| 1. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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| 2. |
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Wilking, N., et al.
(författare)
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Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy
- 2007
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 18:4, s. 694-700
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Tidskriftsartikel (refereegranskat)abstract
- Background: The purpose was to investigate adjuvant marrow-supportive high-dose chemotherapy compared with an equitoxicity-tailored comparator arm. Patients and methods: Five hundred and twenty-five women below theage of 60 years with operated high-risk primary breast cancer were randomised to nine cycles of granulocyte colony-stimulating factor supported and individually tailored FEC (5-fluorouracil, epirubicin, cyclophosphamide), (n = 251) or standard FEC followed by marrow-supported high-dose therapy with CTCb (cyclophosphamide, thiotepa, carboplatin) therapy (n = 274), followed by locoregional radiotherapy and tamoxifen for 5 years. Results: There were 104 breast cancer relapses in the tailored FEC group versus 139 in the CTCb group (double triangular method by Whitehead, P = 0.046), with a median follow-up of all included patients of 60.8 months. The event-free survival demonstrated 121 and 150 events in the tailored FEC- and CTCb group, respectively [P = 0.074, hazard ratio (HR) 0.804, 95% confidence interval (CI) 0.633-1.022]. Ten patients in the tailored FEC regimen developed acute myeloid leukaemia (AML)/myelodysplasia (MDS). One hundred deaths occurred in the tailored FEC group and 121 in the CTCb group (P = 0.287, HR 0.866, 95% CI 0.665-1.129). Conclusion: The update of this study shows an improved outcome linked to the tailored FEC treatment in relation to breast cancer relapse, but also an increased incidence of AML/MDS. © 2007 Oxford University Press.
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| 7. |
- Sten, S., et al.
(författare)
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Erik den heliges skelett
- 2016
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Ingår i: Fornvännen. - 0015-7813. ; 111:1, s. 27-40
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Tidskriftsartikel (refereegranskat)abstract
- No contemporary sources mention Erik Jedvardsson, Sweden's king saint. The only account of his life is the saint's legend, in its preserved form written in the late 13th century, and legends are notoriously untrustworthy. It says that in 1160, in the tenth year of Erik's reign, he was killed by a throne claimant. His remains have rested in a reliquary in Uppsala Cathedral since 1257 at the latest and survived the Reformation. A thorough investigation was made in 1946, and the development of new methods motivated a new investigation in 2014. 23 bones remain that apparently belong to the same individual. (They are accompanied in the reliquary by an unrelated shinbone.) Radiocarbon values are consistent with a death in 1160. The bones belong to a man, 35-40 years old, about 171 cm tall, without any discernible medical conditions. Bone density indicates a life of good nourishment and abundant exercise. The skull has one or two healed wounds that may have been due to weapons. Isotope analysis points to a diet rich in freshwater fish. Stable isotopes also imply that he did not spend his last decade in the expected Uppsala area but rather in Västergötland further south. Insufficient reference materials however make this a very preliminary conclusion. Samples for DNA analysis were collected, but the results are not expected for another year. The saint's legend says that in the king's final battle, the enemy swarmed him, and when he fell to the ground they gave him wound after wound until he lay half dead. They then taunted him and finally cut off his head. The remaining bones have at least nine cuts inflicted in connection with death, seven of them on the legs. No wounds have been found on the ribs or the remaining arm bone, which probably means that the king wore a hauberk but had less protected legs. Both shin bones have cuts inflicted from the direction of the feet, indicating that the victim lay on his front. A neck vertebra has been cut through, which could not have been done without removing the hau berk, i.e. not during battle. This confirms that there was an interlude, as described by the taunting in the legend, between battle and decapitation. At no point do the documented wounds gainsay the account of the fight given by the much later legend.
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| 8. |
- Van Den Berg, F. D., et al.
(författare)
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Product uniformity control - A research collaboration of european steel industries to non-destructive evaluation of microstructure and mechanical properties
- 2018
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Ingår i: Stud. Appl. Electromagn. Mech.. - : IOS Press. - 9781614998358 ; 43, s. 120-129
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Konferensbidrag (refereegranskat)abstract
- In steel manufacturing, the conventional method to determine the mechanical properties and microstructure is by offline, destructive (lab-)characterisation of sample material that is typically taken from the head or the tail of the coil. Since coils can be up to 7 km long, the samples are not always representative for the main coil body. Also, the time delay (typically a few days) between the actual production and the availability of the characterisation results implies that these results cannot be exploited for real-time adaptation of the process settings. Information about the microstructure and material properties can also be obtained from electromagnetic (EM) and ultrasonic (US) parameters, which can be measured in real-time, non-destructively, and over the full length of the steel strip product. With the aim to improve the consistency in product quality by use of inline EM and US measurements, a European project called "Product Uniformity Control" (PUC) has been set up as a broad collaboration between 4 major European Steel Manufacturers and 10 Universities / Research institutes. Using both numerical simulations and experimental characterisations, we study the inline measured EM and US parameters in regard of the microstructural and mechanical properties. In this way, we aim to establish an improved understanding of their mutual relationships, and to apply this knowledge in existing and new nondestructive evaluation techniques. In this paper, the concerted approach of modelling and experimental validation will be addressed, and results of this work will be shown in combination with inline measured data.
