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| 2. |
- Öfverholm, Anna, et al.
(författare)
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Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer
- 2023
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Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting.MethodsWomen with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records.ResultsIn 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding.ConclusionsThis study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.
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| 3. |
- Balboa, Diego, et al.
(författare)
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Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells.
- 2022
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:7, s. 1042-1055
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Tidskriftsartikel (refereegranskat)abstract
- Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.
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- Bergenholtz, Gunnar, 1939, et al.
(författare)
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Treatment of pulps in teeth affected by deep caries - A systematic review of the literature.
- 2013
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Ingår i: Singapore dental journal. - : World Scientific Pub Co Pte Lt. - 0377-5291. ; 34:1, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: This systematic review assesses the effect of methods commonly used to manage the pulp in cases of deep caries lesions, and the extent the pulp chamber remains uninfected and does not cause pulpal or periapical inflammatory lesions and associated tooth-ache over time.STUDY DESIGN: An electronic literature search included the databases PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and Cochrane Reviews from January 1950 to March 2013. In addition, hand searches were carried out. Two reviewers independently evaluated abstracts and full-text articles. An article was read in full if at least one of the two reviewers considered the abstract potentially relevant. Altogether, 161 articles were read in full text. Of these, 24 studies fulfilled established inclusion criteria. Based on studies of at least moderate quality, the quality of evidence of each procedure was rated in four levels according to GRADE.RESULTS: No study reached the high quality level. Twelve were of moderate quality. The overall evidence was insufficient to assess which of indirect pulp capping, stepwise excavation, direct excavation and pulp capping/partial pulpotomy, pulpotomy or pulpectomy is the most effective treatment approach for teeth with deep caries.CONCLUSIONS: Because of the lack of good studies it is not possible to determine whether an injured pulp by deep caries can be maintained or whether it should be removed and replaced with a root canal filling. Both randomized studies and prospective observational studies are needed to investigate whether a pulp exposed to deep caries is best treated by measures intended to preserve it or by pulpectomy and root filling.
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| 6. |
- Bergman, Petra, et al.
(författare)
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Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats.
- 2013
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:8, s. 4066-75
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
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| 7. |
- Catucci, Irene, et al.
(författare)
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Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display chromosome fragility
- 2018
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 20:4, s. 452-457
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Tidskriftsartikel (refereegranskat)abstract
- PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, chromosome fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly chromosome fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.Genetics in Medicine advance online publication, 24 August 2017; doi:10.1038/gim.2017.123.
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| 8. |
- Cirenajwis, Helena, et al.
(författare)
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Molecular stratification of metastatic melanoma using gene expression profiling: prediction of survival outcome and benefit from molecular targeted therapy.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:14, s. 12297-12309
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma is currently divided on a genetic level according to mutational status. However, this classification does not optimally predict prognosis. In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology. Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes. We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group. Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes. We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response. In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02). In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.
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| 9. |
- Cristiani, Riccardo, et al.
(författare)
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High prevalence of associated injuries in anterior cruciate ligament tears: A detailed magnetic resonance imaging analysis of 254 patients
- 2024
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Ingår i: Skeletal Radiology. - : SPRINGER. - 0364-2348 .- 1432-2161.
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To evaluate the type and prevalence of associated injuries by using magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) tears.Methods Data from the Natural Corollaries and Recovery after ACL injury multicenter longitudinal cohort study were analyzed. Between May 2016 and October 2018, patients aged between 15 and 40 years, who had experienced an ACL tear within the last 6 weeks and sought medical attention at one of seven healthcare clinics in Sweden, were invited to participate. The mean time from injury to MRI was 19.6 +/- 15.2 days. An orthopedic knee surgeon and a musculoskeletal radiologist reviewed all the MRI scans. The following structures were assessed: posterior cruciate ligament (PCL), medial collateral ligament (MCL) complex, lateral collateral ligament (LCL), popliteus tendon, medial meniscus (MM), lateral meniscus (LM), and cartilage. In addition, the presence of bone bruising, impaction fractures in the lateral femoral condyle (LFC) or posterolateral tibia (PLT), and Segond fractures were also assessed. Results A total of 254 patients (48.4% males) with a mean age of 25.4 +/- 7.1 years were included. The prevalence of associated injuries was as follows: PCL (0.4%), MCL {41.3% [superficial MCL and deep MCL (dMCL) 16.5%; isolated dMCL 24.8%]}, LCL (2.4%), MM (57.4%), LM (25.2%), cartilage (15.0%), bone bruising (92.9%), impaction fracture in the LFC (45.7%) and PLT (4.7%), and Segond fracture (7.5%).Conclusions The prevalence of associated injuries in patients with ACL tears was high. The findings reported in this study may serve as a reference tool for orthopedic surgeons and radiologists in the diagnosis of associated injuries using MRI in patients with ACL tears.
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| 10. |
- Cristiani, Riccardo, et al.
(författare)
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High prevalence of meniscal ramp lesions in anterior cruciate ligament injuries
- 2023
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Ingår i: Knee Surgery, Sports Traumatology, Arthroscopy. - : Springer. - 0942-2056 .- 1433-7347. ; 31:1, s. 316-324
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate the prevalence of and factors associated with meniscal ramp lesions on magnetic resonance imaging (MRI) in patients with anterior cruciate ligament (ACL) injuries. Methods Data from the Natural Corollaries and Recovery after ACL injury multicentre longitudinal cohort study (NACOX) were analysed. Only patients who underwent MRI were included in this study. All MRI scans were reviewed by an orthopaedic knee surgeon and a musculoskeletal radiologist. The patients were divided into two groups, those with and without ramp lesions according to MRI findings. Univariable and stepwise forward multiple logistic regression analyses were used to evaluate patient characteristics (age, gender, body mass index, pre-injury Tegner activity level, activity at injury) and concomitant injuries on MRI (lateral meniscus, medial collateral ligament [MCL], isolated deep MCL, lateral collateral ligament, pivot-shift-type bone bruising, posteromedial tibial [PMT] bone bruising, medial femoral condyle bone bruising, lateral femoral condyle [LFC] impaction and a Segond fracture) associated with the presence of meniscal ramp lesions. Results A total of 253 patients (52.2% males) with a mean age of 25.4 +/- 7.1 years were included. The overall prevalence of meniscal ramp lesions was 39.5% (100/253). Univariate analyses showed that contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising, LFC impaction and the presence of a Segond fracture increased the odds of having a meniscal ramp lesion. Stepwise forward multiple logistic regression analysis revealed that the presence of a meniscal ramp lesion was associated with contact sports at ACL injury [odds ratio (OR) 2.50; 95% confidence intervals (CI) 1.32-4.72; P = 0.005], pivot-shift-type bone bruising (OR 1.29; 95% CI 1.01-1.67; P = 0.04), PMT bone bruising (OR 4.62; 95% CI 2.61-8.19; P < 0.001) and the presence of a Segond fracture (OR 4.38; 95% CI 1.40-13.68; P = 0.001). Conclusion The overall prevalence of meniscal ramp lesions in patients with ACL injuries was high (39.5%). Contact sports at ACL injury, pivot-shift-type bone bruising, PMT bone bruising and the presence of a Segond fracture on MRI were associated with meniscal ramp lesions. Given their high prevalence, meniscal ramp lesions should be systematically searched for on MRI in patients with ACL injuries. Knowledge of the factors associated with meniscal ramp lesions may facilitate their diagnosis, raising surgeons and radiologists suspicion of these tears.
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