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  • 1.
    Aarnio, Riina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Isacson, Isabella
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gustavsson, Inger M.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Comparison of vaginal self-sampling and cervical sampling by medical professionals for the detection of HPV and CIN2+: a randomized studyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Primary screening with human papillomavirus (HPV) test is more effective in reducing cervical cancer incidence than cytology and it also offers the opportunity to self-sample. We conducted a randomized study to compare vaginal self-sampling with cervical sampling by medical professionals for HPV testing concerning prevalence of HPV and detection of cervical intraepithelial neoplasia (CIN) of grade 2 or worse (CIN2+)  or grade 3 or worse (CIN3+) in primary screening. In total, 11 951 women aged 30–60 years were randomized into two groups, 5961 for self-sampling (SS arm) and 5990 for sampling by medical professionals (SMP arm). Sampling was performed with a Rovers®Viba-brush in the SS arm and a cytobrush in the SMP arm. All samples were applied to an indicating FTA elute card and analyzed for HPV using a clinically validated real-time PCR test (hpVIR). All HPV-positive women performed repeated sampling about six months later using the same procedure as used initially. All HPV-positive women in the second sampling were referred to colposcopy. HPV prevalence in the first test did not differ between the SS arm (6.8%, 167/2466) and the SMP arm (7.8%, 118/1519) (p=0.255). The prevalence of CIN2+ per 1000 screened women was 17 (43/2466 × 1000) (95%CI 13–24) in the SS arm and 21 (32/1519 × 1000) (95%CI 15–30) in the SMP arm. For CIN3+, the prevalence per 1000 screened women was 14 (35/2466 × 1000) (95%CI 10–20) in the SS arm and 15 (23/1519 × 1000) (95%CI 10–23) in the SMP arm.  In conclusion, self-sampling and sampling by medical professionals showed the same prevalence of HPV and detection rate of CIN2+ and CIN3+ in histology.

    Novelty and Impact

    Offering self-sampling in primary cervical screening results in similar rates of HPV prevalence and detection of CIN2+ and CIN3+ compared with sampling by medical professionals when using an FTA card as storage medium and PCR-based HPV test (hpVIR). Considering health-economic aspects, resources should be directed towards self-sampling as a first choice for primary cervical screening, with careful follow-up of this strategy.

  • 2.
    Aarnio, Riina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gustavsson, Inger M.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Diagnostic excision of the cervix in women over 40 years with human papilloma virus persistency and normal cytology2019Inngår i: European journal of obstetrics & gynecology and reproductive biology: X, ISSN 2590-1613, Vol. 3, artikkel-id 100042Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Persistent infection with human papillomavirus (HPV) is recognized as the main risk factor of cervical cancer. Investigation via cytology and colposcopy have lower sensitivity than HPV testing in the diagnosis of high-grade cervical intraepithelial neoplasia (CIN2+). Despite normal cytology and colposcopy findings women with persistent HPV infection have an increased risk of CIN2+. The aim of the study was to evaluate the proportion of histologically confirmed CIN2+ in women with persistent HPV infection and normal Pap smears.

    Study design: From April 2013 until March 2016 we prospectively recruited 91 women over 40 years with persistent HPV infection without any abnormalities in cytology. Of these, 40 women attended a gynecological examination including an HPV test, Pap smear, endocervical cytology, colposcopy with biopsies and diagnostic loop electrosurgical excision procedure (LEEP). Biopsy and LEEP samples were subjected to histological examination.

    Results: CIN2+ was verified by histological examination of the LEEP sample in 6/40 (15%) of the women. All the cytological samples were normal and none of the biopsies confirmed CIN2+. Only 19/40 women still had a persistent HPV infection at the study visit. None of the 21/40 women who had cleared their HPV infection at the study visit had CIN2+ in histology of the LEEP sample.

    Conclusions: A persistent HPV infection needs to be monitored despite normal Pap smears, since 6/40 (15%) women older than 40 years, was revealed to have an undiagnosed CIN2+ when LEEP was performed. Counseling women regarding the risk of cervical cancer and the expected effect of an eventual LEEP can help them to make an optimal informed choice.

    Fulltekst (pdf)
    fulltext
  • 3.
    Aarnio, Riina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Östensson, Ellinor
    Karolinska Institutet.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gustavsson, Inger M.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Cost-effectiveness analysis of repeated self-sampling for HPV testing in primary cervical screening: a randomized studyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Background

    Human papillomavirus (HPV) testing is recommended in primary cervical screening to improve cancer prevention. An advantage of HPV testing is that it can be performed on self-samples, which could increase population coverage and result in a more efficient strategy to identify women at risk of developing cervical cancer. Our objective was to assess whether repeated self-sampling for HPV testing is cost-effective in comparison with Pap smear cytology for detection of cervical intraepithelial neoplasia grade 2 or more (CIN2+) in increasing participation rate in primary cervical screening.

    Methods

    A cost-effectiveness analysis (CEA) was performed on data from a previously published randomized clinical study including 36 390 women aged 30–49 years. Participants were randomized either to perform repeated self-sampling of vaginal fluid for HPV testing (n = 17 997, HPV self-sampling arm) or to midwife-collected Pap smears for cytological analysis (n = 18 393, Pap smear arm).

    Results

    Self-sampling for HPV testing led to 1633 more screened women and 107 more histologically diagnosed CIN2+ at a lower cost vs. midwife-collected Pap smears (€ 228 642 vs. € 781 139). 

    Conclusions

    This study projected that repeated self-sampling for HPV testing increased participation and detection of CIN2+ at a lower cost than midwife-collected Pap smears in primary cervical screening. Offering women a home-based self-sampling may therefore be a more cost-effective alternative than clinic-based screening.

     

  • 4.
    Abdulla, Maysaa
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pandzic, Tatjana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mansouri, Larry
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Ednersson, Susanne Bram
    Sahlgrens Univ Hosp, Dept Pathol, Gothenburg, Sweden.
    Andersson, Per-Ola
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden;Sodra Alvsborg Hosp Boras, Dept Med, Boras, Sweden.
    Hultdin, Magnus
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Fors, Maja
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Erlanson, Martin
    Umea Univ, Dept Radiat Sci, Oncol, Umea, Sweden.
    Degerman, Sofie
    Umea Univ, Dept Med Biosci, Pathol, Umea, Sweden.
    Petersen, Helga Munch
    Copenhagen Univ Hosp, Dept Pathol, Rigshosp, Copenhagen, Denmark.
    Asmar, Fazila
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Gronbaek, Kirsten
    Copenhagen Univ Hosp, Dept Hematol, Rigshosp, Copenhagen, Denmark.
    Enblad, Gunilla
    Uppsala Univ, Expt & Clin Oncol, Dept Immunol Genet & Pathol, Uppsala, Sweden.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2019Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

    Fulltekst (pdf)
    fulltext
  • 5.
    Abramov, Sergei
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Kazan Fed Univ, Inst Fundamental Med & Biol, Kazan, Russia.
    Kozyrev, Sergey V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Farias, Fabiana H. G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Washington Univ, Genome Inst, Sch Med, St Louis, MO USA.
    Dahlqvist, Johanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Leonard, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Alexsson, Andrei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pielberg, Gerli
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hansson-Hamlin, H.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Andersson, G.
    Swedish Univ Agr Sci SLU, Dept Anim Breeding & Genet, Uppsala, Sweden.
    Tandre, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Eloranta, Maija-Leena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Reumatologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ronnblom, L.
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    The risk allele A of rs200395694 associated with SLE in Swedish patients affects on MEF2D gene regulation and alternative splicing2018Inngår i: Human Gene Therapy, ISSN 1043-0342, E-ISSN 1557-7422, Vol. 29, nr 12, s. A44-A44Artikkel i tidsskrift (Annet vitenskapelig)
  • 6.
    Agarwal, Prasoon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Enroth, Stefan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Alzrigat, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Osterborg, Anders
    Nilsson, Kenneth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Öberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Jernberg-Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 7.
    Ahsan, Muhammad
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ek, Weronica E
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Rask-Andersen, Mathias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Karlsson, Torgny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lind-Thomsen, Allan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    The relative contribution of DNA methylation and genetic variants on protein biomarkers for human diseases.2017Inngår i: PLoS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, nr 9, artikkel-id e1007005Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Associations between epigenetic alterations and disease status have been identified for many diseases. However, there is no strong evidence that epigenetic alterations are directly causal for disease pathogenesis. In this study, we combined SNP and DNA methylation data with measurements of protein biomarkers for cancer, inflammation or cardiovascular disease, to investigate the relative contribution of genetic and epigenetic variation on biomarker levels. A total of 121 protein biomarkers were measured and analyzed in relation to DNA methylation at 470,000 genomic positions and to over 10 million SNPs. We performed epigenome-wide association study (EWAS) and genome-wide association study (GWAS) analyses, and integrated biomarker, DNA methylation and SNP data using between 698 and 1033 samples depending on data availability for the different analyses. We identified 124 and 45 loci (Bonferroni adjusted P < 0.05) with effect sizes up to 0.22 standard units' change per 1% change in DNA methylation levels and up to four standard units' change per copy of the effective allele in the EWAS and GWAS respectively. Most GWAS loci were cis-regulatory whereas most EWAS loci were located in trans. Eleven EWAS loci were associated with multiple biomarkers, including one in NLRC5 associated with CXCL11, CXCL9, IL-12, and IL-18 levels. All EWAS signals that overlapped with a GWAS locus were driven by underlying genetic variants and three EWAS signals were confounded by smoking. While some cis-regulatory SNPs for biomarkers appeared to have an effect also on DNA methylation levels, cis-regulatory SNPs for DNA methylation were not observed to affect biomarker levels. We present associations between protein biomarker and DNA methylation levels at numerous loci in the genome. The associations are likely to reflect the underlying pattern of genetic variants, specific environmental exposures, or represent secondary effects to the pathogenesis of disease.