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| 9. |
- Wulaningsih, W., et al.
(författare)
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A competing risks analysis of the association between prediagnostic serum glucose and lipids and breast cancer survival
- 2016
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Ingår i: Cancer Research. - Kings Coll London, Div Canc Studies, Canc Epidemiol Grp, London WC2R 2LS, England. Kings Coll London, Inst Math & Mol Biomed, London WC2R 2LS, England. Uppsala Univ, Uppsala, Sweden. Reg Canc Ctr, Uppsala, Sweden. Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. Karolinska Inst, S-10401 Stockholm, Sweden. AstraZeneca R&D, Mlndal, Switzerland. CALAB Res, Madrid, Spain.. - 0008-5472 .- 1538-7445. ; 76
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 10. |
- Berg, Frenk van den, et al.
(författare)
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Results of the European collaborative project "Product Uniformity Control" to improve the inline sensing of mechanical properties and microstructure of automotive steels
- 2018
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Ingår i: e-Journal of Nondestructive Testing (eJNDT). - 1435-4934. ; 23:8
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Tidskriftsartikel (refereegranskat)abstract
- A European consortium consisting of four major steel manufacturers and ten academic technology institutes has conducted a research and development project, called “Product Uniformity Control“ (PUC) in the period 2013 to 2017. This project aimed to develop and improve non-destructive (inline) measurement techniques to characterise the (uniformity of the) microstructure of steel strip products. In this project, a multitude of strip steel samples from various stages of production have been collected from the four participating steel manufacturers. The samples have been characterised in various ways, namely on their (1) non-destructive measurement parameters using different techniques suited for inline evaluation, (2) fundamental ultrasonic and electromagnetic properties (wave speed, ultrasonic attenuation, magnetisation loops, coercive field), (3) tensile properties (stress-strain curves) and (4) microstructure (by optical micrographs and EBSD images). The correlations between these different characterisations will be addressed. Besides the experimental characterisation, a strong accent has been on modelling activities: during the project, fundamental models have been developed to describe, starting from 2D and 3D microstructures, the ultrasonic and magnetic properties, which are next used as input to sensor models that predict the output of the inline measurement systems. This contribution presents the recent results of experimental work, which underlines the importance of associated modelling studies for the interpretation of the measurement data for the benefit of inline characterisation of the mechanical properties complementary to traditional destructive tensile testing.
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| 11. |
- Dyrskjot, L., et al.
(författare)
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Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR
- 2012
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 107:8, s. 1392-1398
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.
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| 12. |
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| 13. |
- He, Yibo, et al.
(författare)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
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| 14. |
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| 15. |
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| 16. |
- Malmström, Erik, et al.
(författare)
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Targeted mass spectrometry analysis of neutrophil-derived proteins released during sepsis progression.
- 2014
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 112:6, s. 1230-1243
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Tidskriftsartikel (refereegranskat)abstract
- Early diagnosis of severe infectious diseases is essential for timely implementation of lifesaving therapies. In a search for novel biomarkers in sepsis diagnosis we focused on polymorphonuclear neutrophils (PMNs). Notably, PMNs have their protein cargo readily stored in granules and following systemic stimulation an immediate increase of neutrophil-borne proteins can be observed into the circulation of sepsis patients. We applied a combination of mass spectrometry (MS) based approaches, LC-MS/MS and selected reaction monitoring (SRM), to characterise and quantify the neutrophil proteome in healthy or disease conditions. With this approach we identified a neutrophil-derived protein abundance pattern in blood plasma consisting of 20 proteins that can be used as a protein signature for severe infectious diseases. Our results also show that SRM is highly sensitive, specific, and reproducible and, thus, a promising technology to study a complex, dynamic and multifactorial disease such as sepsis.
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| 17. |
- Nadafi, Reza, et al.
(författare)
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Dendritic cell migration to skin-draining lymph nodes is controlled by dermatan sulfate and determines adaptive immunity magnitude
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9:FEB
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Tidskriftsartikel (refereegranskat)abstract
- For full activation of naïve adaptive lymphocytes in skin-draining lymph nodes (LNs), presentation of peptide:MHC complexes by LN-resident and skin-derived dendritic cells (DCs) that encountered antigens (Ags) is an absolute prerequisite. To get to the nearest draining LN upon intradermal immunization, DCs need to migrate from the infection site to the afferent lymphatics, which can only be reached by traversing a collagen-dense network located in the dermis of the skin through the activity of proteolytic enzymes. Here, we show that mice with altered collagen fibrillogenesis resulting in thicker collagen fibers in the skin display a reduced DC migration to the draining LN upon immune challenge. Consequently, the initiation of the cellular and humoral immune response was diminished. Ag-specific CD8+ and CD4+ T cells as well as Ag-specific germinal center B cells and serum immunoglobulin levels were significantly decreased. Hence, we postulate that alterations to the production of extracellular matrix, as seen in various connective tissue disorders, may in the end affect the qualitative outcome of adaptive immunity.
