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1.
  • Ademuyiwa, Adesoji O., et al. (författare)
  • Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
  • 2016
  • Ingår i: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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2.
  • Hudson, Thomas J., et al. (författare)
  • International network of cancer genome projects
  • 2010
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
  • Tidskriftsartikel (refereegranskat)abstract
    • The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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3.
  • Jones, Robert P., et al. (författare)
  • Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma : A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial
  • 2019
  • Ingår i: JAMA Surgery. - : AMER MEDICAL ASSOC. - 2168-6254 .- 2168-6262. ; 154:11, s. 1038-1048
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear.Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival.Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019.Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine.Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence.Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P=.03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P=.04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P=.27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P=.85 and P=.35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P=.03).Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection.Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434. This secondary analysis of a randomized clinical trial investigates patterns of recurrence after adjuvant chemotherapy in pancreatic cancer and the association with survival.
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4.
  • Abreu, Soraia Carvalho, et al. (författare)
  • Lung Inflammatory Environments Differentially Alter Mesenchymal Stromal Cell Behavior
  • 2019
  • Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 317:6, s. 823-831
  • Tidskriftsartikel (refereegranskat)abstract
    • Mesenchymal stromal (stem) cells (MSCs) are increasingly demonstrated to ameliorate experimentally-induced lung injuries through disease-specific anti-inflammatory actions, thus suggesting that different in vivo inflammatory environments can influence MSC actions. To determine the effects of different representative inflammatory lung conditions, human bone marrow-derived MSCs (hMSCs) were exposed to in vitro culture conditions from bronchoalveolar lavage fluid (BALF) samples obtained from patients with either the acute respiratory distress syndrome (ARDS) or with other lung diseases including acute respiratory exacerbations of cystic fibrosis (CF) (non-ARDS). hMSCs were subsequently assessed for time- and BALF concentration-dependent effects on mRNA expression of selected pro- and anti-inflammatory mediators, and for overall patterns of gene and mRNA expression. Both common and disease specific-patterns were observed in gene expression of different hMSC mediators, notably interleukin (IL)-6. Conditioned media obtained from non-ARDS BALF-exposed hMSCs was more effective in promoting an anti-inflammatory phenotype in monocytes than was conditioned media from ARDS BALF-exposed hMSCs. Neutralizing IL-6 in the conditioned media promoted generation of anti-inflammatory monocyte phenotype. These results demonstrated that different lung inflammatory environments differentially alter hMSC behavior. Further identification of these interactions and the driving mechanisms may influence clinical use of MSCs for treating lung diseases.
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5.
  • Al-Shamkhi, Nasrin, 1985-, et al. (författare)
  • Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register.
  • 2023
  • Ingår i: European journal of endocrinology. - : Bioscientifica. - 1479-683X .- 0804-4643. ; 189:2, s. 217-224
  • Tidskriftsartikel (refereegranskat)abstract
    • Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA).Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded.Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively.Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.
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6.
  • Andersson, Alma, et al. (författare)
  • Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions
  • 2021
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases. While transcriptomics have enhanced our understanding for cancer, spatial transcriptomics enable the characterisation of cellular interactions. Here, the authors integrate single cell data with spatial information for HER2 + tumours and develop tools for the prediction of interactions between tumour-infiltrating cells.
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7.
  • Andersson, Alma, et al. (författare)
  • Spatial Deconvolution of HER2-positive Breast Tumors Reveals Novel Intercellular Relationships
  • 2020
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • In the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra-and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. We integrate and spatially map tumor-associated types from single cell data to find: segregated epithelial cells, interactions between B and T-cells and myeloid cells, co-localization of macrophage and T-cell subsets. A model is constructed to infer presence of tertiary lymphoid structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define novel interactions between tumor-infiltrating cells in breast cancer and provide tools generalizing across tissues and diseases.
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8.
  • Andersson, Ulrika, et al. (författare)
  • Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer
  • 2014
  • Ingår i: Neuro-Oncology. - : Oxford University Press. - 1522-8517 .- 1523-5866. ; 16:10, s. 1333-1340
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes.
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9.
  • Ansari, Daniel, et al. (författare)
  • Pancreatic cancer : Yesterday, today and tomorrow
  • 2016
  • Ingår i: Future Oncology. - : Future Medicine Ltd. - 1479-6694 .- 1744-8301. ; 12:16, s. 1929-1946
  • Tidskriftsartikel (refereegranskat)abstract
    • Pancreatic cancer is one of our most lethal malignancies. Despite substantial improvements in the survival rates for other major cancer forms, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Pancreatic cancer is usually detected at an advanced stage and most treatment regimens are ineffective, contributing to the poor overall prognosis. Herein, we review the current understanding of pancreatic cancer, focusing on central aspects of disease management from radiology, surgery and pathology to oncology.
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10.
  • Bogdanska, Jasna, et al. (författare)
  • Tissue distribution of (35)S-labelled perfluorooctane sulfonate in adult mice after oral exposure to a low environmentally relevant dose or a high experimental dose
  • 2011
  • Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 284:1-3, s. 54-62
  • Tidskriftsartikel (refereegranskat)abstract
    • The widespread environmental pollutant perfluorooctane sulfonate (PFOS), detected in most animal species including the general human population, exerts several effects on experimental animals, e.g., hepatotoxicity, immunotoxicity and developmental toxicity. However, detailed information on the tissue distribution of PFOS in mammals is scarce and, in particular, the lack of available information regarding environmentally relevant exposure levels limits our understanding of how mammals (including humans) may be affected. Accordingly, we characterized the tissue distribution of this compound in mice, an important experimental animal for studying PFOS toxicity. Following dietary exposure of adult male C57/BL6 mice for 1-5 days to an environmentally relevant (0.031 mg/kg/day) or a 750-fold higher experimentally relevant dose (23 mg/kg/day) of (35)S-PFOS, most of the radioactivity administered was recovered in liver, bone (bone marrow), blood, skin and muscle, with the highest levels detected in liver, lung, blood, kidney and bone (bone marrow). Following high daily dose exposure, PFOS exhibited a different distribution profile than with low daily dose exposure, which indicated a shift in distribution from the blood to the tissues with increasing dose. Both scintillation counting (with correction for the blood present in the tissues) and whole-body autoradiography revealed the presence of PFOS in all 19 tissues examined, with identification of thymus as a novel site for localization for PFOS and bone (bone marrow), skin and muscle as significant body compartments for PFOS. These findings demonstrate that PFOS leaves the bloodstream and enters most tissues in a dose-dependent manner.
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12.
  • Bogdanska, Jasna, et al. (författare)
  • Tissue distribution of C-14-labelled perfluorooctanoic acid in adult mice after 1-5 days of dietary exposure to an experimental dose or a lower dose that resulted in blood levels similar to those detected in exposed humans
  • 2020
  • Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 239
  • Tidskriftsartikel (refereegranskat)abstract
    • Perfluorooctanoic acid (PFOA), a global environmental pollutant detected in both wildlife and human populations, has several pathophysiological effects in experimental animals, including hepatotoxicity, immunotoxicity, and developmental toxicity. However, details concerning the tissue distribution of PFOA, in particular at levels relevant to humans, are lacking, which limits our understanding of how humans, and other mammals, may be affected by this compound. Therefore, we characterized the tissue distribution of C-14-PFOA in mice in the same manner as we earlier examined its analogues perfluorooctanesulfonate (PFOS) and perfluorobutanesulfonate (PFBS) in order to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1, 3 or 5 days to a low dose (0.06 mg/kg/day) or a higher experimental dose (22 mg/kg/day) of C-14-PFOA, both scintillation counting and whole-body autoradiography revealed the presence of PFOA in most of the 19 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. There were no differences in the pattern of tissue distribution with the low and high dose and the tissue-to-blood ratios were similar. At both doses, PFOA levels were highest in the liver, followed by blood, lungs and kidneys. The body compartments estimated to contain the largest amounts of PFOA were the liver, blood, skin and muscle. In comparison with our identical studies on PFOS and PFBS, PFOA reached considerably higher tissue levels than PFBS, but lower than PFOS. Furthermore, the distribution of PFOA differed notably from that of PFOS, with lower tissue-to-blood ratios in the liver, lungs, kidneys and skin.