    Fulltekst (pdf)
    fulltext
  • 8. Alarcón-Riquelme, Marta E.
    et al.
    Marañón Lizana, Concepción
    Varela Hernández, Nieves
    Delgado-Vega, Angélica M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    La Etiopatogenia en el Lupus Eritematoso Sistémico2013Inngår i: Lupus eritematoso sistémico: Aspectos Clínicos y Terapéuticos, Rosario, Argentina: Carlos Antonio Battagliotti , 2013, 1, s. 65-85Kapittel i bok, del av antologi (Fagfellevurdert)
  • 9.
    Ali, Zafar
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Jameel, Mohammad
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Khan, Kamal
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Fatima, Ambrin
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Raininko, Raili
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities2016Inngår i: Journal of the Neurological Sciences, ISSN 0022-510X, E-ISSN 1878-5883, Vol. 371, s. 105-111Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.

  • 10.
    Ali, Zafar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Zulfiqar, Shumaila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wikström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ullah, Farid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Khan, Ayaz
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Abdullah, Uzma
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Baig, Shahid
    Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, Faisalabad, Pakistan.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Homozygous GRID2 missense mutation predicts a shift in the D-serine binding domain of GluD2 in a case with generalized brain atrophy and unusual clinical features2017Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 18, nr 1, artikkel-id 144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Spinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.

    CASE PRESENTATION: We report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.

    CONCLUSION: The widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.

    Fulltekst (pdf)
    fulltext
  • 11.
    Allen, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 354, artikkel-id 354re3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 12. Ament-Velásquez, Sandra Lorena
    et al.
    Vogan, Aaron A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    Wallerman, Ola
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Hartmann, Fanny
    Gautier, Valérie
    Silar, Philippe
    Giraud, Tatiana
    Johannesson, Hanna
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för ekologi och genetik, Evolutionsbiologi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Systematisk biologi.
    The evolution of the allorecognition gene repertoire in the Podospora anserina species complexManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Across the Tree of Life, self/non-self recognition is typically achieved through highly polymorphic loci under balancing selection. In fungi, vegetative conspecific recognition, or allorecognition, is defined by the compatibility interactions between loci known as het genes. In this study we explore the evolution of the het genes in the model fungus Podospora anserina and its closest relatives (the Podospora anserina species complex). First, we used chromosome-level genome assemblies to resolve their phylogenetic relationships. We found that the species in the complex are well defined but diversified recently and rapidly, leading to high degrees of conflict at deep branches of the phylogeny. Unlike typical orthologous genes from the complex, some allorecognition genes (het-z and het-s) show trans-species polymorphism, a hallmark of long-term balancing selection. By contrast, the het genes belonging to the HNWD family exhibit a high turn-over, with losses and duplications happening often. In particular, the species P. pseudocomata has a considerable increase of HNWD genes. Unexpectedly, we show that the HNWD paralogs have clean defined boundaries flanked by a target site duplication (TSD), implicating a DNA transposon-like mechanism in the genesis of new duplicates. Overall, our data highlights the diversity of evolutionary histories behind individual self/non-self recognition genes at short evolutionary timescales.

  • 13.
    Ameur, Adam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Che, Huiwen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Martin, Marcel
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Bunikis, Ignas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, S-75236 Uppsala, Sweden.
    Dahlberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Höijer, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Häggqvist, Susana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vezzi, Francesco
    Stockholm Univ, DBB, Sci Life Lab, S-11419 Stockholm, Sweden.
    Nordlund, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Dept Med Sci, Sci Life Lab, Mol Med, S-75236 Uppsala, Sweden.
    Olason, Pall
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    De Novo Assembly of Two Swedish Genomes Reveals Missing Segments from the Human GRCh38 Reference and Improves Variant Calling of Population-Scale Sequencing Data2018Inngår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 9, nr 10, artikkel-id 486Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The current human reference sequence (GRCh38) is a foundation for large-scale sequencing projects. However, recent studies have suggested that GRCh38 may be incomplete and give a suboptimal representation of specific population groups. Here, we performed a de novo assembly of two Swedish genomes that revealed over 10 Mb of sequences absent from the human GRCh38 reference in each individual. Around 6 Mb of these novel sequences (NS) are shared with a Chinese personal genome. The NS are highly repetitive, have an elevated GC-content, and are primarily located in centromeric or telomeric regions. Up to 1 Mb of NS can be assigned to chromosome Y, and large segments are also missing from GRCh38 at chromosomes 14, 17, and 21. Inclusion of NS into the GRCh38 reference radically improves the alignment and variant calling from short-read whole-genome sequencing data at several genomic loci. A re-analysis of a Swedish population-scale sequencing project yields > 75,000 putative novel single nucleotide variants (SNVs) and removes > 10,000 false positive SNV calls per individual, some of which are located in protein coding regions. Our results highlight that the GRCh38 reference is not yet complete and demonstrate that personal genome assemblies from local populations can improve the analysis of short-read whole-genome sequencing data.

    Fulltekst (pdf)
    FULLTEXT01
  • 14.
    Ameur, Adam
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Dahlberg, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Olason, Pall
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Vezzi, Francesco
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Karlsson, Robert
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Martin, Marcel
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Viklund, Johan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Kähäri, Andreas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Lundin, Par
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Che, Huiwen
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Eisfeldt, Jesper
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lampa, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Dahlberg, Mats
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagberg, Jonas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Jareborg, Niclas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Liljedahl, Ulrika
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Jonasson, Inger
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Johansson, Åsa
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lundeberg, Joakim
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Syvänen, Ann-Christine
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär medicin. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Lundin, Sverker
    Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Nilsson, Daniel
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nystedt, Björn
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population2017Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, nr 11, s. 1253-1260Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

    Fulltekst (pdf)
    fulltext
  • 15.
    Amini, Rose-Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hollander, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Laszlo, S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Eriksson, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Gustafsson, Kristin Ayoola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Loskog, Angelica S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Lokon Pharma, AB,Uppsala, Sweden.
    Thörn, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients2019Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, artikkel-id 316Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. Results: The percentage of CD3-positive T-cells was lower (p=0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p=0.2) nor the T-cell/monocyte ratio (p=0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7(+)/CD3(-)/CD56(bright)/CD16(dim/-)) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p=0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p=0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p=0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p=0.04). Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

    Fulltekst (pdf)
    FULLTEXT01
  • 16.
    Andréasson, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Nilsson, Martina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Styrman, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Pettersson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Forensic mitochondrial coding region analysis for increased discrimination using pyrosequencing technology2007Inngår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 1, nr 1, s. 35-43Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Analysis of mitochondrial DNA (mtDNA) is very useful when nuclear DNA analysis fails due to degradation or insufficient amounts of DNA in forensic analysis. However, mtDNA analysis has a lower discrimination power compared to what can be obtained by nuclear DNA (nDNA) analysis, potentially resulting in multiple individuals showing identical mtDNA types in the HVI/HVII region. In this study, the increase in discrimination by analysis of mitochondrial coding regions has been evaluated for identical or similar HVI/HVII sequences. A pyrosequencing-based system for coding region analysis, comprising 17 pyrosequencing reactions performed on 15 PCR fragments, was utilised. This assay was evaluated in 135 samples, resulting in an average read length of 81 nucleotides in the pyrosequencing analysis. In the sample set, a total of 52 coding region SNPs were identified, of which 18 were singletons. In a group of 60 samples with 0 or 1 control region difference from the revised Cambridge reference sequence (rCRS), only 12 samples could not be resolved by at least two differences using the pyrosequencing assay. Thus, the use of this pyrosequencing-based coding region assay has the potential to substantially increase the discriminatory power of mtDNA analysis.