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| 18. |
- Ritchie, C., et al.
(författare)
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A systematic review shows minimal evidence for measurement properties of psychological functioning outcomes in whiplash
- 2022
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Ingår i: Journal of Clinical Epidemiology. - : Elsevier Inc.. - 0895-4356 .- 1878-5921. ; 151, s. 29-44
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to systematically identify, synthesize, and appraise studies on the measurement properties of patient-reported outcome measures (PROMs) for anxiety, depression, fear of movement, pain catastrophizing, post-traumatic stress, self-efficacy, and stress in people with whiplash-associated disorders (WAD). Study Design and Setting: PsycINFO, MEDLINE, EMBASE, CINAHL, PILOTS, Web of Science, and Scopus were searched (November 9, 2021). Studies evaluating any measurement property of relevant PROMs in WAD were included. Two reviewers independently screened the studies and assessed the measurement properties in accordance with the COSMIN guidelines. Results: Measurement properties of 10 PROMs were evaluated in WAD: Pictorial Fear of Activity Scale-Cervical (PFActS-C), Tampa Scale of Kinesiophobia-11, Pain Catastrophizing Scale (PCS), Pain Self-Efficacy Questionnaire (PSEQ), PSEQ-4 item, PSEQ-2a, PSEQ-2b, Self-Efficacy Scale, Harvard Trauma Questionnaire, and Post-Traumatic Stress Diagnostic Scale. Content validity was not examined in any of these PROMs in whiplash. Moderate- or high-quality evidence showed adequate internal structure for the PSEQ, PCS, and PFActS-C, whereas the original structures of the remaining seven PROMs were not confirmed in whiplash. Conclusion: Until further research on the measurement properties of these PROMs is available, researchers may opt to use the PSEQ, PCS, or PFActS-C if the construct is aligned with research aims. © 2022 Elsevier Inc.
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| 19. |
- Scott, Aaron M., et al.
(författare)
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Population scale proteomics enables adaptive digital twin modelling in sepsis
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.Competing Interest StatementThe authors have declared no competing interest.Funding StatementL.M. is funded by the Swedish Research Council (grant number VR-2020-02419), the Wallenberg foundation (grant number 2016.0023) and Alfred Österlunds Foundation. J.M. is a Wallenberg academy fellow (KAW 2017.0271) and is also funded by the Swedish Research Council (Vetenskapsrådet, VR) (2019-01646 and 2018-05795), the Wallenberg foundation (KAW2016.0023, KAW2019.0353 and KAW2020.0299), and Alfred Österlunds Foundation. E.M. is funded by Wenner-Gren Foundation (FT2020-0003), the Crafoord Foundation, and the Swedish Society of Medicine (SLS-985287). F.K. is funded by Region Skåne ALF project and the Crafoord Foundation. A.L. is funded by the Swedish Research Council VR 2023-02707 and Region Skåne ALF project 2022-0146.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the Swedish National Ethics Committee (file numbers 2022-01454-01, 2014/741 and 2016/271).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData produced in the present study are available upon reasonable request to the authors
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| 20. |
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| 21. |
- Sterling, M., et al.
(författare)
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Recommendations for a core outcome measurement set for clinical trials in whiplash associated disorders
- 2023
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Ingår i: Pain. - : NLM (Medline). - 0304-3959 .- 1872-6623. ; 164:10, s. 2265-2272
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Inconsistent reporting of outcomes in clinical trials of treatments for whiplash associated disorders (WAD) hinders effective data pooling and conclusions about treatment effectiveness. A multidisciplinary International Steering Committee recently recommended 6 core outcome domains: Physical Functioning, Perceived Recovery, Work and Social Functioning, Psychological Functioning, Quality of Life and Pain. This study aimed to reach consensus and recommend a core outcome set (COS) representing each of the 6 domains. Forty-three patient-reported outcome measures (PROMs) were identified for Physical Functioning, 2 for perceived recovery, 37 for psychological functioning, 17 for quality of life, and 2 for pain intensity. They were appraised in 5 systematic reviews following COSMIN methodology. No PROMs of Work and Social Functioning in WAD were identified. No PROMs had undergone evaluation of content validity in patients with WAD, but some had moderate-to-high-quality evidence for sufficient internal structure. Based on these results, the International Steering Committee reached 100% consensus to recommend the following COS: Neck Disability Index or Whiplash Disability Questionnaire (Physical Functioning), the Global Rating of Change Scale (Perceived Recovery), one of the Pictorial Fear of Activity Scale-Cervical, Pain Self-Efficacy Questionnaire, Pain Catastrophizing Scale, Harvard Trauma Questionnaire, or Posttraumatic Diagnostic Scale (Psychological Functioning), EQ-5D-3L or SF-6D (Quality of Life), numeric pain rating scale or visual analogue scale (Pain), and single-item questions pertaining to current work status and percent of usual work (Work and Social Functioning). These recommendations reflect the current status of research of PROMs of the 6 core outcome domains and may be modified as evidence grows.
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| 22. |
- Tanner, L., et al.