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13.
  • Bogdanska, Jasna, et al. (författare)
  • Tissue distribution of S-35-labelled perfluorobutanesulfonic acid in adult mice following dietary exposure for 1-5 days
  • 2014
  • Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 98, s. 28-36
  • Tidskriftsartikel (refereegranskat)abstract
    • Perfluorobutanesulfonyl fluoride (PBSF) has been introduced as a replacement for its eight-carbon homolog perfluorooctanesulfonyl fluoride (POSF) in the manufacturing of fluorochemicals. Fluorochemicals derived from PBSF may give rise to perfluorobutanesulfonic acid (PFBS) as a terminal degradation product. Although basic mammalian toxicokinetic data exist for PFBS, information on its tissue distribution has only been reported in one study focused on rat liver. Therefore, here we characterized the tissue distribution of PFBS in mice in the same manner as we earlier examined its eight-carbon homolog perfluorooctanesulfonate (PFOS) to allow direct comparisons. Following dietary exposure of adult male C57/BL6 mice for 1,3 or 5 d to 16 mg S-35-PFBS kg(-1) d(-1), both scintillation counting and whole-body autoradiography (WBA) revealed the presence of PFBS in all of the 20 different tissues examined, demonstrating its ability to leave the bloodstream and enter tissues. After 5 d of treatment the highest levels were detected in liver, gastrointestinal tract, blood, kidney, cartilage, whole bone, lungs and thyroid gland. WBA revealed relatively high levels of PFBS in male genital organs as well, with the exception of the testis. The tissue levels increased from 1 to 3 d of exposure but appeared thereafter to level-off in most cases. The estimated major body compartments were whole bone, liver, blood, skin and muscle. This exposure to PFBS resulted in 5-40-fold lower tissue levels than did similar exposure to PFOS, as well as in a different pattern of tissue distribution, including lower levels in liver and lungs relative to blood.
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14.
  • Bolton, Kelly L., et al. (författare)
  • Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
  • 2012
  • Ingår i: JAMA: The Journal of the American Medical Association. - : American Medical Association (AMA). - 1538-3598. ; 307:4, s. 382-390
  • Tidskriftsartikel (refereegranskat)abstract
    • Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Main Outcome Measure Five-year overall mortality. Results The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity=.003). Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. JAMA. 2012;307(4):382-390
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16.
  • Borg, Daniel, et al. (författare)
  • Environmental and Health Risk Assessment of Perfluoroalkylated and Polyfluoroalkylated Substances (PFASs) in Sweden
  • 2012
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Denna rapport sammanfattar resultatet av ett projekt för att ta fram information och ny kunskap gällande möjliga miljö- och hälsorisker av perfluoralkylerade och polyfluoralkylerade ämnen (PFAS) i Sverige. Projektet har utförts i form av en riskbedömning, bestående av en exponeringsbedömning med svenska monitoringdata för 23 utvalda PFAS i människor, däggdjur, fågel och fisk,en farobedömning med toxikologiska data på däggdjur, fågel och fisk för deutvalda ämnena och en riskkaraktärisering för människa, däggdjur, fågel ochfisk. Detta är den första hälso- och miljöriskbedömningen som undersöker ett stort antal PFAS, individuellt och i kombination. I den hälsorelaterade exponeringsbedömningen valdes två populationer ut– människor exponerade indirekt via miljön (dvs. allmänbefolkningen) och enyrkesexponerad grupp – professionella skidvallare. Exponeringsdata i form avPFAS-halter i blod och serum användes. Resultatet visade att de undersökta PFAS-kongenerna förekom i serum i låga ppb-halter (ng/ml) i allmänbefolkningen. I en liten subpopulation av allmänbefolkningen som ätit kontaminerad fisk kunde högre ppb-halter av PFOS uppmätas. I den yrkesexponerade gruppen förekom avsevärt högre koncentrationer av vissa kongener, t exPFNA och PFOA som uppmätts i höga ppb- eller låga ppm- halter (μg/ml),ca 125 och 200 gånger högre än i den allmänna befolkningen. Tidstrendstudieri den allmänna befolkningen visade att halterna av PFOS, PFDS, PFOSA ochPFOA i serum förefaller minska, medan halterna av PFBS, PFHxS, PFNA,PFDA och PFUnDA istället förefaller öka. I den hälsorelaterade farobedömningen användes främst data och slutsatser från redan existerande faro- eller riskbedömningar, som kompletterades med nytillkomna eller andra relevanta data. Två toxikologiska endpoints somidentifierades som gemensamma för PFAS användes: 1) levertoxicitet, och 2)reproduktions/utvecklingstoxicitet. För kongener som saknade toxikologiska data eller interndoser gjordes en ”read-across”, dvs. extrapolering av data, tillden närmaste mest potenta kongenern för respektive endpoint. Andra toxikologiskaendpoints som uppvisade lägre effektnivåer än lever- eller reproduktionstoxicitet beaktades också. Resultatet av farobedömningen visade att deolika PFAS-kongenerna var relativt lika avseende deras potens för lever- ochreproduktionstoxicitet, med utgångspunkter (på engelska ”point-of-departure”)på 4–89 μg/ml serum respektive 4–> 60 μg/ml serum. Användbara toxikologiskadata med interndoser fanns tillgängliga för 4 av 15 kongener i allmänbefolkningen och 5 av 17 kongener för de yrkesexponerade. För några kongenerkunde ytterligare toxikologiska endpoints identifieras (immuntoxicitet, påverkanpå bröstkörtelutveckling, fetma) vid väldigt låga effektnivåer – vid eller undernuvarande exponeringsnivåer för allmänbefolkningen. Epidemiologiska studiervisade motstridiga resultat.Riskkaraktäriseringen visade inte på någon risk1 för lever- eller reproduktionstoxiciteti allmänbefolkningen, vare sig för enskilda kongener eller i kombination. I den subpopulation som ätit kontaminerad fisk kunde däremot enrisk för levertoxicitet påvisas baserat på uppmätta PFOS-halter. För de yrkesexponeradeskidvallarna kunde en risk för levertoxicitet identifieras, baserat på enskilda kongener och i kombination, samt för reproduktionstoxicitet baserat på den samlade PFAS-exponeringen. Det bör dock understrykas attdenna grupp omfattar ett mycket begränsat antal människor i Sverige.I den miljörelaterade exponeringsbedömningen valdes 5 arter/grupper utmed följande vävnadsmatriser: 1) säl (lever), 2) utter (lever), 3) fågel (ägg),4) marin fisk (lever) och 5) högexponerad sötvattensfisk (muskel), baserat påförekomsten av PFAS i dessa arter. Alla dessa finns i, eller är kopplade till, denakvatiska miljön och visar på hur PFAS sprids till miljön. I de terrestra artersom granskades var halterna av PFAS signifikant lägre. PFOS var den dominerande kongenern i alla arter och kunde uppmätas i låga ppm-nivåer eller högappb-nivåer i säl och utter, fågelägg och högexponerad sötvattensfisk, och i lågappb-nivåer i marin fisk. I säl och utter kunde en nedåtgående trend för halterav sulfonater och en ökande trend för halter av karboxylater urskiljas. I äggfrån pilgrimsfalk var alla uppmätta kongener långkedjiga och en tidstrendstudievisade att nivåer av sulfonater var oförändrade eller nedåtgående, och att karboxylater med en kedjelängd av 11–15 kol minskar, men att PFNA ochPFDA ökar. I marin fisk innehåll alla detekterade kongener sex eller fler kolför sulfonater, och nio eller fler kol för karboxylater, vilket troligen återspeglar den högre biokoncentrationsfaktorn (BCF) för långkedjiga kongener. PFAShalterna var betydligt högre i högexponerad sötvattensfisk än i marin fisk. I den miljörelaterade farobedömningen användes för säl och utter samma toxikologiska endpoints och utgångspunkter som i den hälsorelaterade farobedömningen,baserat på deras gemensamma toxikologiska dataunderlag, menmed skillnad i de specifika kongener som undersökts samt att halter i