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| 2. |
- Lindblad, O, et al.
(författare)
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Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
- 2016
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35:39, s. 5119-5131
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Tidskriftsartikel (refereegranskat)abstract
- Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.Oncogene advance online publication, 21 March 2016; doi:10.1038/onc.2016.41.
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| 3. |
- Vallon-Christersson, J., et al.
(författare)
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RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
- 2022
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 33:Suppl 3, s. 144-145
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Konferensbidrag (refereegranskat)abstract
- BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level. Retrospective evaluation in postmenopausal ER+/HER2-/N0 patients suggested that molecular testing could lead to a changed therapy recommendation for almost one-fifth of patients.
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| 4. |
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| 5. |
- Brandsten, C, et al.
(författare)
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Expression of collagen alpha1(I) mRNA variants during tooth and bone formation in the rat
- 1999
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Ingår i: Journal of dental research. - : SAGE Publications. - 0022-0345 .- 1544-0591. ; 78:1, s. 11-19
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Tidskriftsartikel (refereegranskat)abstract
- Collagen al(I) mRNA is composed of two variants of 5 and 6 kb, differing in the length of the 3' untranslated region. In this work, the nucleotide sequences of the two rat mRNA variants were compared, and their expression pattern in cells forming bone, dentin, and cementum were analyzed. The sequences were determined from cDNA inserts of tooth and bone libraries plus directly from PCR fragments, obtained from bone. A total of 5721 bases of the rat collagen α1(I) sequence from cDNA of tooth and bone was determined. All sequences of the short variant were represented in the long variant. Only the alternatively poly-A additions gave rise to the variants in hard tissue. Two oligonucleotides were chosen as probes, one of which recognized, on Northern blots, the two bands of 5 and 6 kb, and the other the 6-kb variant only. The oligonucleotides were used in in situ hybridization experiments, for study of the distribution of the variants in different extracellular matrix-forming cells. Osteoblasts, odontoblasts, and cementum-associated cells were closely examined in sections from rat maxillae from 2 to 25 days of age. A similar or identical pattern of mRNA expression was observed with both oligonucleotides, indicating that the two mRNA variants were co-expressed in all cases.
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| 6. |
- Börjesson, Pål, et al.
(författare)
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Future Production and Utilisation of Biomass in Sweden: Potentials and CO2 Mitigation
- 1997
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Ingår i: Biomass & Bioenergy. - 1873-2909 .- 0961-9534. ; 13:6, s. 399-412
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Tidskriftsartikel (refereegranskat)abstract
- Swedish biomass production potential could be increased significantly if new production methods, such as optimised fertilisation, were to be used. Optimised fertilisation on 25% of Swedish forest land and the use of stem wood could almost double the biomass potential from forestry compared with no fertilisation, as both logging residues and large quantities of excess stem wood not needed for industrial purposes could be used for energy purposes. Together with energy crops and straw from agriculture, the total Swedish biomass potential would be about 230 TWh/yr or half the current Swedish energy supply if the demand for stem wood for building and industrial purposes were the same as today. The new production methods are assumed not to cause any significant negative impact on the local environment. The cost of utilising stem wood produced with optimised fertilisation for energy purposes has not been analysed and needs further investigation. Besides replacing fossil fuels and, thus, reducing current Swedish CO2 emissions by about 65%, this amount of biomass is enough to produce electricity equivalent to 20% of current power production. Biomass-based electricity is produced preferably through co-generation using district heating systems in densely populated regions, and pulp industries in forest regions. Alcohols for transportation and stand-alone power production are preferably produced in less densely populated regions with excess biomass. A high intensity in biomass production would reduce biomass transportation demands. There are uncertainties regarding the future demand for stem wood for building and industrial purposes, the amount of arable land available for energy crop production and future yields. These factors will influence Swedish biomass potential and earlier estimates of the potential vary from 15 to 125 TWh/yr.
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| 7. |
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| 8. |
- Christersson, L. A., et al.