(författare)
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Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis in a murine lung fibrosis model
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues accompanied by aberrant repair processes. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to target underlying pathophysiological mechanisms. The DNA repair protein 8-oxoguanine DNA glycosylase-1 (OGG1) has significant roles in the modulation of inflammation and metabolic syndromes. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study we show Ogg1-targeting siRNA mitigates bleomycin-induced pulmonary fibrosis in male mice, highlighting OGG1 as a tractable target in lung fibrosis. The small molecule OGG1 inhibitor, TH5487, decreases myofibroblast transition and associated pro-fibrotic gene expressions in fibroblast cells. In addition, TH5487 decreases levels of pro-inflammatory mediators, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis conducted in male C57BL6/J mice. OGG1 and SMAD7 interact to induce fibroblast proliferation and differentiation and display roles in fibrotic murine and IPF patient lung tissue. Taken together, these data suggest that TH5487 is a potentially clinically relevant treatment for IPF but further study in human trials is required.
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| 23. |
- van Thuijl, Hinke F., et al.
(författare)
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Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment
- 2015
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Ingår i: Acta Neuropathologica. - : Springer Verlag (Germany). - 0001-6322 .- 1432-0533. ; 129:4, s. 597-607
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Tidskriftsartikel (refereegranskat)abstract
- Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-na less than ve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
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| 24. |
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| 25. |
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| 26. |
- Bady, Pierre, et al.
(författare)
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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients
- 2022
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Ingår i: Acta neuropathologica communications. - : BMC. - 2051-5960. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Elderly patients represent a growing proportion of individuals with glioblastoma, who however, are often excluded from clinical trials owing to poor expected prognosis. We aimed at identifying age-related molecular differences that would justify and guide distinct treatment decisions in elderly glioblastoma patients. The combined DNA methylome (450 k) of four IDH wild-type glioblastoma datasets, comprising two clinical trial cohorts, was interrogated for differences based on the patients age, DNA methylation (DNAm) age acceleration (DNAm age "Horvath-clock" minus patient age), DNA methylation-based tumor classification (Heidelberg), entropy, and functional methylation of DNA damage response (DDR) genes. Age dependent methylation included 19 CpGs (p-value <= 0.1, Bonferroni corrected), comprising a CpG located in the ELOVL2 gene that is part of a 13-gene forensic age predictor. Most of the age related CpGs (n = 16) were also associated with age acceleration that itself was associated with a large number of CpGs (n = 50,551). Over 70% age acceleration-associated CpGs (n = 36,348) overlapped with those associated with the DNA methylation based tumor classification (n = 170,759). Gene set enrichment analysis identified associated pathways, providing insights into the biology of DNAm age acceleration and respective commonalities with glioblastoma classification. Functional methylation of several DDR genes, defined as correlation of methylation with gene expression (r <= -0.3), was associated with age acceleration (n = 8), tumor classification (n = 12), or both (n = 4), the latter including MGMT. DNAm age acceleration was significantly associated with better outcome in both clinical trial cohorts, whereof one comprised only elderly patients. Multivariate analysis included treatment (RT, RT/TMZ -> TMZ; TMZ, RT), MGMT promoter methylation status, and interaction with treatment. In conclusion, DNA methylation features of age acceleration are an integrative part of the methylation-based tumor classification (RTK I, RTK II, MES), while patient age seems hardly reflected in the glioblastoma DNA methylome. We found no molecular evidence justifying other treatments in elderly patients, not owing to frailty or co-morbidities.
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| 27. |
- Bonnefoi, H., et al.
(författare)
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Pathological complete response after neoadjuvant chemotherapy is an independent predictive factor irrespective of simplified breast cancer intrinsic subtypes: a landmark and two-step approach analyses from the EORTC 10994/BIG 1-00 phase III trial
- 2014
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Ingår i: Annals of Oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 25:6, s. 1128-1136
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Tidskriftsartikel (refereegranskat)abstract
- Pathological complete response (pCR) following chemotherapy is strongly associated with both breast cancer subtype and long-term survival. Within a phase III neoadjuvant chemotherapy trial, we sought to determine whether the prognostic implications of pCR, TP53 status and treatment arm (taxane versus non-taxane) differed between intrinsic subtypes. Patients were randomized to receive either six cycles of anthracycline-based chemotherapy or three cycles of docetaxel then three cycles of eprirubicin/docetaxel (T-ET). pCR was defined as no evidence of residual invasive cancer (or very few scattered tumour cells) in primary tumour and lymph nodes. We used a simplified intrinsic subtypes classification, as suggested by the 2011 St Gallen consensus. Interactions between pCR, TP53 status, treatment arm and intrinsic subtype on event-free survival (EFS), distant metastasis-free survival (DMFS) and overall survival (OS) were studied using a landmark and a two-step approach multivariate analyses. Sufficient data for pCR analyses were available in 1212 (65%) of 1856 patients randomized. pCR occurred in 222 of 1212 (18%) patients: 37 of 496 (7.5%) luminal A, 22 of 147 (15%) luminal B/HER2 negative, 51 of 230 (22%) luminal B/HER2 positive, 43 of 118 (36%) HER2 positive/non-luminal, 69 of 221(31%) triple negative (TN). The prognostic effect of pCR on EFS did not differ between subtypes and was an independent predictor for better EFS [hazard ratio (HR) = 0.40, P < 0.001 in favour of pCR], DMFS (HR = 0.32, P < 0.001) and OS (HR = 0.32, P < 0.001). Chemotherapy arm was an independent predictor only for EFS (HR = 0.73, P = 0.004 in favour of T-ET). The interaction between TP53, intrinsic subtypes and survival outcomes only approached statistical significance for EFS (P = 0.1). pCR is an independent predictor of favourable clinical outcomes in all molecular subtypes in a two-step multivariate analysis.