leveranvändes som interdos istället för serum. Användbara toxikologiska data medinterndoser i lever var tillgängliga för 4 av 17 kongener, varav data för övrigakongener behövde extrapoleras. För fågel togs enbart data från reproduktionstoxicitetsstudiermed interndoser uppmätta i ägg i beaktande, vilka fannstillgängliga för 5 av 15 kongener, varav de övriga behövde extrapoleras. Få relevanta studier på reproduktionstoxicitet av PFAS i fågel fanns tillgängliga, och i dessa kunde endast effekter påvisas för PFOS. Dataunderlaget på PFAS i fågel kan därför anses osäkert med avseende på toxiska effekter, effektnivåeroch de extrapoleringar som gjorts. För fisk så fanns data tillgängliga för 5 av17 kongener och toxiska effektnivåer och utgångspunkter bör betraktas som högst osäkra beroende på att olika typer av studier, arter, och endpoints har använts, vilket gör dem väldigt svåra att jämföra mellan olika kongener. Dessa extrapoleringar är därför högst osäkra.Resultatet av riskkaraktäriseringen för säl och utter visade på risk för levertoxicitetoch reproduktionstoxicitet för enskilda kongener och/eller i kombination.Det bör poängteras att slutsatser gällande säl och utter är baserade pågenomsnittsnivåer av PFAS vid den sista tidpunkten i tidstrendstudier, och att nivåerna kan vara högre på individnivå, vilket skulle resultera i lägre säkerhetsmarginaler.För reproduktionstoxicitet i fågel kunde en risk påvisas, där de högsta halterna i pilgrimsfalksägg (provtagna 2006) översteg de halter iägg där en studie visat toxiska effekter, och där den genomsnittliga halten varnära de toxiska effektnivåerna. Det kan därför inte uteslutas att halterna av PFOS i dessa ägg kan ge upphov skadliga effekter. För marin och högexponerad sötvattensfisk indikerar tillgängliga data ingen risk för skadliga effekter. Det bör dock tydliggöras att data för fisk, monitoring såväl som toxicitetsdata och dess extrapoleringar är förknippade med en hög grad av osäkerhet p.g.a.brister i dataunderlaget.
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17.
  • Borg, Daniel, et al. (författare)
  • Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.
  • 2009
  • Ingår i: Abstracts of the 46th Congress of the European Societies of Toxicology. - : Elsevier BV. ; 189:SI, s. S147-S147
  • Konferensbidrag (refereegranskat)abstract
    • Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.
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18.
  • Borg, Daniel (författare)
  • Tissue distribution studies and risk assessment of perfluoroalkylated and polyfluoroalkylated substances (PFASs)
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Perfluoroalkylated and polyfluoroalkylated substances (PFASs) represent a large class of man-made chemicals. These substances have emerged as environmental contaminants due to their extraordinary resistance to degradation, potential for bioaccumulation, toxicity and a global presence in humans, wildlife and the environment. In the Swedish population 17 PFASs have so far been analyzed in blood. In animal studies, PFASs cause liver toxicity and reproductive/developmental toxicity as well as a range of other toxic effects. Detailed data on the tissue distribution of PFASs, which could contribute to better understanding of their toxicity, are limited. Also, health risk assessment information has been lacking for all PFASs except the most studied, perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). The aims of this thesis were to 1) generate detailed tissue distribution data on PFOS in perinatal and adult mice and on its replacement chemical perfluorobutane sulfonate (PFBS) in adult mice; and 2) and assess potential risks to human health associated with exposure to the 17 PFASs analyzed in the general Swedish population and occupationally exposed ski waxers, for all PFASs individually and in combination. The results of the experiments showed that following exposure of pregnant dams PFOS was readily transferred to mouse fetuses resulting in tissue levels similar to or higher than maternal blood levels. PFOS was markedly distributed to the perinatal and maternal lungs; showing the highest levels of the tissues analyzed in fetuses/pups on gestational day 20 and postnatal day 1. This finding may help to explain the respiratory distress seen in neonatal and adult rodents following exposure to PFOS. Further, in adult male mice after short-term dietary exposure to one environmentally relevant low dose and one experimentally relevant high dose, PFOS was recovered in all 19 examined tissues, with similar tissue distribution profiles at both doses, though with a higher tissue:blood ratio at the higher dose. The highest concentrations of PFOS were found in liver, lungs, blood, kidneys and whole bone and the major body compartments were liver, bone, blood, skin and muscle. Blood hemoglobin levels were markedly increased at the high dose which could be connected to the localization of PFOS in bone marrow. In a similar experiment PFBS was recovered in all 20 examined tissues in adult male mice after short-term dietary exposure to the same molar concentration as the high dose of PFOS. The distribution and compartment profiles were similar to those of PFOS with the exception of a remarkably high concentration in cartilage. Also, PFBS displayed significantly lower tissue concentrations and tissue: blood ratios than PFOS and a less marked erythropoietic effect. The risk assessment of PFASs showed that hepatotoxicity and reproductive/ developmental toxicity may be of concern for high local exposure and occupational exposure but indicated no risk for the general population. Concern for the less studied endpoints immunotoxicity and altered mammary gland development was identified for the general population and the occupationally exposed. A need of additional toxicological data for all investigated toxicological endpoints was recognized. Altogether, the work included in this thesis has generated experimental data that can be used to improve risk assessment of PFASs. It has also assessed the risks associated with current exposures to PFASs in Sweden and identified data needs.
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19.
  • Borg, Markus, et al. (författare)
  • An Analytical View ofTest Results Using CityScapes
  • 2018
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • t— In this paper we map test results from a real ASIC project on to the file structure of the design under test andpresent it as a cityscape. In the cityscape each house is a file where its height reflects the number of commits to that file. Thecolor reflects the fraction of bad commits.We identify error prone areas (red "bad" neighborhoods) as well as the most active areas (tall "downtown" areas). Thecityscape also allows us to identify potential test coverage holes (tall green buildings) where there are a lot of activities but nofailures.
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20.
  • Borg, Markus, et al. (författare)
  • Enabling Visual Design Verification Analytics– From Prototype Visualizations to anAnalytics Tool using the Unity Game Engine
  • 2018
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • The ever-increasing architectural complexity in contemporary ASIC projects turns Design Verification (DV)into a highly advanced endeavor. Pressing needs for short time-to-market has made automation a key solution in DV.However, recurring execution of large regression suites inevitably leads to challenging amounts of test results. Following thedesign science paradigm, we present an action research study to introduce visual analytics in a commercial ASIC project. Wedevelop a cityscape visualization tool using the game engine Unity. Initial evaluations are promising, suggesting that the tooloffers a novel approach to identify error-prone parts of the design, as well as coverage holes.
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21.