  • 17.
    Angius, Andrea
    et al.
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Uva, Paolo
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Oppo, Manuela
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Buers, Insa
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Persico, Ivana
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy.
    Onano, Stefano
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Cuccuru, Gianmauro
    Ctr Adv Studies Res & Dev Sardinia CRS4, Sci & Technol Pk Polaris, Pula, Italy.
    Van Allen, Margot I.
    Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada;BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada;Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Hulait, Gurdip
    BC Childrens & Womens Hlth Ctr, Prov Hlth Serv Author, Vancouver, BC, Canada.
    Aubertin, Gudrun
    Victoria Isl Hlth Author, Dept Med Genet, Victoria, BC, Canada.
    Muntoni, Francesco
    UCL Great Ormond St Hosp, Dubowitz Neuromuscular Ctr, London, England;Univ Hosp Wales, Inst Med Genet, Cardiff, S Glam, Wales.
    Fry, Andrew E.
    Annerén, Göran
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Stattin, Evalena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Palomares-Bralo, Maria
    Santos-Simarro, Fernando
    Cucca, Francesco
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Crisponi, Giangiorgio
    Clin St Anna, Cagliari, Italy.
    Rutsch, Frank
    Munster Univ, Cells Mot Cluster Excellence, Munster, Germany;Munster Univ, Childrens Hosp, Dept Gen Pediat, Munster, Germany.
    Crisponi, Laura
    CNR, Ist Ric Genet & Biomed, Cagliari, Italy;Univ Sassari, Dipartimento Sci Biomed, Sassari, Italy.
    Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses2019Inngår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, nr 5, s. 607-614Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

  • 18.
    Angsten, Gertrud
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Gustafson, Elisabet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Christofferson, Rolf H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Barnkirurgisk forskning.
    Resolution of infantile intestinal pseudo-obstruction in a boy2017Inngår i: Journal of Osteoporosis and Physical Activity, ISSN 2052-3211, E-ISSN 2213-5766, Vol. 24, s. 28-34Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A term boy with spontaneous passage of meconium exhibited episodes of abdominal distension and diarrhea. Due to failure to thrive and suspicion of Hischsprung's disease he was referred to our university hospital at five months of age. Rectal biopsies were normal. Laparotomy revealed dilation of the small bowel and colon without any mechanical obstruction. Full thickness bowel biopsies were taken and a loop ileostomy was constructed. Histopathology revealed fibrosing myopathy, Cajal cell hypertrophy, and neuronal degeneration in both the large and small bowel. The small bowel showed mastocytosis without inflammation. A central venous catheter was placed for vascular access, replaced three times and later switched to a subcutaneous venous port. Catheters were locked after use with vancomycin-heparin and later taurolidine. The individually tailored home parenteral nutrition contained unsaturated fatty acid lipids to reduce cholestasis. Initial insufficient growth was improved after correction of partial parenteral nutrition based on a metabolic balance study. The ileostomy was revised once and finally taken down at 11 years of age following one year without parenteral support. At follow-up at 13 years of age he has episodes of moderate abdominal pain and has entered puberty and reports a high quality of life. (C) 2017 The Authors. Published by Elsevier Inc.

    Fulltekst (pdf)
    fulltext
  • 19.
    Attwood, Misty M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Rask-Andersen, Mathias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Orphan Drugs and Their Impact on Pharmaceutical Development2018Inngår i: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 39, nr 6, s. 525-535Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    High levels of productivity, with an increasing number of approvals for new molecular entities (NMEs) by the FDA during the past decade, have coincided with the emergence of innovative drugs for treatments of rare diseases that have utilized the FDA orphan drug program. Since 2000, NMEs with orphan designation encompass a significant portion of approved drugs and constitute about 80% of the approved drugs that have established novel human genome-encoded products in recent years. Biological approvals are also expanding, with 40% of the approved biological agents having orphan designation. This trend illustrates a pivot within the pharmaceutical industry: from research programs that focus on canonical blockbuster indications and targets, towards the establishment of new treatments for rare and difficult to treat diseases.

  • 20.
    Bakalkin, Georgy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Watanabe, Hiroyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Kononenko, Olga
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Stålhandske, Lada
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Marklund, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    TBI induced spinal cord plasticity: The endogenous opioid system mediates trauma effects on motor reflexes2016Inngår i: Brain Injury, ISSN 0269-9052, E-ISSN 1362-301X, Vol. 30, nr 5-6, s. 712-712Artikkel i tidsskrift (Annet vitenskapelig)
  • 21.
    Bandaru, Manoj Kumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Zebrafish models for large-scale genetic screens in dyslipidemia and atherosclerosis: Validation and application2019Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized. The overall aim of my thesis is to develop and validate novel in vivo model systems that are suitable for high-throughput, image-based genetic screens in coronary artery disease and related traits, and use these model systems to systematically characterize positional candidate genes.

    In Study I, I developed an experimental pipeline to validate the suitability of zebrafish larvae as a model system for systematic, large-scale characterization of drugs and genes associated with dyslipidemia and atherosclerosis. Using this pipeline, I showed that five days of overfeeding and cholesterol supplementation have independent pro-atherogenic effects in zebrafish larvae, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1). Finally, the pipeline helped me to identify putative causal genes for circulating lipids and early-stage atherosclerosis (LPAR2 and GATAD2A).

    In Study II, I characterized cardiometabolic traits in apoc2 mutant zebrafish larvae and found that, similar to humans, larvae with two non-functional apoc2 alleles have higher whole-body levels of triglycerides and total cholesterol, and more vascular lipid deposition than larvae without mutations in apoc2. Interestingly, apoc2 mutant larvae also had lower glucose levels after adjusting for triglyceride levels, suggesting that therapeutic stimulation of apoc2 to prevent hypertriglyceridemia may result in hyperglycemia. Still, zebrafish larvae with mutations in apoc2 can be a useful model to identify and characterize additional causal genes for triglyceride metabolism.

    In Study III, I examined the effects of mutations in pcsk9 on atherosclerosis and diabetes-related traits in nearly 5,000 zebrafish larvae. Similar to the loss-of-function mutations in PCSK9 in humans, larvae with mutations in pcsk9 had lower LDLc levels and were protected from early-stage atherosclerosis. Interestingly, mutations in pcsk9 also resulted in fewer pancreatic β-cells in 10 days old larvae, which suggests the higher risk of diabetes in humans with mutations in PCSK9 may result from a direct effect on the beta cell.

    Based on these large-scale proof-of-concept studies, my thesis confirms that zebrafish larvae can be used for large-scale, systematic genetic screens in dyslipidemia and early-stage atherosclerosis.

    Delarbeid
    1. Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Åpne denne publikasjonen i ny fane eller vindu >>Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosis
    Vise andre…
    (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    Abstract [en]

    Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

    Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

    Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

    Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-378939 (URN)
    Tilgjengelig fra: 2019-03-11 Laget: 2019-03-11 Sist oppdatert: 2019-11-24
    2. Apoc2 mutant zebrafish: a model for hypertriglyceridemia and early-stage atherosclerosis
    Åpne denne publikasjonen i ny fane eller vindu >>Apoc2 mutant zebrafish: a model for hypertriglyceridemia and early-stage atherosclerosis
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Zebrafish larvae in a hypertriglyceridemic background can be useful to identify and characterize causal genes for triglyceride metabolism. A previous, small-scale study suggested that apolipoprotein C-II (apoc2)-mutant zebrafish larvae can be used to model hypertriglyceridemia-induced atherosclerosis. We aimed to replicate these findings in a large-scale study and asses if APOC-II may represent a useful therapeutic target. We generated apoc2 mutant zebrafish using CRISPR-Cas9 and examined cardiometabolomic traits in their offspring (F1 generation). Systematic characterization of 384 larvae using our image and assay-based, high-throughput pipeline showed that compound heterozygous larvae for loss of function mutations in apoc2 (n=35) have higher whole-body levels of triglycerides (0.71±0.16 SD), HDL cholesterol (0.32±0.15 SD) and total cholesterol (0.37±0.18 SD), and a trend for lower whole-body glucose levels (0.23±0.14 SD) compared with larvae without mutations in apoc2 (n=174). Such larvae also tended to have more vascular lipid deposition, however this effect did not reach significance (P=0.12). Interestingly, the trends for lower whole-body glucose levels and more vascular lipid deposition in larvae with anticipated loss of functional apoc2 reached significance when larvae (n=3812) from other screens, in which apoc2 was not experimentally perturbed were included as additional wildtype controls. Thus, our large-scale study confirms the role of apoc2 in hypertriglyceridemia and early-stage atherosclerosis. While apoc2 mutant zebrafish model can be used as a genetic background to identify and characterize causal genes for triglyceride metabolism, independent and opposite effects on triglycerides and glucose suggest that APOC-II is likely not a suitable target for prevention and treatment of coronary artery disease.

    Emneord
    Apolipoprotein C-II, APOC2, Hypertriglyceridemia, Dyslipidemia, Atherosclerosis, Zebrafish, CRISPR
    HSV kategori
    Forskningsprogram
    Medicinsk genetik; Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-396067 (URN)
    Tilgjengelig fra: 2019-11-19 Laget: 2019-11-19 Sist oppdatert: 2019-11-24
    3. Image-based, in vivo characterization of cardiometabolic consequences of mutations in pcsk9
    Åpne denne publikasjonen i ny fane eller vindu >>Image-based, in vivo characterization of cardiometabolic consequences of mutations in pcsk9
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Based on the association of loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) with low plasma LDL cholesterol levels, inhibition of the PCSK9 protein using monoclonal antibodies have emerged as an effective treatment option to lower LDL cholesterol levels and reduce the risk of coronary artery disease. Despite these beneficial effects, PCSK9 inhibitors may increase the risk of diabetes. In this study, we mimicked the mechanistic action of PCSK9 inhibitors in humans by inducing mutations in pcsk9 in zebrafish and examining their effects on dyslipidemia, early-stage atherosclerosis and diabetes-related traits in data from nearly 5000 zebrafish larvae. At 10 days of age, larvae with mutations in pcsk9 were characterized by lower whole-body LDL cholesterol levels (beta±SE -0.056±0.025 SD units) and protection against early-stage atherosclerosis, with less vascular lipid deposition (-0.133±0.035 SD) and less co-localization of macrophages with lipids (-0.086±0.032 SD). Mutant larvae also had fewer pancreatic β-cells (-0.153±0.055 SD). Thus, our findings in pcsk9 mutant larvae are in line with results from people carrying loss-of-function PCSK9 mutations, and are also in line with the effects of PCSK9 inhibitors in humans. Further, our results suggest that mutations in pcsk9 may increase the risk of diabetes through a direct effect on pancreatic β-cells.

