| 1. |
|
|
| 2. |
- Antoniou, A. C., et al.
(författare)
-
Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers : Implications for risk prediction
- 2010
-
Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 70:23, s. 9742-9754
-
Tidskriftsartikel (refereegranskat)abstract
- The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.
|
|
| 3. |
- Borg, Helena
(författare)
-
Bladder and bowel dysfunction in children with anorectal malformations : Blås och tarmdysfunktion hos barn med anorektala missbildningar
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bowel dysfunction is seen in all children with anorectal malformations (ARMs) and is strongly related to associated anomalies commonly found in these patients. The presence of a megarectosigmoid (MRS) further contributes to chronic constipation and overflow incontinence. There is a great heterogeneity in reported functional results probably due to the fact that the criteria used to evaluate long-term outcome have been quite variable. In addition, results are often given for different ages together. By using more precise criteria as developed by the Krickenbeck conference 2005, and by following ARM patients longitudinally, the reporting of functional outcome should be more uniform and reliable. Aims: To study the impact of spinal cord malformation on bladder and bowel function and to describe changes in bowel function during long term follow up in children with ARM. To identify predictors influencing bowel functional outcome and evaluate outcome after surgical or conservative treatment of MRS. Finally, to longitudinally follow bladder function in these children and to identify the prevalence of neurogenic (NBD) and non-neurogenic bladder dysfunction. Material and methods: 41 patients with ARM, excluding perineal fistulas, were consecutively included in this prospective longitudinal study. Investigations of bowel function were performed at ages 5, 10, 15 yrs. using a structured questionnaire and three weeks registrations of bowel movements, soiling, use of pads and enemas. 52 healthy children of similar ages and gender were used as control. The bowel was also investigated with a colostogram in the neonatal period, followed by a contrast enema 6 months after stoma closure and after that on an individual basis if MRS was diagnosed. Investigations of bladder function were performed with urodynamics before and after the PSARP procedure and regularly during follow-up in patients with an obvious NBD. In addition, at the ages 5, 10 and 15 yrs. all children were aimed to be investigated with a structured urinary questionnaire, a three-day voiding/leakage diary and flow-residual measurements. Scoring systems were used for evaluation of bowel and bladder function. Spinal cord malformations were diagnosed with spinal ultrasound followed by MRI in the neonatal period. Sacral anomalies were detected by plain radiographs. Results: There was a successive improvement in bowel function during childhood and adolescence, but function did not achieve the level of healthy children. At the age of 10 years continence overall was achieved in 59%. Neurogenic bladder dysfunction was found in 22% of children with ARM and symptoms remained constant during follow up. Symptoms of non-neurogenic LUTD were present in 34%. However, the findings were transient and in most cases seen only at one of the follow up evaluations. Negative predictors for bowel function during follow up were spinal cord malformation in combination with NBD, complex type of fistula (high recto- urethral and bladder neck fistula) and sacral agenesis. Whether non-neurogenic LUTD was associated with constipation and poor bowel function could not be confirmed even if these children had lower bowel scores than those with normal bladder function. MRS was not established as a predictor of bowel function, although girls with MRS at age 5 years had lower bowel scores compared to patients with normal rectal configuration. It was also shown that surgical treatment of MRS did not have better outcome regarding bowel function compared to bowel management only. Conclusion: In this longitudinal study of ARM patients from childhood to adolescence, bowel function overall was shown to improve when estimated in relation to continence, soiling and constipation. Bladder function was also evaluated and NBD was diagnosed in 22%, and non-neurogenic bladder symptoms in 34% of the patients. Negative predictors for improvement in bowel function during growing up were spinal cord malformation, NBD and complex type of fistula malformation. MRS did not emerge as a predictor for functional outcome.
|
|
| 4. |
- Borg, Helena, et al.
(författare)
-
Longitudinal study of bowel function in children with anorectal malformations.
- 2013
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 48:3, s. 597-606
-
Tidskriftsartikel (refereegranskat)abstract
- Longitudinal follow-up of changes in bowel function in children with anorectal malformations (ARMs) with or without spinal cord pathology and neurogenic bladder dysfunction (NBD) as they grow. Another purpose was to identify predictors influencing bowel functional outcome.
|
|
| 5. |
- Borg, Helena, et al.
(författare)
-
Megarectosigmoid in children with anorectal malformations: Long term outcome after surgical or conservative treatment.
- 2014
-
Ingår i: Journal of pediatric surgery. - : Elsevier BV. - 1531-5037 .- 0022-3468. ; 49:4, s. 564-9
-
Tidskriftsartikel (refereegranskat)abstract
- Megarectosigmoid (MRS) is commonly seen in children with anorectal malformations (ARM) and contributes to the high incidence of constipation. Surgical resection has been advocated by some, whereas others propose intense bowel management as the treatment of choice. The aim of this study was to evaluate outcome of both bowel function and configuration after surgical or conservative treatment of MRS in ARM patients.
|
|
| 6. |
- Larsdotter Mellström, Helena, et al.