  • Borg, Markus, et al. (författare)
  • The AIQ Meta-Testbed : Pragmatically Bridging Academic AI Testing and Industrial Q Needs
  • 2021
  • Ingår i: Lecture Notes in Business Information Processing. - Cham : Springer Science and Business Media Deutschland GmbH. - 1865-1348 .- 1865-1356. - 9783030658533 ; 404, s. 66-77
  • Tidskriftsartikel (refereegranskat)abstract
    • AI solutions seem to appear in any and all application domains. As AI becomes more pervasive, the importance of quality assurance increases. Unfortunately, there is no consensus on what artificial intelligence means and interpretations range from simple statistical analysis to sentient humanoid robots. On top of that, quality is a notoriously hard concept to pinpoint. What does this mean for AI quality? In this paper, we share our working definition and a pragmatic approach to address the corresponding quality assurance with a focus on testing. Finally, we present our ongoing work on establishing the AIQ Meta-Testbed. 
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22.
  • Borg, O Anders, et al. (författare)
  • Photochemistry of bromofluorobenzenes.
  • 2006
  • Ingår i: J Phys Chem A Mol Spectrosc Kinet Environ Gen Theory. - 1089-5639. ; 110, s. 7045-
  • Tidskriftsartikel (refereegranskat)
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23.
  • Borg, O. Anders, et al. (författare)
  • Predissociation of Chlorobenzene, beyond the pseudo-diatomic model
  • 2008
  • Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614 .- 1873-4448. ; 456:4-6, s. 123-126
  • Tidskriftsartikel (refereegranskat)abstract
    • Dissociation of chlorobenzene via the lowest singlet excited state has been investigated by means of pump-probe femtosecond spectroscopy and spin-orbit corrected ab initio quantum chemistry. We have found that the so far accepted model with a (1)pi pi* -> (3)pi/n sigma* reaction mechanism has to be amended. We suggest that the mechanism goes via a transition from (1)pi pi* to a pi sigma* state that is to 90% a singlet. Further, three nuclear degrees of freedom required to describe the dissociation have been defined.
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24.
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25.
  • Borg, Sabina, et al. (författare)
  • Factors associated with non-attendance at exercise-based cardiac rehabilitation
  • 2019
  • Ingår i: BMC Sports Science, Medicine and Rehabilitation. - : BMC. - 2052-1847. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundDespite its well-established positive effects, exercise-based cardiac rehabilitation (exCR) is underused in patients following an acute myocardial infarction (AMI). The aim of the study was to identify factors associated with non-attendance at exCR in patients post-AMI in a large Swedish cohort.MethodsA total of 31,297 patients who have suffered an AMI, mean age 62.4 ± 4 years, were included from the SWEDEHEART registry during the years 2010–2016. Comparisons between attenders and non-attenders at exCR were done at baseline for the following variables: age, sex, body mass index, occupational status, smoking, previous diseases, type of index cardiac event and intervention, and left ventricular function. Distance of residence from the hospital and type of hospital were added as structural variables in logistic regression analyses, with non-attendance at exCR at one-year follow-up as dependent, and with individual and structural variables as independent variables.ResultsIn total, 16,214 (52%) of the patients did not attend exCR. The strongest predictor for non-attendance was distance to the exCR centre (OR 1.75 [95% CI: 1.64–1.86]). Other predictors for non-attendance included smoking, history of stroke, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), AMI or diabetes, male sex, being retired vs. being employed, and being followed-up at a county hospital. Patients with ST-elevation myocardial infarction (STEMI) and those intervened with PCI or CABG were more likely to attend exCR.ConclusionsA distance greater than 16 km was associated with increased probability of non-attendance at exCR, as were smoking, a higher burden of comorbidities, and male sex. A better understanding of individual and structural factors can support the development of future rehabilitation services.
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26.
  • Breitholtz, Magnus, et al. (författare)
  • An evaluation of free water surface wetlands as tertiary sewage water treatment of micro-pollutants
  • 2012
  • Ingår i: Ecotoxicology and Environmental Safety. - : Elsevier BV. - 0147-6513 .- 1090-2414. ; 78, s. 63-71
  • Tidskriftsartikel (refereegranskat)abstract
    • Increased attention is currently directed towards potential negative effects of pharmaceuticals and other micro-pollutants discharged into the aquatic environment via municipal sewage water. A number of additional treatment technologies, such as ozonation, have therefore been suggested as promising tools for improving the removal efficiency of pharmaceuticals in existing Sewage Treatment Plants (STPs). Constructed wetlands are also capable of removing a variety of micro-pollutants, including some pharmaceuticals, and could hence be a resource efficient complement to more advanced treatment technologies. The purpose of the present study was therefore to increase the knowledge base concerning the potential use of constructed wetlands as a treatment step to reduce emissions of organic micro-pollutants from municipal sewage effluents. Under cold winter conditions, incoming and outgoing waters from four Swedish free water surface wetlands, operated as final treatment steps of sewage effluent from municipal STPs, were sampled and analyzed for levels of a set of 92 pharmaceuticals and 22 inorganic components as well as assessed using subchronic ecotoxicity tests with a macro-alga and a crustacean. Sixty-five pharmaceuticals were detected in the range from 1 ng L-1 to 7.6 mu g L-1 in incoming and outgoing waters from the four investigated wetlands. Although the sampling design used in the present study lacks the robustness of volume proportional to 24 h composite samples, the average estimated removal rates ranged from 42% to 52%, which correlates to previous published values. The effects observed in the ecotoxicity tests with the macro-alga (EC(50)s in the range of 7.5-46%) and the crustacean (LOECs in the range of 11.25-90%) could not be assigned to either pharmaceutical residues or metals, but in general showed that these treatment facilities release water with a relatively low toxic potential, comparable to water that has been treated with advanced tertiary treatments. From the present study it can be concluded that constructed wetlands may provide a complementary sewage treatment option, especially where other treatment is lacking today. To fully remove micro-pollutants from sewage effluent, however, other more advanced treatment technologies are likely needed.
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27.
  • Drake, Thomas M., et al. (författare)
  • Outcomes following small bowel obstruction due to malignancy in the national audit of small bowel obstruction
  • 2019
  • Ingår i: European Journal of Surgical Oncology. - : Elsevier BV. - 0748-7983 .- 1532-2157. ; 45:12, s. 2319-2324
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2019 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology Introduction: Patients with cancer who develop small bowel obstruction are at high risk of malnutrition and morbidity following compromise of gastrointestinal tract continuity. This study aimed to characterise current management and outcomes following malignant small bowel obstruction. Methods: A prospective, multicentre cohort study of patients with small bowel obstruction who presented to UK hospitals between 16th January and 13th March 2017. Patients who presented with small bowel obstruction due to primary tumours of the intestine (excluding left-sided colonic tumours) or disseminated intra-abdominal malignancy were included. Outcomes included 30-day mortality and in-hospital complications. Cox-proportional hazards models were used to generate adjusted effects estimates, which are presented as hazard ratios (HR) alongside the corresponding 95% confidence interval (95% CI). The threshold for statistical significance was set at the level of P ≤ 0.05 a-priori. Results: 205 patients with malignant small bowel obstruction presented to emergency surgery services during the study period. Of these patients, 50 had obstruction due to right sided colon cancer, 143 due to disseminated intraabdominal malignancy, 10 had primary tumours of the small bowel and 2 patients had gastrointestinal stromal tumours. In total 100 out of 205 patients underwent a surgical intervention for obstruction. 30-day in-hospital mortality rate was 11.3% for those with primary tumours and 19.6% for those with disseminated malignancy. Severe risk of malnutrition was an independent predictor for poor mortality in this cohort (adjusted HR 16.18, 95% CI 1.86 to 140.84, p = 0.012). Patients with right-sided colon cancer had high rates of morbidity. Conclusions: Mortality rates were high in patients with disseminated malignancy and in those with right sided colon cancer. Further research should identify optimal management strategy to reduce morbidity for these patient groups.