    Emneord
    Proprotein convertase subtilisin/kexin type 9, PCSK9, LDL cholesterol, Diabetes, Zebrafish, CRISPR
    HSV kategori
    Forskningsprogram
    Medicinsk genetik; Genetik
    Identifikatorer
    urn:nbn:se:uu:diva-396068 (URN)
    Tilgjengelig fra: 2019-11-19 Laget: 2019-11-19 Sist oppdatert: 2019-11-24
    Fulltekst (pdf)
    fulltext
    Download (jpg)
    presentationsbild
  • 22.
    Bandaru, Manoj Kumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Emmanouilidou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Erik, Ingelsson
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University.
    den Hoed, Marcel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Apoc2 mutant zebrafish: a model for hypertriglyceridemia and early-stage atherosclerosisManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Zebrafish larvae in a hypertriglyceridemic background can be useful to identify and characterize causal genes for triglyceride metabolism. A previous, small-scale study suggested that apolipoprotein C-II (apoc2)-mutant zebrafish larvae can be used to model hypertriglyceridemia-induced atherosclerosis. We aimed to replicate these findings in a large-scale study and asses if APOC-II may represent a useful therapeutic target. We generated apoc2 mutant zebrafish using CRISPR-Cas9 and examined cardiometabolomic traits in their offspring (F1 generation). Systematic characterization of 384 larvae using our image and assay-based, high-throughput pipeline showed that compound heterozygous larvae for loss of function mutations in apoc2 (n=35) have higher whole-body levels of triglycerides (0.71±0.16 SD), HDL cholesterol (0.32±0.15 SD) and total cholesterol (0.37±0.18 SD), and a trend for lower whole-body glucose levels (0.23±0.14 SD) compared with larvae without mutations in apoc2 (n=174). Such larvae also tended to have more vascular lipid deposition, however this effect did not reach significance (P=0.12). Interestingly, the trends for lower whole-body glucose levels and more vascular lipid deposition in larvae with anticipated loss of functional apoc2 reached significance when larvae (n=3812) from other screens, in which apoc2 was not experimentally perturbed were included as additional wildtype controls. Thus, our large-scale study confirms the role of apoc2 in hypertriglyceridemia and early-stage atherosclerosis. While apoc2 mutant zebrafish model can be used as a genetic background to identify and characterize causal genes for triglyceride metabolism, independent and opposite effects on triglycerides and glucose suggest that APOC-II is likely not a suitable target for prevention and treatment of coronary artery disease.

  • 23.
    Bandaru, Manoj Kumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Emmanouilidou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Ranefall, Petter
    von der Heyde, Benedikt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mazzaferro, Eugenia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Klingström, Tiffany
    Masiero, Mauro
    Dethlefsen, Olga
    Ledin, Johan
    Larsson, Anders
    Brooke, Hannah
    Wählby, Carolina
    Ingelsson, Erik
    den Hoed, Marcel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Zebrafish larvae as a model system for systematic characterization of drugs and genes in dyslipidemia and atherosclerosisInngår i: Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Hundreds of loci have been robustly associated with circulating lipids, atherosclerosis and coronary artery disease; but for most loci the causal genes and mechanisms remain uncharacterized.

    Methods: We developed a semi-automated experimental pipeline for systematic, quantitative, large-scale characterization of mechanisms, drugs and genes associated with dyslipidemia and atherosclerosis in a zebrafish model system. We validated our pipeline using a dietary (n>2000), drug treatment (n>1000), and genetic intervention (n=384).

    Results: Our results show that five days of overfeeding and cholesterol supplementation had independent pro-atherogenic effects, which could be diminished by concomitant treatment with atorvastatin and ezetimibe. CRISPR-Cas9-induced mutations in orthologues of proof-of-concept genes resulted in higher LDL cholesterol levels (apoea), and more early stage atherosclerosis (apobb.1).

    Conclusions: In summary, our pipeline facilitates systematic, in vivo characterization of drugs and candidate genes to increase our understanding of disease etiology, and can likely help identify novel targets for therapeutic intervention.

  • 24.
    Bandaru, Manoj Kumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Mazzaferro, Eugenia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Emmanouilidou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Erik, Ingelsson
    Department of Medicine, Division of Cardiovascular Medicine, Stanford University.
    den Hoed, Marcel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Image-based, in vivo characterization of cardiometabolic consequences of mutations in pcsk9Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Based on the association of loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) with low plasma LDL cholesterol levels, inhibition of the PCSK9 protein using monoclonal antibodies have emerged as an effective treatment option to lower LDL cholesterol levels and reduce the risk of coronary artery disease. Despite these beneficial effects, PCSK9 inhibitors may increase the risk of diabetes. In this study, we mimicked the mechanistic action of PCSK9 inhibitors in humans by inducing mutations in pcsk9 in zebrafish and examining their effects on dyslipidemia, early-stage atherosclerosis and diabetes-related traits in data from nearly 5000 zebrafish larvae. At 10 days of age, larvae with mutations in pcsk9 were characterized by lower whole-body LDL cholesterol levels (beta±SE -0.056±0.025 SD units) and protection against early-stage atherosclerosis, with less vascular lipid deposition (-0.133±0.035 SD) and less co-localization of macrophages with lipids (-0.086±0.032 SD). Mutant larvae also had fewer pancreatic β-cells (-0.153±0.055 SD). Thus, our findings in pcsk9 mutant larvae are in line with results from people carrying loss-of-function PCSK9 mutations, and are also in line with the effects of PCSK9 inhibitors in humans. Further, our results suggest that mutations in pcsk9 may increase the risk of diabetes through a direct effect on pancreatic β-cells.

  • 25.
    Banihani, Rudaina
    et al.
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    Baskin, Berivan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Halliday, William
    Univ Toronto, Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada..
    Kobayashi, Jeff
    Univ Toronto, Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada..
    Kawamura, Anne
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    McAdam, Laura
    Univ Toronto, Dept Paediat, Div Dev Paediat, Toronto, ON M5S 1A1, Canada.;Holland Bloorview Kids Rehabil Hosp, Child Dev Program, Toronto, ON, Canada..
    Ray, Peter N.
    Univ Toronto, Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Dept Mol Genet, Toronto, ON, Canada..
    Yoon, Grace
    Univ Toronto, Hosp Sick Children, Dept Paediat, Div Neurol, Toronto, ON M5G 1X8, Canada.;Univ Toronto, Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada..
    A Novel Mutation in DMD (c.10797+5G > A) Causes Becker Muscular Dystrophy Associated with Intellectual Disability2016Inngår i: Journal of Developmental and Behavioral Pediatrics, ISSN 0196-206X, E-ISSN 1536-7312, Vol. 37, nr 3, s. 239-244Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Severe intellectual disability has been reported in a subgroup of patients with Duchenne muscular dystrophy but is not typically associated with Becker muscular dystrophy. Patient: The authors report a 13-year-old boy, with severe intellectual disability (Wechsler Intelligence Scales for Children-IV, Full Scale IQ < 0.1 percentile), attention-deficit hyperactivity disorder, and mild muscle weakness. He had elevated serum creatine kinase and dystrophic changes on muscle biopsy. Dystrophin immunohistochemistry revealed decreased staining with the C-terminal and mid-rod antibodies and essentially absent staining of the N-terminal immunostain. Sequencing of muscle mRNA revealed aberrant splicing due to a c.10797+5G > A mutation in DMD. Conclusion: Dystrophinopathy may be associated with predominantly cognitive impairment and neurobehavioral disorder, and should be considered in the differential diagnosis of unexplained cognitive or psychiatric disturbance in males.