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| 28. |
- Darby, S, et al.
(författare)
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Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death : meta-analysis of individual patient data for 10,801 women in 17 randomised trials
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 378:9804, s. 16-1707
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk.METHODS: We undertook a meta-analysis of individual patient data for 10,801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease.FINDINGS: Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7-17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6-6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2-17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8-5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10-19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1-12·5), 1·1% (-2·0 to 4·2), and 0·1% (-7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5-27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8-15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease.INTERPRETATION: After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made.FUNDING: Cancer Research UK, British Heart Foundation, and UK Medical Research Council.
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| 29. |
- Davies, C, et al.
(författare)
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Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen : patient-level meta-analysis of randomised trials
- 2011
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 378:9793, s. 771-784
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As trials of 5 years of tamoxifen in early breast cancer mature, the relevance of hormone receptor measurements (and other patient characteristics) to long-term outcome can be assessed increasingly reliably. We report updated meta-analyses of the trials of 5 years of adjuvant tamoxifen. METHODS: We undertook a collaborative meta-analysis of individual patient data from 20 trials (n=21,457) in early breast cancer of about 5 years of tamoxifen versus no adjuvant tamoxifen, with about 80% compliance. Recurrence and death rate ratios (RRs) were from log-rank analyses by allocated treatment. FINDINGS: In oestrogen receptor (ER)-positive disease (n=10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0·53 [SE 0·03] during years 0-4 and RR 0·68 [0·06] during years 5-9 [both 2p<0·00001]; but RR 0·97 [0·10] during years 10-14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10-19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0·67 [0·08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0·71 [0·05] during years 0-4, 0·66 [0·05] during years 5-9, and 0·68 [0·08] during years 10-14; p<0·0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality. INTERPRETATION: 5 years of adjuvant tamoxifen safely reduces 15-year risks of breast cancer recurrence and death. ER status was the only recorded factor importantly predictive of the proportional reductions. Hence, the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen. FUNDING: Cancer Research UK, British Heart Foundation, and Medical Research Council.
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| 30. |
- Ebenå, G., et al.
(författare)
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A comparison of methods for mine tailings sterilisation
- 2003
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Ingår i: Proc. ICARD 2003, 6th Int. Conf. on Acid Rock Drainage, Cairns, Australia, July 14 – 17, 2003. ; , s. 1013-
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Konferensbidrag (refereegranskat)abstract
- The study of microbial sulfide oxidation and oxidation rates of tailings requires the use of sterile control samples in laboratory experiments for comparison purposes. The need for sterile tailings sand is also apparent in the study of microbial communities and processes. This study compares six different methods with regard to sterilisation efficiency and investigates chemical and mineralogical changes in the samples as the result of sample treatment. In addition, the effect of sterilisation on mineral weathering rates is also studied. The efficiency of the different methods with regard to sterility is estimated by most probable numbers (MPN) of both sulfur and iron oxidising bacteria. The sterilisation methods that were compared are: washing with sterile water, washing with ethanol, applying antibiotics, repeated heating to 70°C, autoclaving, and γ-irradiation. There are several possible drawbacks with the different methods, including the risk of an applied chemical acting as a substrate for micro-organisms in the system, and the risk of altering the tailings. The results show a substantial difference in sterilisation efficiency between the treatments. For example, autoclaving, repeated heating, ethanol and irradiation efficiently kill micro-organisms, rendering an undetectable amount of bacteria after one month of incubation, whilst washing with water exhibits virtually no microbiological effect, with a bacterial content comparable to the control. The use of antibiotics for sterilisation ranks intermediate: the lag-phase was twice as long in the antibiotics treatment compared with the controls. X-ray diffraction, optical and electron microscopy, Mössbauer spectroscopy, and mineral magnetism indicate no significant change in the bulk mineralogical composition. However, X-ray photoelectron spectroscopy analyses show that with some of the treatments, sulfides are partially oxidised, as indicated by the formation of sulfate and partially – oxidised sulfur species at the tailings surfaces. Aerated batch weathering experiments performed on sterilised tailings samples and untreated controls indicated that while the initial rates of element (S, Fe, Cu, Zn, Mg, Na, K, Ca) release may differ between the samples, over the course of ~100 days of experiment at pH 2 and room temperature, the rates declined toward a similar value for all samples. To conclude, there does not appear to be one perfect method for tailings sterilisation. Autoclaving and heating damage the mineral grain structure and oxidise the sulfide surfaces. Ethanol, antibiotics and rinsing greatly alter the pore water chemistry through the washing procedure. In addition, ethanol and denatured antibiotics might serve as a substrate and also, in the case of antibiotics, adhere to mineral surfaces thus obstructing chemical reactions. Irradiation seems to be the preferable method on an overall basis, although the formation of surface Fe3+ was suggested by Mössbauer spectroscopy.