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28.
  • Gomis Ferreira, Melissa Ines, 1987-, et al. (författare)
  • Comparing the toxic potency in vivo of long-chain perfluoroalkyl acids and fluorinated alternatives
  • 2018
  • Ingår i: Environment International. - : Elsevier BV. - 0160-4120 .- 1873-6750. ; 113, s. 1-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Since 2000, long-chain perfluoroalkyl acids (PFAAs) and their respective precursors have been replaced by numerous fluorinated alternatives. The main rationale for this industrial transition was that these alternatives were considered less bioaccumulative and toxic than their predecessors. In this study, we evaluated to what extent differences in toxicological effect thresholds for PFAAs and fluorinated alternatives, expressed as administered dose, were confounded by differences in their distribution and elimination kinetics. A dynamic one-compartment toxicokinetic (TK) model for male rats was constructed and evaluated using test data from toxicity studies for perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorobutane sulfonic acid (PFBS), perfluorooctanoic acid (PFOA), perfluoroctanesulfonic acid (PFOS) and ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate (GenX). Dose-response curves of liver enlargement from sub-chronic oral toxicity studies in male rats were converted to internal dose in serum and in liver to examine the toxicity ranking of PFAAs and fluorinated alternatives. Converting administered doses into equivalent serum and liver concentrations reduced the variability in the dose-response curves for PFBA, PFHxA, PFOA and GenX. The toxicity ranking using modeled serum (GenX>PFOA>PFHxA>PFBA) and liver (GenX>PFOA≈PFHxA≈PFBA) concentrations indicated that some fluorinated alternatives have similar or higher toxic potency than their predecessors when correcting for differences in toxicokinetics. For PFOS and perfluorobutane sulfonic acid (PFBS) the conversion from administered dose to serum concentration equivalents did not change the toxicity ranking. In conclusion, hazard assessment based on internal exposure allows evaluation of toxic potency and bioaccumulation potential independent of kinetics and should be considered when comparing fluorinated alternatives with their predecessors.
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29.
  • Goodwin, Richard J. A., et al. (författare)
  • Conductive carbon tape used for support and mounting of both whole animal and fragile heat-treated tissue sections for MALDI MS imaging and quantitation
  • 2012
  • Ingår i: Journal of Proteomics. - : Elsevier BV. - 1874-3919 .- 1876-7737. ; 75:16, s. 4912-4920
  • Tidskriftsartikel (refereegranskat)abstract
    • Analysis of whole animal tissue sections by MALDI MS imaging (MSI) requires effective sample collection and transfer methods to allow the highest quality of in situ analysis of small or hard to dissect tissues. We report on the use of double-sided adhesive conductive carbon tape during whole adult rat tissue sectioning of carboxymethyl cellulose (CMC) embedded animals, with samples mounted onto large format conductive glass and conductive plastic MALDI targets, enabling MSI analysis to be performed on both TOF and FT-ICR MALDI mass spectrometers. We show that mounting does not unduly affect small molecule MSI detection by analyzing tiotropium abundance and distribution in rat lung tissues, with direct on-tissue quantitation achieved. Significantly, we use the adhesive tape to provide support to embedded delicate heat-stabilized tissues, enabling sectioning and mounting to be performed that maintained tissue integrity on samples that had previously been impossible to adequately prepare section for MSI analysis. The mapping of larger peptidomic molecules was not hindered by tape mounting samples and we demonstrate this by mapping the distribution of PEP-19 in both native and heat-stabilized rat brains. Furthermore, we show that without heat stabilization PEP-19 degradation fragments can detected and identified directly by MALDI MSI analysis.This article is part of a Special Issue entitled: Imaging Mass Spectrometry: A User's Guide to a New Technique for Biological and Biomedical Research.
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30.
  • Himonakos, Christos, et al. (författare)
  • Long-term Follow-up of 84 Patients With Giant Prolactinomas-A Swedish Nationwide Study.
  • 2023
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : Oxford University Press. - 1945-7197 .- 0021-972X. ; 108:12
  • Tidskriftsartikel (refereegranskat)abstract
    • To describe the clinical presentation and treatment outcomes in a nationwide cohort of patients with giant prolactinomas.Register-based study of patients with giant prolactinomas [serum prolactin (PRL) > 1000 µg/L, tumor diameter ≥40 mm] identified in the Swedish Pituitary Register 1991-2018.Eighty-four patients [mean age 47 (SD ±16) years, 89% men] were included in the study. At diagnosis, the median PRL was 6305 µg/L (range 1450-253 000), the median tumor diameter was 47 mm (range 40-85), 84% of the patients had hypogonadotropic hypogonadism, and 71% visual field defects. All patients were treated with a dopamine agonist (DA) at some point. Twenty-three (27%) received 1 or more additional therapies, including surgery (n = 19), radiotherapy (n = 6), other medical treatments (n = 4), and chemotherapy (n = 2). Ki-67 was ≥10% in 4/14 tumors. At the last follow-up [median 9 years (interquartile range (IQR) 4-15)], the median PRL was 12 µg/L (IQR 4-126), and the median tumor diameter was 22 mm (IQR 3-40). Normalized PRL was achieved in 55%, significant tumor reduction in 69%, and combined response (normalized PRL and significant tumor reduction) in 43%. In the primary DA-treated patients (n = 79), the reduction in PRL or tumor size after the first year predicted the combined response at the last follow-up (P < .001 and P = .012, respectively).DAs effectively reduced PRL and tumor size, but approximately 1 patient out of 4 needed multimodal treatment. Our results suggest that the response to DA after 1 year is useful for identifying patients who need more careful monitoring and, in some cases, additional treatment.
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31.
  • Karlsson, Daniel, et al. (författare)
  • Experimental and theoretical study of the photodissociation of bromo-3-fluorobenzene
  • 2008
  • Ingår i: Journal of Chemical Physics. - : AIP Publishing. - 0021-9606 .- 1089-7690. ; 128:3, s. 034307-
  • Tidskriftsartikel (refereegranskat)abstract
    • The UV photodissociation of bromo-3-fluorobenzene under collisionless conditions has been studied as a function of the excitation wavelength between 255 and 265 nm. The experiments were performed using ultrafast pump-probe laser spectroscopy. To aid in the interpretation of the results, it was necessary to extend the theoretical framework substantially compared to previous studies, to also include quantum dynamical simulations employing a two-dimensional nuclear Hamiltonian. The nonadiabatic potential energy surfaces (PES) were parameterized against high-level MS-CASTP2 quantum chemical calculations, using both the C–Br distance and the out-of-plane bending of the bromine as nuclear parameters. We show that the wavelength dependence of the photodissociation via the S0→1ππ*→1πσ* channel, accessible with a ∼ 260 nm pulse, is captured in this model. We thereby present the first correlation between experiments and theory within the quantitative regime.
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32.
  • Kotera, Yasuhiro, et al. (författare)
  • Cross-cultural insights from two global mental health studies: self-enhancement and ingroup biases
  • Ingår i: International Journal of Mental Health and Addiction. - 1557-1882.