  • 26.
    Baskaran, Sathishkumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, nr 8, s. 1080-1091Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

    Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

    Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

    Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

    Fulltekst (pdf)
    fulltext
  • 27.
    Baskin, Berivan
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Hosp Sick Children, Dept Pediat Lab Med, Toronto, Canada.
    Kalia, Lorraine V.
    Toronto Western Hosp, Morton & Gloria Shulman Movement Disorders Clin, Toronto, Canada; Toronto Western Hosp, Edmond J Safra Program Parkinsons Dis, Toronto, Canada; Univ Toronto, Univ Hlth Network, Div Neurol, Dept Med, Toronto, Canada.
    Banwell, Brenda L.
    Univ Philadelphia, Perelman Sch Med, Childrens Hosp Philadelphia, Philadelphia, USA.
    Ray, Peter N.
    Hosp Sick Children, Dept Pediat Lab Med, Toronto, Canada; Univ Toronto, Dept Mol Genet, Toronto, Canada.
    Yoon, Grace
    Univ Toronto, Hosp Sick Children, Dept Pediat, Div Clin & Metab Genet, Toronto, Canada; Univ Toronto, Hosp Sick Children, Dept Pediat, Div Neurol, Toronto, Canada.
    Complex genomic rearrangement in SPG11 due to a DNA replication-based mechanism2017Inngår i: Movement Disorders, ISSN 0885-3185, E-ISSN 1531-8257, Vol. 32, s. 1792-1794Artikkel i tidsskrift (Fagfellevurdert)
  • 28.
    Bengtsson, Daniel
    et al.
    Linkoping Univ, Dept Clin & Expt Med, S-58183 Linkoping, Sweden.;Kalmar Cty Hosp, Dept Internal Med, S-39185 Kalmar, Sweden..
    Joost, Patrick
    Lund Univ, Inst Clin Sci, Dept Oncol & Pathol, S-22184 Lund, Sweden..
    Aravidis, Christos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Stenmark, Marie Askmalm
    Linkoping Univ, Div Clin Genet, Dept Clin & Expt Med, S-58185 Linkoping, Sweden.;Off Med Serv, Dept Clin Genet, S-22184 Lund, Sweden.;Lund Univ, Div Clin Genet, Dept Lab Med, S-22184 Lund, Sweden..
    Backman, Ann-Sofie
    Karolinska Univ Hosp, Ctr Digest Dis, S-17176 Stockholm, Sweden.;Karolinska Inst, Inst Med, S-17176 Stockholm, Sweden..
    Melin, Beatrice
    Umea Univ, Dept Radiat Sci, Oncol, S-90187 Umea, Sweden..
    von Salome, Jenny
    Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden..
    Zagoras, Theofanis
    Sahlgrens Univ Hosp, Dept Clin Pathol & Genet, S-41345 Gothenburg, Sweden..
    Gebre-Medhin, Samuel
    Lund Univ, Div Clin Genet, Dept Lab Med, S-22184 Lund, Sweden.;Karolinska Univ Hosp, Dept Clin Genet, S-17176 Stockholm, Sweden..
    Burman, Pia
    Lund Univ, Dept Endocrinol, Skane Univ Hosp, SE-20502 Malmo, Sweden..
    Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort2017Inngår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 102, nr 11, s. 3928-3932Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patient's germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.

  • 29.
    Bergendal, Birgitta
    et al.
    Inst Postgrad Dent Educ, Natl Oral Disabil Ctr Rare Disorders, POB 1030, SE-55111 Jonkoping, Sweden.;Jonkoping Univ, Sch Hlth & Welf, Jonkoping, Sweden..
    Norderyd, Johanna
    Inst Postgrad Dent Educ, Natl Oral Disabil Ctr Rare Disorders, POB 1030, SE-55111 Jonkoping, Sweden.;Jonkoping Univ, Sch Hlth & Welf, Jonkoping, Sweden..
    Zhou, Xiaolei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency2016Inngår i: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 17, artikkel-id 88Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The WNT10A protein is critical for the development of ectodermal appendages. Variants in the WNT10A gene may be associated with a spectrum of ectodermal abnormalities including extensive tooth agenesis. Methods: In seven patients with severe tooth agenesis we identified anomalies in primary dentition and additional ectodermal symptoms, and assessed WNT10A mutations by genetic analysis. Results: Investigation of primary dentition revealed peg-shaped crowns of primary mandibular incisors and three individuals had agenesis of at least two primary teeth. The permanent dentition was severely affected in all individuals with a mean of 21 missing teeth. Primary teeth were most often present in positions were succedaneous teeth were missing. Furthermore, most existing molars had taurodontism. Light, brittle or coarse hair was reported in all seven individuals, hyperhidrosis of palms and soles in six individuals and nail anomalies in two individuals. The anomalies in primary dentition preceded most of the additional ectodermal symptoms. Genetic analysis revealed that all seven individuals were homozygous or compound heterozygous for WNT10A mutations resulting in C107X, E222X and F228I. Conclusions: We conclude that tooth agenesis and/or peg-shaped crowns of primary mandibular incisors, severe oligodontia of permanent dentition as well as ectodermal symptoms of varying severity may be predictors of biallelic WNT10A mutations of importance for diagnosis, counselling and follow-up.

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  • 30.
    Berggren, Daniel Moreno
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Folkvaljon, Yasin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Engvall, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Sundberg, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Lambe, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Antunovic, Petar
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Garelius, Hege
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Dept Med, Gothenburg, Sweden.
    Lorenz, Fryderyk
    Umea Univ, Dept Med Biosci, Umea, Sweden.
    Nilsson, Lars
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Rasmussen, Bengt
    Orebro Univ Hosp, Sch Med Sci, Orebro, Sweden.
    Lehmann, Sören
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hellstrom-Lindberg, Eva
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Huddinge, Ctr Haematol & Regenerat Med, Stockholm, Sweden.
    Jadersten, Martin
    Karolinska Inst, Karolinska Univ Hosp, Dept Med Huddinge, Ctr Haematol & Regenerat Med, Stockholm, Sweden.
    Ejerblad, Elisabeth
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register2018Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, nr 5, s. 614-627Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2<bold></bold>9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P<0<bold></bold>001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0<bold></bold>05) and for WPSS compared to IPSS (P=0<bold></bold>07). IPSS-R was superior to both IPSS and WPSS for patients aged 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

  • 31.
    Berggrund, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Lundberg, Martin
    OLINK Prote, Uppsala Sci Pk, SE-75183 Uppsala, Sweden.
    Assarsson, Erika
    OLINK Prote, Uppsala Sci Pk, SE-75183 Uppsala, Sweden.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Lindquist, David
    Umeå Univ, Dept Radiat Sci, SE-90187 Umeå, Sweden.
    Hallmans, Göran
    Umeå Univ, Dept Publ Hlth & Clin Med, Nutr Res, SE-90187 Umeå, Sweden.
    Grankvist, Kjell
    Umeå Univ, Dept Med Biosci, Clin Chem, SE-90187 Umeå, Sweden.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gyllensten, Ulf
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Identification of Candidate Plasma Protein Biomarkers for Cervical Cancer Using the Multiplex Proximity Extension Assay2019Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 18, nr 4, s. 735-743Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared with controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared with population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.

  • 32.
    Berggrund, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Gustavsson, Inger M.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Aarnio, Riina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Lindberg, Julia Hedlund
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Sanner, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Wikström, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Enroth, Stefan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Gyllensten, Ulf B.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    HPV viral load in self-collected vaginal fluid samples as predictor for presence of cervical intraepithelial neoplasia.2019Inngår i: Virology Journal, ISSN 1743-422X, E-ISSN 1743-422X, Vol. 16, artikkel-id 146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE: This study was performed to evaluate the use of high-risk HPV (hrHPV) viral load in screening tests for cervical cancer to predict persistent infection and presence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

    METHODS: We followed women between 30 and 60 years of age who performed self-sampling of vaginal fluid and subsequently a hrHPV test. Women who were hrHPV positive in their screening test repeated the hrHPV test 3-6 months later and were included in the present study.

    RESULTS: Our results show that women with a persistent HPV16 infection had higher HPV viral load in their primary screening test than women with transient infections (p = 5.33e-03). This was also true for sum of viral load for all hrHPV types in the primary screening test (p = 3.88e-07). 48% of women with persistent HPV16 infection and CIN2+ had an increase in HPV16 titer in the follow-up test, as compared to only 20% of women with persistent infection but without CIN2+ lesions. For the sum of all hrHPV types, 41% of women with persistent infection and CIN2+ had an increase in titer as compared to 26% of women without CIN2 + .

    CONCLUSIONS: The results show that hrHPV viral load in the primary screening HPV test is associated with the presence of CIN2+ and could be used in triaging hrHPV positive women for different follow-up strategies or recall times. Serial testing of hrHPV viral load has the potential to distinguish women with CIN2+ lesions from women with persistent infection but without CIN2+ lesions.

    Fulltekst (pdf)
    fulltext
  • 33.
    Berghoff, Bork A.
    et al.
    Justus Liebig Univ, Inst Mikrobiol & Mol Biol, Giessen, Germany..
    Karlsson, Torgny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Kallman, Thomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wagner, Gerhart E. H.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Mikrobiologi.
    Grabherr, Manfred G.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    RNA-sequence data normalization through in silico prediction of reference genes: the bacterial response to DNA damage as case study2017Inngår i: BioData Mining, ISSN 1756-0381, E-ISSN 1756-0381, Vol. 10, artikkel-id 30Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Measuring how gene expression changes in the course of an experiment assesses how an organism responds on a molecular level. Sequencing of RNA molecules, and their subsequent quantification, aims to assess global gene expression changes on the RNA level (transcriptome). While advances in high-throughput RNA-sequencing (RNA-seq) technologies allow for inexpensive data generation, accurate post-processing and normalization across samples is required to eliminate any systematic noise introduced by the biochemical and/or technical processes. Existing methods thus either normalize on selected known reference genes that are invariant in expression across the experiment, assume that the majority of genes are invariant, or that the effects of up-and down-regulated genes cancel each other out during the normalization.