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| 31. |
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| 32. |
- Ekman-Ordeberg, G, et al.
(författare)
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Low molecular weight heparin stimulates myometrial contractility and cervical remodeling in vitro
- 2009
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Ingår i: Acta Obstet Gynecol Scand. - : Wiley. ; 88:9, s. 984-989
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The low molecular weight heparin, Dalteparin, shortens human labor time. The aim of this study was to investigate if the mechanism behind this effect involves myometrial contractility and cervical ripening and if the anticoagulative activity is necessary for its effect. DESIGN: Experimental in vitro study. SETTING: Lund University and Karolinska Institute, Sweden. METHODS: The effect of low molecular weight heparins with or without anticoagulative properties on myometrial contractility was measured in vitro on smooth muscle strips from biopsies obtained at elective cesarean sections. The effects on cervical ripening were assessed in cervical fibroblasts cultured from explants of cervical biopsies obtained at delivery. MAIN OUTCOME MEASURES: Mean force and number of contractions in uterine smooth muscle strips and interleukin-8 (IL-8) secretion in cervical fibroblasts. RESULTS: Myometrial smooth muscle strips pretreated with low molecular weight heparins showed increased contractile activity compared to untreated smooth muscle strips. Secretion of IL-8 from cultured cervical fibroblasts was significantly increased after treatment with low molecular weight heparin. Both these effects were independent of anticoagulative activity of the low molecular weight heparin. CONCLUSIONS: A possible underlying mechanism for the shortened labor time after low molecular weight heparin treatment is enhanced myometrial contractility and an increased IL-8 secretion in cervical fibroblast, mimicking the final cervical ripening in vivo. Our data support the notion that anticoagulant activity is not required to promote labor.
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| 33. |
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| 34. |
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| 35. |
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| 36. |
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| 37. |
- Gleisner, M., et al.
(författare)
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Comparison of sulfide oxidation in unweathered pyretic mine tailings
- 2003
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Ingår i: Proc. ICARD 2003, 6th Int. Conf. on Acid Rock Drainage, Cairns, Australia, July 14 – 17, 2003. ; , s. 1027-1030
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Konferensbidrag (refereegranskat)abstract
- The study focuses on sulfide oxidation processes in unweathered pyrite-rich mine tailings from a soil-covered impoundment in northern Sweden. To simulate the oxygen-limited conditions in water saturated tailings two long-term column experiments were performed. Results are presented for the first 11 months of the experiments at room temperature. The tailings used in the experiments were of two different grain sizes (one coarse grained, in the range 0.02 - 0.6 mm with a grain surface area of 1.86 m2 g-1, and one fine-grained, in the range 0.0015 - 0.06 mm with a grain surface area of 10.00 m2 g-1) and with slightly different mineralogical composition. The S:Fe molar ratio in the leachates (1.0 - 1.5) indicates either that pyrrhotite is the main iron sulfide undergoing oxidation in our experiments, or, alternatively that the S:Fe molar ratio in the leachate is determined by pyrite weathering in conjunction with other processes releasing iron or immobilising sulfate. However, speciation modelling of the leachates indicates that ferrihydrite was close to saturation, suggesting that a ferric oxyhydroxide may have dissolved/ precipitated during the experimental period, thereby affecting the S:Fe molar ratio. Pyrite oxidation rates obtained from the two column experiments during ‘steady-state’ were 2.25 × 10-13 and 8.45 × 10-14 mol m-2 s-1 in the coarse and fine tailings, respectively. Pyrrhotite oxidation rates, as an alternative, were 2.31 × 10-12 and 1.24 × 10-11 mol m-2 s-1 in the coarse and fine tailings, respectively. Natural microbial activity was confirmed in both the tailings and the leachates; therefore, the obtained oxidation rates are not strictly abiotic. It is thus concluded, based on the experimental results, that tailing heterogeneity will result in zones with different oxidation rates, related to their physical and chemical properties.
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| 38. |
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| 39. |
- Green, Henrik, et al.
(författare)
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Pegylated liposomal doxorubicin as first-line monotherapy in elderly women with locally advanced or metastatic breast cancer : Novel treatment predictive factors identified
- 2011
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 313:2, s. 145-153
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the efficacy and safety of single-agent pegylated liposomal doxorubicin (PLD) as first-line treatment for elderly women with advanced breast cancer and evaluated predictive markers for response and toxicity. Twenty-five women >= 65 years received 40 mg/m(2) PLD every 28 days. Time to treatment failure (TTF), response rate, time to progression (TTP) and overall survival (OS) was calculated. The ABCB1 single nucleotide polymorphisms (SNP), tumor MRN complex, and TOPOII alpha were analyzed. A mean of 7.4 cycles PLD were administered and TIT was 5.5 months and OS 20.6 months. ABCB1 SNPs were found to correlate to both efficacy and toxicity, while tumor expression of the MRN complex and TOPOII alpha correlated to TTP. PLD is a safe and effective treatment for elderly breast cancer patients. Also potential predictive markers were identified.