(författare)
-
Seasonal polyphenism in life history traits : time costs of direct development in a butterfly
- 2010
-
Ingår i: Behavioral Ecology and Sociobiology. - : Springer Science and Business Media LLC. - 0340-5443 .- 1432-0762. ; 64:9, s. 1377-1383
-
Tidskriftsartikel (refereegranskat)abstract
- Insects with two or more generations per year will generally experience different selection regimes depending on the season, and accordingly show seasonal polyphenisms. In butterflies, seasonal polyphenism has been shown with respect to morphology, life history characteristics and behaviour. In temperate bivoltine species, the directly developing generation is more time-constrained than the diapause generation, and this may affect various life history traits such as mating propensity (time from eclosion to mating). Here, we test whether mating propensity differs between generations in Pieris napi, along with several physiological parameters, i.e. male sex pheromone synthesis, and female ovigeny index and fecundity. As predicted, individuals of the directly developing generation-who have shorter time for pupal development-are more immature at eclosion; males take longer to synthesise the male sex pheromone after eclosion and take longer to mate than diapause generation males. Females show the same physiological pattern; the directly developing females lay fewer eggs than diapausing females during the first days of their life. Nevertheless, the directly developing females mate faster after eclosion than diapausing females, indicating substantial adult time stress in this generation and possibly an adaptive value of shortening the pre-reproductive period. Our study highlights how time stress can be predictably different between generations, affecting both life history and behaviour. By analysing several life history traits simultaneously, we adopt a multi-trait approach to examining how adaptations and developmental constraints likely interplay to shape these seasonal polyphenisms.
|
|
| 7. |
- Larsdotter Mellström, Helena, 1978-, et al.
(författare)
-
Timing of Male Sex Pheromone Biosynthesis in a Butterfly – Different Dynamics under Direct or Diapause Development
- 2012
-
Ingår i: Journal of Chemical Ecology. - : Springer Science+Business Media B.V.. - 0098-0331 .- 1573-1561. ; 38:5, s. 584-591
-
Tidskriftsartikel (refereegranskat)abstract
- The life history traits and behavior of the butterfly are well-known, as the species is often used as a model organism for evolutionary and ecological studies. The species has two or more generations per year in the major part of its temperate distribution, and as different selection pressures affect the different generations, both behavioral and physiological seasonal polyphenisms have been shown previously. Here, we explored the dynamics of male sex pheromone production. The two generations are shown to have significantly different scent compositions early in life; the direct developers-who have shorter time for pupal development-need the first 24 hr of adult life after eclosion to synthesize the sex pheromone citral (geranial and neral 1:1)-whereas the diapausing individuals who have spent several months in the pupal stage eclose with adult scent composition. Resource allocation and biosynthesis also were studied in greater detail by feeding butterflies C-13 labeled glucose either in the larval or adult stage, and recording incorporation into geranial, neral, and other volatiles produced. Results demonstrate that the pheromone synthesized by newly eclosed adult males is based on materials ingested in the larval stage, and that adult butterflies are able to synthesize the pheromone components geranial and neral and the related alcohols also from adult intake of glucose. In summary, our study shows that time-stress changes the timing in biosynthesis of the complete pheromone between generations, and underpins the importance of understanding resource allocation and the physiological basis of life history traits.
|
|
| 8. |
- 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.
|
|
| 9. |
- Newie, Inga, et al.
(författare)
-
The HER2-Encoded miR-4728-3p Regulates ESR1 through a Non-Canonical Internal Seed Interaction.
- 2014
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5
-
Tidskriftsartikel (refereegranskat)abstract
- Since the early 1980s remarkable progress has been made in understanding the role of the HER2 locus in carcinogenesis, but many details of its regulatory network are still elusive. We recently reported the finding of 367 new human microRNA (miRNA) genes of which one, mir-4728, is encoded in an intron of the HER2 gene. Here, we confirm that the HER2 oncogene is a bi-functional locus encoding the membrane receptor and a functional miRNA gene. We further show that miR-4728-3p has alternative functionalities depending on the region used for interaction with its target; the canonical seed between nucleotides 2-8 or a novel, more internal seed shifted to nucleotides 6-12. Analysis of public data shows that this internal seed region, although rare compared to the far more abundant canonical 2-8 seed interaction, can also direct targeted down-regulation by other miRNAs. Through the internal seed, miR-4728-3p regulates expression of estrogen receptor alpha, an interaction that would have remained undetected if classic rules for miRNA-target interaction had been applied. In summary, we present here an alternative mode of miRNA regulation and demonstrate this dual function of the HER2 locus, linking the two major biomarkers in breast cancer.
|
|
| 10. |
- Olausson, Michael, 1956, et al.
(författare)
-
In vivo application of tissue-engineered veins using autologous peripheral whole blood: A proof of concept study
- 2014
-
Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 1:1, s. 72-79
-
Tidskriftsartikel (refereegranskat)abstract
- Vascular diseases are increasing health problems affecting >25 million individuals in westernized societies. Such patients could benefit fromtransplantation of tissue-engineered vascular grafts using autologous cells. One challenge that has limited this development is the need for cell isolation, and risks associated with ex vivo expanded stem cells. Herewe demonstrate a novel approach to generate transplantable vascular grafts using decellularized allogeneic vascular scaffolds, repopulatedwith peripheralwhole blood (PWB) in vitro in a bioreactor. Circulating, VEGFR-2+/CD45+ and a smaller fraction of VEGFR-2+/CD14+ cells contributed to repopulation of the graft. SEMmicrographs showed flat cells on the luminal surface of the grafts consistentwith endothelial cells. For clinical validation, two autologous PWBtissue-engineered vein conduits were prepared and successfully used for bypass procedures in two pediatric patients. These results provide a proof of principle for the generation of transplantable vascular grafts using a simple autologous blood sample, making it clinically feasible globally.
|
|