    Results: Here, we present a novel method, moose(2), which predicts invariant genes in silico through a dynamic programming (DP) scheme and applies a quadratic normalization based on this subset. The method allows for specifying a set of known or experimentally validated invariant genes, which guides the DP. We experimentally verified the predictions of this method in the bacterium Escherichia coli, and show how moose(2) is able to (i) estimate the expression value distances between RNA-seq samples, (ii) reduce the variation of expression values across all samples, and (iii) to subsequently reveal new functional groups of genes during the late stages of DNA damage. We further applied the method to three eukaryotic data sets, on which its performance compares favourably to other methods. The software is implemented in C++ and is publicly available from http://grabherr.github.io/moose2/.

    Conclusions: The proposed RNA-seq normalization method, moose(2), is a valuable alternative to existing methods, with two major advantages: (i) in silico prediction of invariant genes provides a list of potential reference genes for downstream analyses, and (ii) non-linear artefacts in RNA-seq data are handled adequately to minimize variations between replicates.

    Fulltekst (pdf)
    fulltext
  • 34.
    Berglund, Britta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pettersson, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Pigg, Maritta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Kristiansson, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Self-reported quality of life, anxiety and depression in individuals with Ehlers-Danlos syndrome (EDS): a questionnaire study2015Inngår i: BMC Musculoskeletal Disorders, ISSN 1471-2474, E-ISSN 1471-2474, Vol. 16, artikkel-id 89Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Many individuals with Ehlers-Danlos Syndrome (EDS) are hypermobile, suffer from long term pain, and have complex health problems. Since these sometimes have no objective physical signs, individuals with EDS sometimes are referred for psychiatric evaluation. The aim was therefore to identify the level of anxiety and quality of life in a Swedish group of individuals with EDS. Methods: A postal survey in 2008 was distributed to 365 members over 18 years of the Swedish National EDS Association and 250 with EDS diagnosis responded. Two questionnaires, the Hospital Anxiety and Depression Scale (HADS) and SF-36, were used. A Swedish population study was used to compare results from SF-36. Independent Student's t-test was used to compare differences between groups, possible relationships were tested using Spearman's correlation coefficient and the General Linear Model was used for regression analyses. Higher scores on HADS represent higher levels of anxiety and depression and higher scores on SF-36 represent higher quality of health. Results: Of the respondents 74.8% scored high on anxiety and 22.4% scored high on depression on the HADS. Age, tiredness and back pain was independently associated with the HAD anxiety score in a multiple regression analysis, When comparing the SF-36 scores from the EDS group and a Swedish population group, the EDS group scored significantly lower, indicating lower health-related quality of health than the general population (p < 0.001). Conclusions: In comparison with a Swedish population group, a lower health-related quality of life was found in the EDS group. Also, higher levels of anxiety and depression were detected in individuals with EDS. The importance to explore the factors behind these results and what initiatives can be taken to alleviate the situation for this group is emphasized.

    Fulltekst (pdf)
    fulltext
  • 35.
    Bergman, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Klinisk obstetrik. Ctr Clin Res, Falun, Sweden.
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden;UCL Inst Neurol, Queen Sq, London, England;UK Dementia Res Inst, London, England.
    Kaihola, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Hagberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Perinatal Ctr, Dept Obstet & Gynecol, Gothenburg, Sweden;Kings Coll London, Ctr Developing Brain, London, England.
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Molndal, Sweden;Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden.
    Åkerud, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study2018Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 5, artikkel-id e0196025Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective To evaluate if concentrations of the neuronal proteins neurofilament light chain and tau are changed in women developing preeclampsia and to evaluate the ability of a combination of neurofilament light chain, tau, S100B and neuron specific enolase in identifying neurologic impairment before diagnosis of preeclampsia. Methods A nested case-control study within a longitudinal study cohort was performed. 469 healthy pregnant women were enrolled between 2004-2007 and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Plasma concentrations of tau and neurofilament light chain were analyzed in 16 women who eventually developed preeclampsia and 36 controls throughout pregnancy with single molecule array (Simoa) method and compared within and between groups. S100B and NSE had been analyzed previously in the same study population. A statistical model with receiving characteristic operation curve was constructed with the four biomarkers combined. Results Plasma concentrations of neurofilament light chain were significantly increased in women who developed preeclampsia in gestational week 33 (11.85 ng/L, IQR 7.48-39.93 vs 6.80 ng/L, IQR 5.65-11.40) and 37 (22.15 ng/L, IQR 10.93-35.30 vs 8.40 ng/L, IQR 6.40-14.30) and for tau in gestational week 37 (4.33 ng/L, IQR 3.97-12.83 vs 3.77 ng/L, IQR 1.91-5.25) in contrast to healthy controls. A combined model for preeclampsia with tau, neurofilament light chain, S100B and neuron specific enolase in gestational week 25 displayed an area under the curve of 0.77, in week 28 it was 0.75, in week 33 it was 0.89 and in week 37 it was 0.83. Median week for diagnosis of preeclampsia was at 38 weeks of gestation. Conclusion Concentrations of both tau and neurofilament light chain are increased in the end of pregnancy in women developing preeclampsia in contrast to healthy pregnancies. Cerebral biomarkers might reflect cerebral involvement before onset of disease.

    Fulltekst (pdf)
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  • 36.
    Bhoi, Sujata
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Cortese, Diego
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mattsson, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Sevov, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Smedby, Karin E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Juliusson, Gunnar
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr 2, s. E63-E65Artikkel i tidsskrift (Fagfellevurdert)
  • 37.
    Bjersand, Kathrine
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Seidal, Tomas
    Department of Pathology, Halmstad Medical Center Hospital, Halmstad, Sweden.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Åkerud, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Skírnisdottir, Ingiridur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    The clinical and prognostic correlation of HRNPM and SLC1A5 in pathogenesis and prognosis in epithelial ovarian cancer2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 6, artikkel-id e0179363Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVES: To evaluate the prognostic effect of the Heterogeneous nuclear ribonucleoprotein type M (HNRPM) and Solute carrier 1A5 (SLC1A5) in FIGO-stages I-II epithelial ovarian cancer.

    METHODS: A retrospective cohort study was designed to investigate the prognostic effect of HNRPM and SLC1A5, and the association with clinical-pathologic characteristics in 131 patients with FIGO-stages I-II epithelial ovarian cancer. Tissue microarrays were constructed and protein levels were assessed by immunohistochemistry (IHC).

    RESULTS: Positive HRNPM status was associated with positive staining for PUMA (P = 0.04), concomitant PUMA and p21 staining (P = 0.005), and VEGF-R2 (P = 0.003). Positive SLC1A5 staining was associated with positive staining of p27 (P = 0.030), PUMA (P = 0.039), concomitant PUMA and p27 staining, and VEGF-R2 (P = 0.039). In non-serous tumors (n = 72), the SLC1A5 positivity was associated with recurrent disease (P = 0.01). In a multivariable logistic regression analysis FIGO-stage (OR = 12.4), tumor grade (OR = 5.1) and SLC1A5 positivity (OR = 0.1) were independent predictive factors for recurrent disease. Disease-free survival (DFS) in women with SLC1A5-positive non-serous tumors was 92% compared with of 66% in patients with SLC1A5-negative non-serous tumors (Log-rank = 15.343; P = 0.008). In Cox analysis with DFS as endpoint, FIGO-stage (HR = 4.5) and SLC1A5 status (HR = 0.3) were prognostic factors.

    CONCLUSIONS: As the proteins HRNPM and SLC1A5 are associated with the cell cycle regulators p21 or p27, the apoptosis regulators PTEN and PUMA, and the VEGF-R2 it is concluded that both proteins have role in the pathogenesis of ovarian cancer. In patients with non-serous ovarian cancer SLC1A5 protects from recurrent disease, presumably by means of biological mechanisms that are unrelated to cytotoxic drug sensitivity.

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    fulltext
  • 38. Bogdanowicz, Wiesław
    et al.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Branicki, Wojciech
    Lembring, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Gajewska, Marta
    Kupiec, Tomasz
    Genetic identification of putative remains of the famous astronomer Nicolaus Copernicus2009Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, nr 30, s. 12279-12282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We report the results of mitochondrial and nuclear DNA analyses of skeletal remains exhumed in 2005 at Frombork Cathedral in Poland, that are thought to be those of Nicolaus Copernicus (1473-1543). The analyzed bone remains were found close to the altar Nicolaus Copernicus was responsible for during his tenure as priest. The mitochondrial DNA (mtDNA) profiles from 3 upper molars and the femurs were identical, suggesting that the remains originate from the same individual. Identical mtDNA profiles were also determined in 2 hairs discovered in a calendar now exhibited at Museum Gustavianum in Uppsala, Sweden. This calendar was the property of Nicolaus Copernicus for much of his life. These findings, together with anthropological data, support the identification of the human remains found in Frombork Cathedral as those of Nicolaus Copernicus. Up-to-now the particular mtDNA haplotype has been observed only 3 times in Germany and once in Denmark. Moreover, Y-chromosomal and autosomal short tandem repeat markers were analyzed in one of the tooth samples, that was much better preserved than other parts of the skeleton. Molecular sex determination revealed that the skeleton is from a male individual, and this result is consistent with morphological investigations. The minimal Y-chromosomal haplotype determined in the putative remains of Nicolaus Copernicus has been observed previously in many countries, including Austria, Germany, Poland, and the Czech Republic. Finally, an analysis of the SNP located in the HERC2 gene revealed the C/C genotype that is predominant in blue-eyed humans, suggesting that Copernicus may have had a light iris color.