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| 40. |
- Hakamies-Blomqvist, Liisa, et al.
(författare)
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Quality of life in patients with metastatic breast cancer receiving either docetaxel or sequential methotrexate and 5-fluorouracil : A multicentre randomised phase III trial by the Scandinavian breast group
- 2000
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 36:11, s. 1411-7
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to evaluate the effects of two alternative chemotherapy regimes on the quality of life (QoL) of patients with advanced breast cancer. In a multicentre trial, 283 patients were randomised to receive either docetaxel (T) or sequential methotrexate and 5-fluorouracil (MF). QoL was assessed at baseline and before each treatment using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). Initial compliance in the QoL study was 96% and the overall compliance 82%. QoL data were available for 245 patients (T 130 and 115 MF). Both treatment groups showed some improvement in emotional functioning during treatment, with a significant difference favouring the MF group at treatment cycles 5 and 6. In the T group, the scores on the other functional scales remained stable throughout the first six cycles. There were significant differences favouring the MF group on the social functioning scale at treatment cycle 6 and on the Global QoL scale at treatment cycles 5 and 6. On most symptom and single-item scales there were no statistically significant differences between the groups. However, at baseline, the T patients reported more appetite loss, at treatment cycles 2-4, the MF patients reported more nausea/vomiting, and at treatment cycle 6, the T patients reported more symptoms of fatigue, dyspnoea and insomnia. There were no statistically significant differences between the groups in the mean change scores of the functional and symptom scales. Interindividual variance was, however, larger in the T group. Differences in QoL between the two treatment groups were minor. Hence, given the expectancy of comparable QoL outcomes, the choice of treatment should be made on the basis of the expected clinical effect.
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| 41. |
- Hao, X. J., et al.
(författare)
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Dendrimers as scaffolds for multifunctional reversible addition-fragmentation chain transfer agents : Syntheses and polymerization
- 2004
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Ingår i: Journal of Polymer Science Part A. - : Wiley. - 0887-624X .- 1099-0518. ; 42:23, s. 5877-5890
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Tidskriftsartikel (refereegranskat)abstract
- The synthesis and characterization of novel first- and second-generation true dendritic reversible addition-fragmentation chain transfer (RAFT) agents carrying 6 or 12 pendant 3-benzylsulfanylthiocarbonylsulfanylpropionic acid RAFT end groups with Z-group architecture based on 1,1,1-hydroxyphenyl ethane and trimethylolpropane cores are described in detail. The multifunctional dendritic RAFT agents have been used to prepare star polymers of poly(butyl acrylate) (PBA) and polystyrene (PS) of narrow polydispersities (1.4 < polydispersity index < 1.1 for PBA and 1.5 < polydispersity index < 1.3 for PS) via bulk free-radical polymerization at 60 degreesC. The novel dendrimer-based multifunctional RAFT agents effect an efficient living polymerization process, as evidenced by the linear evolution of the number-average molecular weight (M.) with the monomer-polymer conversion, yielding star polymers with molecular weights of up to M-n = 160,000 g mol(-1) for PBA (based on a linear PBA calibration) and up to M. = 70,000 g mol(-1) for PS (based on a linear PS calibration). A structural change in the chemical nature of the dendritic core (i.e., 1,1,1-hydroxyphenyl ethane vs trimethylolpropane) has no influence on the observed molecular weight distributions. The star-shaped structure of the generated polymers has been confirmed through the cleavage of the pendant arms off the core of the star-shaped polymeric materials.
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| 42. |
- Harth, E. M., et al.
(författare)
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The effect of macromolecular architecture in nanomaterials : A comparison of site isolation in porphyrin core dendrimers and their isomeric linear analogues
- 2002
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 124:15, s. 3926-3938
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Forskningsöversikt (refereegranskat)abstract
- The influence of macromolecular architecture on the physical properties of polymeric materials has been studied by comparing poly(benzyl ether) dendrons with their exact linear analogues. The results clearly confirm the anticipation that dendrimers are unique when compared to other architectures. Physical properties, from hydrodynamic volume to crystallinity, were shown to be different, and in a comparative study of core encapsulation in macromolecules of different architecture, energy transduction from the polymer backbone to a porphyrin core was shown to be different for dendrimers as compared to that of isomeric four- or eight-arm star polymers. Fluorescence excitation revealed strong, morphology dependent intramolecular energy transfer in the three macromolecular isomers investigated, Even at high generations, the dendrimers exhibited the most efficient energy transfer, thereby indicating that the dendritic architecture affords superior site isolation to the central porphyrin it surrounds.
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| 43. |
- Hartman, Erik, et al.
