growth traits indicating a considerable genetic component for most traits. Population structure and kinship between accessions were taken into account in the association analyses. In total, 39 marker-trait associations were found where four were specifically connected to plasticity and interestingly one particular marker was associated to several different plasticity growth traits. Otherwise association consistency was poor, possibly due to accession by environment interactions which were demonstrated by the low structure adjusted accession correlations across environments (ranging from 0.40 to 0.58). However, one marker association with biomass fresh weight was repeatedly observed in the same environment over two harvest years. For some traits where several associations were found, the markers jointly explained over 20% of the accession variation. The result from this study using a population of unrelated accessions has given useful information about marker-trait associations especially highlighting marker-plasticity associations and genotype-by-environment interactions as important factors to take account of in future strategies of Salix breeding.
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