(författare)
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Topical application of tetracycline‐HCl in human periodontitis
- 1993
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Ingår i: Journal of Clinical Periodontology. - : John Wiley & Sons. - 0303-6979 .- 1600-051X. ; 20:2, s. 88-95
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Tidskriftsartikel (refereegranskat)abstract
- Previous in vitro studies have suggested that tetracycline‐HCl (TTC‐HCl) is adsorbed and actively released from root dentin. The aim of the current study was to evaluate the binding to and release of TTC‐HCl from human root dentin surfaces in vivo, and to evaluate the clinical utility of TTC‐HCl irrigation as an adjunct to scaling and root planing. Experiment I utilized two contralateral mandibular single‐rooted teeth which were examined in four adults with severe generalized periodontitis. One tooth in each patient was carefully scaled and root planed, under local anesthesia, and the other used as an unsealed control. Each subgingival root surface was irrigated for 5 min with an aqueous TTC‐HCl solution at a concentration of 100 mg/ml. Gingival crevicular fluid samples were collected on paper strips for the next three weeks. The TTC‐HCl concentrations in each sample were determined by the inhibition zone of B. cereus cultured on agar plates. The TTC‐HCl concentrations in gingival crevicular fluid collected 15 min after irrigation were 3100±670 μg/ml from the scaled lesions and 4700±1300 μg/ml from the unsealed root surfaces. The antibiotic concentrations decreased logarithmically over the next 7 days; 1500±270 μ/g/ml and 1100±330μ/g/ml at 2 h. 880±350μ/g/ml and 1300±360 μ/g/ml at 6 h and 19±5μ/g/ml and 31±26 μ/g/ml at 1 week for scaled and unsealed root surfaces, respectively. Results for week two and three indicated an average of over 8 μg/ml. The TTC‐HCl concentrations in gingival crevicular fluid from scaled and unsealed root surfaces were not statistically different at any time point. The tetracycline irrigation resulted in release of tetracycline at concentrations well above therapeutic concentrations for at least 1 week. Experiment II comprised 11 patients with severe adult periodontitis. All subjects were scaled and root planed prior to baseline measurements. The patients were monitored by the following parameters: probing pocket depth (PPD), probing attachment level (PAL), gingival index (GI) and plaque index (PI). 54 contralateral teeth exhibiting residual pocket depths of 5 mm were selected. Within each pair identified for the study, teeth were randomly assigned as test or control sites. After baseline measurement, each subgingival root surface was irrigated for 5 min; either with an aqueous TTC‐HCl solution of 100 mg/ml (test), or a 0.9% NaCl solution (control). At 3 and 6 months post‐treatment, the PI was unchanged for both groups. The GI index was reduced (0.062 > p > 0.001) in a similar manner for both groups. PPD showed statistically significant (p < 0.001) mean/patient decrease of similar magnitudes, 2.3±1.0 mm (test), and ‐1.6±0.8 mm (control) at 3 months, and ‐2.1±1.1 mm (test), and ‐1.4±0.9 mm at 6 months (control), respectively. Also, PAL measurements indicated a statistically significant average gain/patient of 2.1±1.1 mm in the test group (p<0.00l) and again of 1.2±1.0 mm in the controls (p = 0.002) at 3 months, and 1.8±1.1 mm (test; p<0.001) and 1.0±0.9 mm (controls; p= 0.005) at 6 months. Comparisons of the changes, between the groups, indicated statistically greater gain of PAL in the test group at both the 3 (p= 0.042) and 6 months (p= 0.034) intervals. These results suggest that TTC‐HCl irrigation of root surfaces for long periods of time (5 min) results in a subsequent release of active antibiotic into the gingival fluid at therapeutic levels for at least 1 week. TTC‐HCl irrigation resulted in significantly greater attachment gain as compared to scaling and root planing alone over at least a month period of healing.
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| 9. |
- Christersson, M, et al.
(författare)
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Gossiping with bounded size messages in ad hoc radio networks (Extended abstract)
- 2002
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Ingår i: Automata, Languages and Programming / Lecture Notes in Computer Science. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 0302-9743 .- 1611-3349. ; 2380, s. 377-389
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Konferensbidrag (refereegranskat)abstract
- We study deterministic algorithms for the gossiping problem in ad hoc radio networks under the assumption that each combined message contains at most b(n) single messages or bits of auxiliary information, where b is an integer function and n is the number of nodes in the network. We term such a restricted gossiping problem b(n) -gossiping. We show that rootn-gossiping in an ad hoc radio network on n nodes can be done deterministically in time (O) over tilde (n(3/2)) which asymptotically matches the best known upper bound on the time complexity of unrestricted deterministic gossiping(dagger). Our upper bound on rootn-gossiping is tight up to a poly-logarithmic factor and it implies similarly tight upper bounds on b(n)-gossiping where function b is computable and 1 less than or equal to b(n) : rootn holds. For symmetric ad hoc radio networks, we show that even 1-gossiping can be done deterministically in time (O) over tilde (n(3/2)). We also demonstrate that O(n(t))-gossiping in a symmetric ad hoc radio network on n nodes can be done in time O(n(2-t)). Note that the latter upper bound is o(n(3/2)) when the size of a combined message is w(n(1/2)). Furthermore, by adopting known results on repeated randomized broadcasting in symmetric ad hoc radio networks, we derive a randomized protocol for 1-gossiping in these networks running in time (O) over tilde (n) on the average. Finally, we observe that when a collision detection mechanism is available, even deterministic 1-gossiping in symmetric ad hoc radio networks can be performed in time (O) over tilde (n).
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| 10. |
- Diogo Löfgren, Christina, et al.
(författare)
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The Challenge of Measuring Viscoelastic Properties of Human Whole Saliva to Fit Clinical Purpose
- 2015
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Ingår i: International Journal of Oral and Dental Health. - : ClinMed International. - 2469-5734. ; 1:4
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Tidskriftsartikel (refereegranskat)abstract
- To understand the protective functions of saliva secreted from different glands in the masticatory process, it is of interest to study its viscoelastic properties. Characterization of saliva samples are not that easily performed in a clinical setting, since most of the experimental techniques and instruments available are developed for research purposes. The aim of this study was to characterize how the viscoelastic properties of saliva can be measured and monitored using two laboratory instruments. Unstimulated whole saliva from 11 healthy volunteers was characterized using two instruments, an ARES-G2 rheometer and a Bohlin Oscillating Cup Rheometer. Measurements performed on unstimulated human whole saliva showed that the ARES rheometer will in linear viscoelastic conditions of the sample give absolute viscoelastic numbers of undisturbed saliva whilst the BOCR can be used to give an indication of gel strength, gel formation, and gel stability in viscoelastic samples being sheared in their non-linear viscoelastic region by introducing a Saliva Gel Strength Index, SGSI. Both methods clearly illustrate the presence of viscoelastic properties in saliva.
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