(författare)
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Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The incorporation of machine learning methods into proteomics workflows improves the identification of disease-relevant biomarkers and biological pathways. However, machine learning models, such as deep neural networks, typically suffer from lack of interpretability. Here, we present a deep learning approach to combine biological pathway analysis and biomarker identification to increase the interpretability of proteomics experiments. Our approach integrates a priori knowledge of the relationships between proteins and biological pathways and biological processes into sparse neural networks to create biologically informed neural networks. We employ these networks to differentiate between clinical subphenotypes of septic acute kidney injury and COVID-19, as well as acute respiratory distress syndrome of different aetiologies. To gain biological insight into the complex syndromes, we utilize feature attribution-methods to introspect the networks for the identification of proteins and pathways important for distinguishing between subtypes. The algorithms are implemented in a freely available open source Python-package ( https://github.com/InfectionMedicineProteomics/BINN ).
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| 44. |
- Hatton, Fiona L., et al.
(författare)
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Xyloglucan-Functional Latex Particles via RAFT-Mediated Emulsion Polymerization for the Biomimetic Modification of Cellulose
- 2016
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Ingår i: Biomacromolecules. - : American Chemical Society (ACS). - 1525-7797 .- 1526-4602. ; 17:4, s. 1414-1424
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we report a novel class of latex particles composed of a hemicellulose, xyloglucan (XG), and poly(methyl methacrylate) (PMMA), specially designed to enable a biomimetic modification of cellulose. The formation of the latex particles was achieved utilizing reversible addition-fragmentation chain transfer (RAFT) mediated surfactant-free emulsion polymerization employing XG as a hydrophilic macromolecular RAFT agent (macroRAFT). In an initial step, XG was functionalized at the reducing chain end to bear a dithioester. This XG macroRAFT was subsequently utilized in water and chain extended with methyl methacrylate (MMA) as hydrophobic monomer, inspired by a polymerization-induced self-assembly (PISA) process. This yielded latex nanoparticles with a hydrophobic PMMA core stabilized by the hydrophilic XG chains at the corona. The molar mass of PMMA targeted was varied, resulting in a series of stable latex particles with hydrophobic PMMA content between 22 and 68 wt % of the total solids content (5-10%). The XG-PMMA nanoparticles were subsequently adsorbed to a neutral cellulose substrate (filter paper), and the modified surfaces were analyzed by FT-IR and SEM analyses. The adsorption of the latex particles was also investigated by quartz crystal microbalance with dissipation monitoring (QCM-D), where the nanoparticles were adsorbed to negatively charged model cellulose surfaces. The surfaces were analyzed by atomic force microscopy (AFM) and contact angle (CA) measurements. QCM-D experiments showed that more mass was adsorbed to the surfaces with increasing molar mass of the PMMA present. AFM of the surfaces after adsorption showed discrete particles, which were no longer present after annealing (160 °C, 1 h) and the roughness (Rq) of the surfaces had also decreased by at least half. Interestingly, after annealing, the surfaces did not all become more hydrophobic, as monitored by CA measurements, indicating that the surface roughness was an important factor to consider when evaluating the surface properties following particle adsorption. This novel class of latex nanoparticles provides an excellent platform for cellulose modification via physical adsorption. The utilization of XG as the anchoring molecule to cellulose provides a versatile methodology, as it does not rely on electrostatic interactions for the physical adsorption, enabling a wide range of cellulose substrates to be modified, including neutral sources such as cotton and bacterial nanocellulose, leading to new and advanced materials.
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| 45. |
- Hedegaard, Jakob, et al.
(författare)
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Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
- 2016
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 30:1, s. 27-42
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Tidskriftsartikel (refereegranskat)abstract
- Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal-and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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| 46. |
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| 47. |
- Jesberger, M., et al.
(författare)
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Hyperbranched polymers as scaffolds for multifunctional reversible addition-fragmentation chain-transfer agents : A route to polystyrene-core-polyesters and polystyrene-block-poly(butyl acrylate)-core-polyesters
- 2003
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Ingår i: Journal of Polymer Science Part A. - : Wiley. - 0887-624X .- 1099-0518. ; 41:23, s. 3847-3861
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Tidskriftsartikel (refereegranskat)abstract
- Polydisperse hyperbranched polyesters were modified for use as novel multifunctional reversible addition-fragmentation chain-transfer (RAFT) agents. The polyester-core-based RAFT agents were subsequently employed to synthesize star polymers of n-butyl acrylate and styrene with low polydispersity (polydispersity index < 1.3) in a living free-radical process. Although the polyester-core-based RAFT agent mediated polymerization of n-butyl acrylate displayed a linear evolution of the number-average molecular weight (M.) up to high monomer conversions (>70%) and molecular weights [M-n > 140,000 g mol(-1), linear poly(methyl methacrylate) equivalents)], the corresponding styrene-based system reached a maximum molecular weight at low conversions (approximate to30%, M-n = 45,500 g mol(-1), linear polystyrene equivalents). The resulting star polymers were subsequently used as platforms for the preparation of star block copolymers of styrene and n-butyl acrylate with a polyester core with low polydispersities (polydispersity index < 1.25). The generated polystyrene-based star polymers were successfully cast into highly regular honeycomb-structured microarrays.
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| 48. |
- Kamat, Ashish M, et al.
(författare)
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Bladder cancer
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10061, s. 2796-2810
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Forskningsöversikt (refereegranskat)abstract
- Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.
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| 49. |
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| 50. |
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