  • 39.
    Bondeson, Marie-Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ericson, Katharina
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Univ Uppsala Hosp, Dept Pathol & Cytol, Uppsala, Sweden.
    Gudmundsson, Sanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ameur, Adam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wesström, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning Dalarna. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Frykholm, Carina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wilbe, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A nonsense mutation in CEP55 defines a new locus for a Meckel-like syndrome, an autosomal recessive lethal fetal ciliopathy.2017Inngår i: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 92, nr 5, s. 510-516Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mutations in genes involved in the cilium-centrosome complex are called ciliopathies. Meckel-Gruber syndrome (MKS) is a ciliopathic lethal autosomal recessive syndrome characterized by genetically and clinically heterogeneous manifestations, including renal cystic dysplasia, occipital encephalocele and polydactyly. Several genes have previously been associated with MKS and MKS-like phenotypes, but there are still genes remaining to be discovered. We have used whole exome sequencing (WES) to uncover the genetics of a suspected autosomal recessive Meckel syndrome phenotype in a family with two affected fetuses. RNA studies and histopathological analysis was performed for further delineation. WES lead to identification of a homozygous nonsense mutation c.256C>T (p.Arg86*) in CEP55 (centrosomal protein of 55 kDa) in the affected fetus. The variant has previously been identified in carriers in low frequencies, and segregated in the family. CEP55 is an important centrosomal protein required for the mid-body formation at cytokinesis. Our results expand the list of centrosomal proteins implicated in human ciliopathies and provide evidence for an essential role of CEP55 during embryogenesis and development of disease.

  • 40.
    Bonfiglio, F.
    et al.
    Biodonostia Hlth Res Inst, Dept Gastrointestinal & Liver Dis, Donostia San Sebastian, Gipuzkoa, Spain; Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Henstrom, M.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Nag, A.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.
    Hadizadeh, F.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Zheng, T.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Cenit, M. C.
    Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Tigchelaar, E.
    Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Williams, F.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England.
    Reznichenko, A.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Ek, Weronica E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Rivera, N. V.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Homuth, G.
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Gen, Greifswald, Germany.
    Aghdassi, A. A.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany.
    Kacprowski, T.
    Univ Med Greifswald, Interfac Inst Genet & Funct Genom, Dept Funct Gen, Greifswald, Germany.
    Mannikko, M.
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland.
    Karhunen, V.
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland; Oulu Univ Hosp, Oulu, Finland;Imperial Coll London, Dept Epidemiol & Biostat, London, England.
    Bujanda, L.
    Biodonostia Hlth Res Inst, Dept Gastrointestinal & Liver Dis, Donostia San Sebastian, Gipuzkoa, Spain; Univ Basque Country, UPV EHU, Ctr Invest Biomed Red Enfermedades Hepat & Digest, San Sebastian, Spain.
    Rafter, J.
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Sweden.
    Wijmenga, C.
    Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    Ronkainen, J.
    Univ Oulu, Ctr Life Course Hlth Res, Oulu, Finland; Primary Hlth Care Ctr, Tornio, Finland.
    Hysi, P.
    Kings Coll London, Dept Ophthalmol, St Thomas Hosp Campus, London, England.
    Zhernakova, A.
    Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands.
    D'Amato, M.
    Biodonostia Hlth Res Inst, Dept Gastrointestinal & Liver Dis, Donostia San Sebastian, Gipuzkoa, Spain; Karolinska Inst, Dept Med Solna, Unit Clin Epidemiol, Stockholm, Sweden; BioCruces Hlth Res Inst, Bilbao, Spain; Basque Sci Fdn, IKERBASQUE, Bilbao, Spain.
    A GWAS meta-analysis from 5 population-based cohorts implicates ion channel genes in the pathogenesis of irritable bowel syndrome2018Inngår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 30, nr 9, artikkel-id e13358Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundIrritable bowel syndrome (IBS) shows genetic predisposition, however, large-scale, powered gene mapping studies are lacking. We sought to exploit existing genetic (genotype) and epidemiological (questionnaire) data from a series of population-based cohorts for IBS genome-wide association studies (GWAS) and their meta-analysis. MethodsBased on questionnaire data compatible with Rome III Criteria, we identified a total of 1335 IBS cases and 9768 asymptomatic individuals from 5 independent European genotyped cohorts. Individual GWAS were carried out with sex-adjusted logistic regression under an additive model, followed by meta-analysis using the inverse variance method. Functional annotation of significant results was obtained via a computational pipeline exploiting ontology and interaction networks, and tissue-specific and gene set enrichment analyses. Key ResultsSuggestive GWAS signals (P5.0x10(-6)) were detected for 7 genomic regions, harboring 64 gene candidates to affect IBS risk via functional or expression changes. Functional annotation of this gene set convincingly (best FDR-corrected P=3.1x10(-10)) highlighted regulation of ion channel activity as the most plausible pathway affecting IBS risk. Conclusion & InferencesOur results confirm the feasibility of population-based studies for gene-discovery efforts in IBS, identify risk genes and loci to be prioritized in independent follow-ups, and pinpoint ion channels as important players and potential therapeutic targets warranting further investigation.

  • 41. Bonfiglio, F
    et al.
    Hysi, P G
    Ek, Weronica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karhunen, V
    Rivera, N V
    Männikkö, M
    Nordenstedt, H
    Zucchelli, M
    Bresso, F
    Williams, F
    Tornblom, H
    Magnusson, P K
    Pedersen, N L
    Ronkainen, J
    Schmidt, P T
    D'Amato, M
    A meta-analysis of reflux genome-wide association studies in 6750 Northern Europeans from the general population2017Inngår i: Neurogastroenterology and Motility, ISSN 1350-1925, E-ISSN 1365-2982, Vol. 29, nr 2, artikkel-id e12923Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Gastroesophageal reflux disease (GERD), the regurgitation of gastric acids often accompanied by heartburn, affects up to 20% of the general population. Genetic predisposition is suspected from twin and family studies but gene-hunting efforts have so far been scarce and no conclusive genome-wide study has been reported. We exploited data available from general population samples, and studied self-reported reflux symptoms in relation to genome-wide single nucleotide polymorphism (SNP) genotypes.

    METHODS: We performed a GWAS meta-analysis of three independent population-based cohorts from Sweden, Finland, and UK. GERD cases (n=2247) and asymptomatic controls (n=4503) were identified using questionnaire-derived symptom data. Upon stringent quality controls, genotype data for more than 2.5M markers were used for association testing. Bioinformatic characterization of genomic regions associated with GERD included gene-set enrichment analysis (GSEA), in silico prediction of genetic risk effects on gene expression, and computational analysis of drug-induced gene expression signatures using Connectivity Map (cMap).

    KEY RESULTS: We identified 30 GERD suggestive risk loci (P≤5×10(-5) ), with concordant risk effects in all cohorts, and predicted functional effects on gene expression in relevant tissues. GSEA revealed involvement of GERD risk genes in biological processes associated with the regulation of ion channel and cell adhesion. From cMap analysis, omeprazole had significant effects on GERD risk gene expression, while antituberculosis and anti-inflammatory drugs scored highest among the repurposed compounds.

    CONCLUSIONS: We report a large-scale genetic study of GERD, and highlight genes and pathways that contribute to further our understanding of its pathogenesis and therapeutic opportunities.

  • 42.
    Bus, Magdalena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Genomik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Collecting and Preserving Biological Samples from Challenging Environments for DNA Analysis2014Inngår i: Biopreservation and Biobanking, ISSN 1947-5535, E-ISSN 1947-5543, Vol. 12, nr 1, s. 17-22Artikkel i tidsskrift (Fagfellevurdert)
  • 43.
    Bus, Magdalena M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Edlund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forensic Analysis of Mitochondrial and Autosomal Markers Using Pyrosequencing®.2015Inngår i: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1315, s. 379-396Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Forensic casework analyses often face challenges, such as limited genetic material with or without fragmentation and damage. To compensate for low amounts and degradation, shorter amplicons are often applied in the analysis. Also, a change of markers might be necessary using mitochondrial instead of autosomal markers. In addition, forensic research often involves analysis of large number of samples for marker evaluation and population-database compilation. Therefore, a flexible, robust but also rapid method for the detection of variation is highly useful. Pyrosequencing(®) is a rapid, reliable, easy-to-use method for sequence analysis. The method is well suited for rapid forensic analysis of a few targets or analysis of a single target in many samples. It allows sequencing of very short amplicons, which facilitates analysis of degraded DNA. Here we present the use of Pyrosequencing, a robust method for sensitive forensic analysis of mitochondrial DNA, autosomal STRs, and Y-chromosome STRs and SNPs.