  • Tidskriftsartikel (refereegranskat)abstract
    • This commentary highlights two cross-cultural issues identified from our global mental health (GMH) research, RECOLLECT (Recovery Colleges Characterisation and Testing) 2: self-enhancement and ingroup biases. Self-enhancement is a tendency to maintain and express unrealistically positive self-views. Ingroup biases are differences in one’s evaluation of others belonging to the same social group. These biases are discussed in the context of GMH research using self-report measures across cultures. GMH, a field evolving since its Lancet series introduction in 2007, aims to advance mental health equity and human rights. Despite a 16.5-fold increase in annual GMH studies from 2007 to 2016, cross-cultural understanding remains underdeveloped. We discuss the impact of individualism versus collectivism on self-enhancement and ingroup biases. GMH research using concepts, outcomes, and methods aligned with individualism may give advantages to people and services oriented to individualism. GMH research needs to address these biases arising from cross-cultural differences to achieve its aim.
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33.
  • Kuchenbaecker, Karoline B., et al. (författare)
  • Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers
  • 2017
  • Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 × 10-53). InBRCA2 carriers, the strongest association with BC risk was seen for the overall BCPRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 × 10-20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.
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34.
  • Lidfeldt, August, et al. (författare)
  • Enabling Image Recognition on Constrained Devices Using Neural Network Pruning and a CycleGAN
  • 2020
  • Ingår i: ACM International Conference Proceeding Series. - New York, NY, USA : Association for Computing Machinery. - 9781450388207
  • Konferensbidrag (refereegranskat)abstract
    • Smart cameras are increasingly used in surveillance solutions in public spaces. Contemporary computer vision applications can be used to recognize events that require intervention by emergency services. Smart cameras can be mounted in locations where citizens feel particularly unsafe, e.g., pathways and underpasses with a history of incidents. One promising approach for smart cameras is edge AI, i.e., deploying AI technology on IoT devices. However, implementing resource-demanding technology such as image recognition using deep neural networks (DNN) on constrained devices is a substantial challenge. In this paper, we explore two approaches to reduce the need for compute in contemporary image recognition in an underpass. First, we showcase successful neural network pruning, i.e., we retain comparable classification accuracy with only 1.1% of the neurons remaining from the state-of-the-art DNN architecture. Second, we demonstrate how a CycleGAN can be used to transform out-of-distribution images to the operational design domain. We posit that both pruning and CycleGANs are promising enablers for efficient edge AI in smart cameras.
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35.
  • Loman, Niklas, et al. (författare)
  • Abstract P2-02-09: Breast cancer subtype distribution and circulating tumor DNA in response to neoadjuvant chemotherapy: Experiences from a preoperative cohort within SCAN-B
  • 2018
  • Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
  • Konferensbidrag (refereegranskat)abstract
    • Introduction: Preoperative chemotherapy in early breast cancer increases the rate of breast preservation and provides prognostic information. In the case of residual disease, a change in subtypes may be observed. Sensitive and reproducible biomarkers predicting treatment response early during the treatment course are needed in order to better exploit the potential benefit of an individualized preoperative treatment.Material and Methods: In an ongoing prospective study within the population-based SCAN-B project (NCT02306096), patients undergoing preoperative chemotherapy for early or locally recurrent breast cancer have been treated with iv Epirubicin and Cyclophosphamide q3w x 3 in sequence with either Docetaxel q3w x 3 or Paclitaxel q1w x 9 with a preoperative intent. HER2-positive cases also received HER2-directed treatment. At baseline, patients were staged using sentinel node biopsy for clinically node-negative patients and CT scan for cytologically confirmed node-positive cases. A clinical core needle biopsy as well as tissue from the surgical specimen was collected for determination of conventional biomarkers including ER, PgR, HER2 and Ki67. Tumor biopsies for biomolecule-extraction and RNA-sequencing were taken using ultrasound guidance and collected fresh in RNAlater at baseline, after 2 treatment cycles, as well as at surgery. Blood plasma samples were collected at baseline, after one-, three-, and six- 3w treatment cycles, and post-surgery. Using RNA-sequencing data, somatic mutations were identified in the tumor biopsies and personalized analyses for circulating tumor DNA (ctDNA) were performed. A pathological complete remission (pCR) was defined as the complete disappearance of invasive breast cancer in the breast and axilla at time of definitive surgery. Subtyping was performed using modified St Gallen criteria (2013).Results: Thus far, 45 patients aged 24-74 years have been included, of which 34 (76 %) were clinical stage 2 and 11 (24%) were stage 3. The subtype distribution at baseline was five Luminal A-like (11 %), 21 Luminal B-like (HER2 negative) (47 %), 8 HER2-positive (18 %) and 11 Triple-negative (ductal) (24 %). The rates of pCR in 38 operated cases to date were 0/3 Luminal A-like, 3/19 Luminal B-like (HER2 negative), 2/8 HER2-positive, and 4/7 Triple-negative (overall 24 % pCR rate). One patient did not undergo surgery due to clinically progressive disease. In 25 cases with evaluable residual disease at surgery, there was a shift in the subtype in 13 (52 %), the majority of which represented a transition from Luminal B to Luminal A. No Triple-negative cases underwent a change in subtype during treatment. Results of the ctDNA analyses will be presented at the meeting.Discussion: We have established an infrastructure allowing for an extensive evaluation of preoperative chemotherapy in early breast cancer. The goal is to develop methods to refine response-guided treatment in early breast cancer using molecular responses in the tumor as well as in the blood circulation. The patients continue to be prospectively monitored with iterative ctDNA analyses during follow-up.
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36.
  • Martinez, Maria Månsson, et al. (författare)
  • Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA
  • 2022
  • Ingår i: Clinical diabetes and endocrinology. - : Springer Science and Business Media LLC. - 2055-8260. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.METHODS: Subjects (n = 57) at 2-50 years of age, positive for two or more islet autoantibodies were assessed by fasting plasma insulin, glucose, HbA1c as well as First Phase Insulin Response (FPIR) in IvGTT, followed 1 month later by OGTT, and 1 week of CGM (n = 24).RESULTS: Autoantibodies against GAD65 (GADA; n = 52), ZnT8 (ZnT8A; n = 40), IA-2 (IA-2A; n = 38) and insulin (IAA; n = 28) were present in 9 different combinations of 2-4 autoantibodies. Fasting glucose and HbA1c did not differ between the two visits. The estimate of the linear relationship between log2-transformed FPIR as the outcome and log2-transformed area under the OGTT glucose curve (AUC) as the predictor, adjusting for age and sex was - 1.88 (- 2.71, - 1.05) p = 3.49 × 10-5. The direction of the estimates for all glucose metabolism measures was positive except for FPIR, which was negative. FPIR was associated with higher blood glucose. Both the median and the spread of the CGM glucose data were significantly associated with higher glucose values based on OGTT, higher HbA1c, and lower FPIR. There was no association between glucose metabolism, autoantibody number and type except that there was an indication that the presence of at least one of ZnT8(Q/R/W) A was associated with a lower log2-transformed FPIR (- 0.80 (- 1.58, - 0.02), p = 0.046).CONCLUSIONS: The sole use of two or more islet autoantibodies as inclusion criterion for Stage 1 diabetes in prevention trials is unsatisfactory. Staging type 1 diabetes needs to take the heterogeneity in beta-cell function and glucose metabolism into account.TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02605148 , November 16, 2015.
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37.
  • Martrat, Griselda, et al. (författare)
  • Exploring the link between MORF4L1 and risk of breast cancer
  • 2011
  • Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 13:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Proteins encoded by Fanconi anemia (FA) and/or breast cancer (BrCa) susceptibility genes cooperate in a common DNA damage repair signaling pathway. To gain deeper insight into this pathway and its influence on cancer risk, we searched for novel components through protein physical interaction screens. Methods: Protein physical interactions were screened using the yeast two-hybrid system. Co-affinity purifications and endogenous co-immunoprecipitation assays were performed to corroborate interactions. Biochemical and functional assays in human, mouse and Caenorhabditis elegans models were carried out to characterize pathway components. Thirteen FANCD2-monoubiquitinylation-positive FA cell lines excluded for genetic defects in the downstream pathway components and 300 familial BrCa patients negative for BRCA1/2 mutations were analyzed for genetic mutations. Common genetic variants were genotyped in 9,573 BRCA1/2 mutation carriers for associations with BrCa risk. Results: A previously identified co-purifying protein with PALB2 was identified, MRG15 (MORF4L1 gene). Results in human, mouse and C. elegans models delineate molecular and functional relationships with BRCA2, PALB2, RAD51 and RPA1 that suggest a role for MRG15 in the repair of DNA double-strand breaks. Mrg15-deficient murine embryonic fibroblasts showed moderate sensitivity to g-irradiation relative to controls and reduced formation of Rad51 nuclear foci. Examination of mutants of MRG15 and BRCA2 C. elegans orthologs revealed phenocopy by accumulation of RPA-1 (human RPA1) nuclear foci and aberrant chromosomal compactions in meiotic cells. However, no alterations or mutations were identified for MRG15/MORF4L1 in unclassified FA patients and BrCa familial cases. Finally, no significant associations between common MORF4L1 variants and BrCa risk for BRCA1 or BRCA2 mutation carriers were identified: rs7164529, P-trend = 0.45 and 0.05, P-2df = 0.51 and 0.14, respectively; and rs10519219, P-trend = 0.92 and 0.72, P-2df = 0.76 and 0.07, respectively. Conclusions: While the present study expands on the role of MRG15 in the control of genomic stability, weak associations cannot be ruled out for potential low-penetrance variants at MORF4L1 and BrCa risk among BRCA2 mutation carriers.
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38.
  • McDade, Lucinda A., et al. (författare)
  • Phylogenetic placement, delimitation, and relationships among genera of the enigmatic Nelsonioideae (Lamiales: Acanthaceae)
  • 2012
  • Ingår i: Taxon. - : Wiley. - 0040-0262 .- 1996-8175. ; 61:3, s. 637-651
  • Tidskriftsartikel (refereegranskat)abstract
    • We took a two-tiered approach to test monophyly of Nelsonioideae and place the group within Lamiales, and to determine relationships among taxa within the group. Phylogenetic analysis of a molecular dataset (ndhF+trnL-F) for a broad sample of Lamiales supports monophyly of Nelsonioideae and places the clade with strong support as sister to a lineage composed of all other plants treated as Acanthaceae (Avicennia, Thunbergioideae, Acanthoideae). We propose to treat this entire group as Acanthaceae s.l. and hypothesize that indurate, explosively dehiscent capsules are a synapomorphy for the family, albeit with autapomorphic fruit types in Avicennia and Mendoncia. These results further support monophyly of family-level groups that have emerged from recent studies of Lamiales but are largely unsuccessful in resolving relationships among these groups, as also encountered by other workers. Our results contradict some aspects of relationships that have seemed resolved by earlier studies, notably among Byblidaceae, Scrophulariaceae, Thomandersia, and other Lamiales. Among Nelsonioideae, analysis of sequence data from rapidly evolving genic regions (trnS-G, ndhF-rpl32+rpl32-trnL((UAG)), nrITS) and a larger sample of nelsonioids (i.e., all genera and multiple taxa to represent the diversity of species-rich genera) indicates that Nelsonia and Elytraria are monophyletic with strong support, but with only moderate support for Nelsonia as the first branching clade and Elytraria sister to the remaining nelsonioids. An African clade comprising monospecific Saintpauliopsis sister to Anisosepalum (two of three species sampled) is sister to a clade that includes all sampled members of pantropical Staurogyne plus New World Gynocraterium and Asian Ophiorrhiziphyllon. Gynocraterium is sister to all sampled members of New World Staurogyne; this last clade is sister to a clade comprising the other sampled Staurogyne plus Ophiorrhiziphyllon, which is nested among Asian Staurogyne. The taxonomic implications of these patterns of relationship are discussed. Our results suggest that Nelsonioideae have a complex history of inter-continental dispersals compared to other lineages of Acanthaceae of similar to much larger size in terms of number of species, making it an interesting group for biogeographic study.
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39.
  • McDade, Lucinda A, et al. (författare)
  • Phylogenetic placement, delineation, and relationships among genera of the enigmatic Nelsonioideae (Lamiales: Acanthaceae)
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • We took a two-tiered approach to test monophyly of Nelsonioideae and place the group within Lamiales, and to determine relationships among taxa within the group. Phylogenetic analysis of a molecular data set (ndhF + trnLF) for a broad sample of Lamiales supports monophyly of Nelsonioideae and places the clade with strong support as sister to a lineage composed of all other plants treated as Acanthaceae (i.e., Avicennia, Thunbergioideae, Acanthoideae). We propose to treat this entire group as Acanthaceae s.l. and advance indurate, explosively dehiscent capsules as a synapomorphy for the family, albeit with autapomorphic fruit types in Avicennia and Mendoncia. These results further support monophyly of family level groups that have emerged from recent studies of Lamiales but are largely not successful in resolving relationships among these groups, as also encountered by other workers. In fact, our results contradict some aspects of relationships that have seemed resolved by earlier studies, notably among Byblidaceae, Scrophulariaceae, Thomandersia, and other Lamiales. Among Nelsonioideae, analysis of sequence data from more rapidly evolving genic regions (i.e., trnS-G, ndhF-rpl32 + rpl32-trnL(UAG), nrITS) and a larger sample of nelsonioids (i.e., all genera and multiple taxa to represent the diversity of species-rich genera) indicates that Nelsonia and Elytraria are monophyletic with strong support but with only moderate support for Nelsonia as the first branching clade and Elytraria sister to the remaining nelsonioids. An African clade comprising monospecific Saintpauliopsis sister to Anisosepalum (2 of 3 species sampled) is sister to a clade that includes all sampled members of pantropical Staurogyne plus New World Gynocraterium and Asian Ophiorrhiziphyllon. Gynocraterium is sister to all sampled members of New World Staurogyne; this last clade is sister to a clade comprising the other sampled Staurogyne plus Ophiorrhiziphyllon which is nested among Asian Staurogyne. The taxonomic implications of these patterns of relationship are discussed. Our results suggest that Nelsonioideae have a complex history of inter-continental dispersals compared to other acanth lineages of similar to much larger size in terms of number of species, making it an interesting group for biogeographic study.
  •  
40.
  • Neoptolemos, John P., et al. (författare)
  • Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4) : a multicentre, open-label, randomised, phase 3 trial
  • 2017
  • Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 389:10073, s. 1011-1024
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer.Methods: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1: 1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m(2) gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m(2) oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434.Findings: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28.0 months (95% CI 23.5-31.5) compared with 25.5 months (22.7-27.9) in the gemcitabine group (hazard ratio 0.82 [95% CI 0.68-0.98], p=0.032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group.Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma.
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41.
  • Nepomuceno, Thales C., et al. (författare)
  • BRCA1 frameshift variants leading to extended incorrect protein C termini
  • 2023
  • Ingår i: Human Genetics and Genomics Advances. - : Elsevier. - 2666-2477. ; 4:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Carriers of BRCA1 germline pathogenic variants are at substantially higher risk of developing breast and ovarian cancer than the general population. Accurate identification of at-risk individuals is crucial for risk stratification and the implementation of targeted preventive and therapeutic interventions. Despite significant progress in variant classification efforts, a sizable portion of reported BRCA1 variants remain as variants of uncertain clinical significance (VUSs). Variants leading to premature protein termination and loss of essential functional domains are typically classified as pathogenic. However, the impact of frameshift variants that result in an extended incorrect terminus is not clear. Using validated functional assays, we conducted a systematic functional assessment of 17 previously reported BRCA1 extended incorrect terminus variants (EITs) and concluded that 16 constitute loss-of-function variants. This suggests that most EITs are likely to be pathogenic. However, one variant, c.5578dup, displayed a protein expression level, affinity to known binding partners, and activity in transcription and homologous recombination assays comparable to the wild-type BRCA1 protein. Twenty-three additional carriers of c.5578dup were identified at a US clinical diagnostic lab and assessed using a family history likelihood model providing, in combination with the functional data, a likely benign interpretation. These results, consistent with family history data in the current study and available data from ClinVar, indicate that most, but not all, BRCA1 variants leading to an extended incorrect terminus constitute loss-of-function variants and underscore the need for comprehensive assessment of individual variants.
  •  
42.
  • Nik-Zainal, Serena, et al. (författare)
  • Mutational Processes Molding the Genomes of 21 Breast Cancers
  • 2012
  • Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5, s. 979-993
  • Tidskriftsartikel (refereegranskat)abstract
    • All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
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43.
  •  
44.
  • Rebbeck, Timothy R., et al. (författare)
  • Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
  • 2016
  • Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
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45.
  • Ritscher, Amélie, et al. (författare)
  • Zurich Statement on Future Actions on Per - and Polyfluoroalkyl Substances (PFASs)
  • 2018
  • Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 126:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Per - and polyfluoroalkyl substances (PFASs) are man-made chemicals that contain at least one perfluoroalkyl moiety, -CnF2n-. To date, over 4,000 unique PFASs have been used in technical applications and consumer products, and some of them have been detected globally in human and wildlife biomonitoring studies. Because of their extraordinary persistence, human and environmental exposure to PFASs will be a long-term source of concern. Some PFASs such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) have been investigated extensively and thus regulated, but for many other PFASs, knowledge about their current uses and hazards is still very limited or missing entirely. To address this problem and prepare an action plan for the assessment and management of PFASs in the coming years, a group of more than 50 international scientists and regulators held a two-day workshop in November, 2017. The group identified both the respective needs of and common goals shared by the scientific and the policy communities, made recommendations for cooperative actions, and outlined how the science-policy interface regarding PFASs can be strengthened using new approaches for assessing and managing highly persistent chemicals such as PFASs.
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46.
  • Silberstein, Daniel, 1987- (författare)
  • Humanity Washed Ashore : Visual representations of practices, people, and the borders of Europe
  • 2020
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Over the past decade, Frontex (European Border and Coast Guard Agency) has emerged as a central actor for the European Union’s migration and border policies. This doctoral dissertation examines the role of Frontex in constructing understandings of borders, practices, and people present in these spaces as well as more ambivalent representations of risk, unease, and (in)security. The study is based on material produced by Frontex during the period 2010-2016. More specifically, the dissertation explores how borders, practices, and people as well as risk, unease, and (in)security are produced through representational practices. In doing so, this dissertation examines how Frontex is normalised as the EU’s central actor at Europe’s borders. Unlike previous studies on Frontex, which have tended to focus on either the practices of the agency, its legal context, or use of technology, this dissertation examines Frontex as a producer of different discourses. Secondly, this dissertation adds to the existing research on Frontex by examining their visual material. Likewise, in contrast to much of the research in the field of Critical Border Studies (CBS), which has focused on the performative aspects of how borders are produced, this dissertation adds to the field of CBS by examining how borders are performed through representational practices of visual material. In order to examine representational practices of (in)securitisation by which Frontex is normalised as the EU’s central actor at Europe’s borders, this dissertation draws primarily on the research on (in)securitisation while adding a visual aspect to create a framework termed visual (in)securitisation. The overall findings cast light on the complexity of processes of (in)securitisation and the performances of borders and offers new ways of understanding both processes. The findings point to the role of images in shaping conditions for processes of (in)securitisation, influencing how borders, practices, and people in these spaces are understood. Empirically, this dissertation demonstrates the significance of integrating images whilst analysing how (in)security and borders are produced and how Frontex are normalised as the EU’s central actor at Europe’s borders. Theoretically, it highlights the relationship between images and ambiguity, ambivalence, risk, and unease in processes of (in)securitisation as well as the role of images in performing borders.
  •  
47.
  • Van Bulck, Liesbet, et al. (författare)
  • Patient-reported outcomes of adults with congenital heart disease from eight European countries : scrutinising the association with healthcare system performance
  • 2019
  • Ingår i: European Journal of Cardiovascular Nursing. - : Sage Publications. - 1474-5151 .- 1873-1953. ; 18:6, s. 465-473
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Inter-country variation in patient-reported outcomes of adults with congenital heart disease has been observed. Country-specific characteristics may play a role. A previous study found an association between healthcare system performance and patient-reported outcomes. However, it remains unknown which specific components of the countries’ healthcare system performance are of importance for patient-reported outcomes.Aims: The aim of this study was to investigate the relationship between components of healthcare system performance and patient-reported outcomes in a large sample of adults with congenital heart disease.Methods: A total of 1591 adults with congenital heart disease (median age 34 years; 51% men; 32% simple, 48% moderate and 20% complex defects) from eight European countries were included in this cross-sectional study. The following patient-reported outcomes were measured: perceived physical and mental health, psychological distress, health behaviours and quality of life. The Euro Health Consumer Index 2015 and the Euro Heart Index 2016 were used as measures of healthcare system performance. General linear mixed models were conducted, adjusting for patient-specific variables and unmeasured country differences.Results: Health risk behaviours were associated with the Euro Health Consumer Index subdomains about patient rights and information, health outcomes and financing and access to pharmaceuticals. Perceived physical health was associated with the Euro Health Consumer Index subdomain about prevention of chronic diseases. Subscales of the Euro Heart Index were not associated with patient-reported outcomes.Conclusion: Several features of healthcare system performance are associated with perceived physical health and health risk behaviour in adults with congenital heart disease. Before recommendations for policy-makers and clinicians can be conducted, future research ought to investigate the impact of the healthcare system performance on outcomes further.
  •  
48.
  • Wu, Jun, et al. (författare)
  • Control of composition and morphology in InGaAs nanowires grown by metalorganic vapor phase epitaxy
  • 2013
  • Ingår i: Journal of Crystal Growth. - : Elsevier BV. - 0022-0248. ; 383, s. 158-165
  • Tidskriftsartikel (refereegranskat)abstract
    • InGaAs nanowires grown by Metalorganic Vapor Phase Epitaxy (MOVPE) are promising candidates in future device technologies. The control of the chemical composition of InGaAs nanowires is not trivial due to the In atom diffusion from the substrate, which causes significant variations in the chemical composition along the nanowire. In this work, we report on the growth of InGaAs nanowires on (111)B InAs substrates followed by the characterization using high-resolution x-ray diffraction (HRXRD), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM) as well as scanning transmission electron microscopy (STEM) in combination with energy dispersive X-ray spectroscopy (EDS). By detailed analyses of the HRXRD spectra and their variations with nanowires grown for different times, fundamental insight was gained into tapering formation and chemical composition gradient of the nanowires. The measurements show that acceptable uniformity of In and Ga concentrations along InGaAs nanowires can be achieved, and the maximum achievable nanowire length without tapering depends on the nanowire density. Finally, by carefully choosing the growth conditions, the morphology of the InGaAs nanowire can be further optimized. (C) 2 013 Elsevier B.V. All rights reserved
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49.
  • Zapatka, Marc, et al. (författare)
  • The landscape of viral associations in human cancers
  • 2020
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 320-330
  • Tidskriftsartikel (refereegranskat)abstract
    • Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
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50.
  • 2021
  • swepub:Mat__t
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