  • 44.
    Bus, Magdalena M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Karas, Ognjen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Multiplex pyrosequencing of InDel markers for forensic DNA analysis2016Inngår i: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 37, nr 23-24, s. 3039-3045Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The capillary electrophoresis (CE) technology is commonly used for fragment length separation of markers in forensic DNA analysis. In this study, pyrosequencing technology was used as an alternative and rapid tool for the analysis of biallelic InDel (insertion/deletion) markers for individual identification. The DNA typing is based on a subset of the InDel markers that are included in the Investigator (R) DIPplex Kit, which are sequenced in a multiplex pyrosequencing analysis. To facilitate the analysis of degraded DNA, the polymerase chain reaction (PCR) fragments were kept short in the primer design. Samples from individuals of Swedish origin were genotyped using the pyrosequencing strategy and analysis of the Investigator (R) DIPplex markers with CE. A comparison between the pyrosequencing and CE data revealed concordant results demonstrating a robust and correct genotyping by pyrosequencing. Using optimal marker combination and a directed dispensation strategy, five markers could be multiplexed and analyzed simultaneously. In this proof-of-principle study, we demonstrate that multiplex InDel pyrosequencing analysis is possible. However, further studies on degraded samples, lower DNA quantities, and mixtures will be required to fully optimize InDel analysis by pyrosequencing for forensic applications. Overall, although CE analysis is implemented in most forensic laboratories, multiplex InDel pyrosequencing offers a cost-effective alternative for some applications.

  • 45.
    Bus, Magdalena M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lembring, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kjellstrom, Anna
    Stockholm Univ, Dept Archaeol & Class Studies, Osteoarchaeol Res Lab, S-10691 Stockholm, Sweden.
    Strobl, Christina
    Med Univ Innsbruck, Inst Legal Med, A-6020 Innsbruck, Austria.
    Zimmermann, Bettina
    Med Univ Innsbruck, Inst Legal Med, A-6020 Innsbruck, Austria.
    Parson, Walther
    Med Univ Innsbruck, Inst Legal Med, A-6020 Innsbruck, Austria;Penn State Univ, Forens Sci Program, University Pk, PA 16802 USA.
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mitochondrial DNA analysis of a Viking age mass grave in Sweden2019Inngår i: Forensic Science International: Genetics, ISSN 1872-4973, E-ISSN 1878-0326, Vol. 42, s. 268-274Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In 1998, a Viking Age mass grave was discovered and excavated at St. Laurence's churchyard in Sigtuna, Sweden. The excavated bones underwent osteoarchaeological analysis and were assigned to at least 19 individuals. Eleven skeletons showed sharp force trauma from bladed weapons. Mass graves are an unusual finding from this time period, making the burial context extraordinary. To investigate a possible maternal kinship among the individuals, bones and teeth from the skeletal remains were selected for mitochondrial DNA (mtDNA) analysis. Sanger sequencing of short stretches of the hypervariable segments I and II (HVS-I and HVS-II) was performed. A subset of the samples was also analysed by massively parallel sequencing analysis (MPS) of the entire mtDNA genome using the Precision ID mtDNA Whole Genome Panel. A total of 15 unique and three shared mtDNA profiles were obtained. Based on a combination of genetic and archaeological data, we conclude that a minimum of 20 individuals was buried in the mass grave. The majority of the individuals were not maternally related. However, two possible pairs of siblings or mother-child relationships were identified. All individuals were assigned to West Eurasian haplogroups, with a predominance of haplogroup H. Although the remains showed an advanced level of DNA degradation, the combined use of Sanger sequencing and MPS with the Precision ID mtDNA Whole Genome Panel revealed at least partial mtDNA data for all samples.

  • 46.
    Bus, Magdalena M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Nilsson, Martina
    Swedish Police Author, Div Invest, Forens Sect, S-10675 Stockholm, Sweden..
    Allen, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Analysis of Mitochondrial DNA from a Burned, Ninhydrin-Treated Paper Towel2016Inngår i: Journal of Forensic Sciences, ISSN 0022-1198, E-ISSN 1556-4029, Vol. 61, nr 3, s. 828-832Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Contact-based evidence is likely to have limited quantities of DNA and may yield mixed profiles due to preexisting or contaminating DNA. In a recent arson investigation, a paper towel was collected and used as circumstantial evidence. The paper towel was partially burned and was likely set on fire with flammable liquid. As part of the investigation, the paper towel was treated with ninhydrin to visualize fingerprint evidence. Initial DNA analysis of two swabs was negative for short tandem repeat (STR) markers and revealed a mixture of mitochondrial DNA (mtDNA). Analysis of 13 additional cuttings yielded four more mixed profiles, but also two samples with a common single-source profile. The single-source mtDNA profile matched that of the primary suspect in the case. Thus, even if initial mtDNA analysis yields a mixed profile, a sampling strategy involving multiple locations can improve the chance of obtaining valuable single-source mtDNA profiles from compromised evidence in criminal casework.

  • 47.
    Carlevaro-Fita, Joana
    et al.
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Lanzos, Andres
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Feuerbach, Lars
    Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany.
    Hong, Chen
    Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany;Deutsch Krebsforschungszentrum, Appl Bioinformat, DE-69120 Heidelberg, Germany.
    Mas-Ponte, David
    Barcelona Inst Sci & Technol, Ctr Gen Regulat CRG, Dr Aiguader 88, E-08003 Barcelona, Spain;Univ Pompeu Fabra UPF, Barcelona, Spain;Inst Hosp Mar Invest Med IMIM, Dr Aiguader 88, E-08003 Barcelona, Spain.
    Pedersen, Jakob Skou
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark;Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Johnson, Rory
    Univ Hosp, Dept Med Oncol, Inselspital, CH-3010 Bern, Switzerland;Univ Bern, CH-3010 Bern, Switzerland;Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Univ Bern, Grad Sch Cellular & BioMed Sci, CH-3012 Bern, Switzerland.
    Abascal, Federico
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
    Amin, Samirkumar B.
    Univ Texas MD Anderson Canc Ctr, Dept Gen Med, Houston, TX 77030 USA;Jackson Lab Gen Med, Farmington, CT 06032 USA;Baylor Coll Med, Quantitat & Computat Biosci Grad Program, Houston, TX 77030 USA.
    Bader, Gary D.
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.
    Barenboim, Jonathan
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Beroukhim, Rameen
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA;Harvard Med Sch, Boston, MA 02115 USA.
    Bertl, Johanna
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark;Aarhus Univ, Dept Math, DK-8000 Aarhus, Denmark.
    Boroevich, Keith A.
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan.
    Brunak, Soren
    Tech Univ Denmark, DK-2800 Lyngby, Denmark;Univ Copenhagen, DK-2200 Copenhagen, Denmark.
    Campbell, Peter J.
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England;Univ Cambridge, Dept Haematol, Cambridge CB2 2XY, England.
    Chakravarty, Dimple
    Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol Res, Div Canc Med, Houston, TX 77030 USA.
    Chan, Calvin Wing Yiu
    German Canc Res Ctr, Div Theoret Bioinformat, DE-69120 Heidelberg, Germany;Heidelberg Univ, Fac Biosci, DE-69120 Heidelberg, Germany.
    Chen, Ken
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Choi, Jung Kyoon
    Korea Adv Inst Sci & Technol, Daejeon 34141, South Korea.
    Deu-Pons, Jordi
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Dhingra, Priyanka
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA.
    Diamanti, Klev
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Fink, J. Lynn
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Univ Queensland, Inst Mol BioSci, Queensland Ctr Med Gen, St Lucia, Qld 4072, Australia.
    Fonseca, Nuno A.
    Univ Porto, Res Ctr Biodivers & Genet Resources, CIBIO InBIO, P-4485601 Vairao, Portugal;European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England.
    Frigola, Joan
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain.
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, I-20052 Monza, Italy.
    Garsed, Dale W.
    Peter MacCallum Canc Ctr, Melbourne, Vic 3000, Australia;Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3052, Australia.
    Gerstein, Mark
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA;Yale Univ, Dept Comp Sci, New Haven, CT 06520 USA;Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Getz, Gad
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02129 USA;Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02115 USA.
    Gonzalez-Perez, Abel
    Inst Hosp Mar Invest Med IMIM, Dr Aiguader 88, E-08003 Barcelona, Spain;Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Guo, Qianyun
    Aarhus Univ, Bioinformat Res Ctr BiRC, DK-8000 Aarhus, Denmark.
    Gut, Ivo G.
    Univ Pompeu Fabra UPF, Barcelona, Spain;Barcelona Inst Sci & Technol BIST, Ctr Gen Regulat CRG, CNAG CRG, E-08028 Barcelona, Spain.
    Haan, David
    Univ Calif, BioMol Engn Dept, Santa Cruz, CA 95064 USA.
    Hamilton, Mark P.
    Stanford Univ, Dept Internal Med, Stanford, CA 94305 USA.
    Haradhvala, Nicholas J.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Harmanci, Arif O.
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Univ Texas Hlth Sci Ctr, Ctr Precis Hlth, Sch BioMed Informat, Houston, TX 77030 USA.
    Helmy, Mohamed
    Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada.
    Herrmann, Carl
    German Canc Res Ctr, Div Theoret Bioinformat, DE-69120 Heidelberg, Germany;Univ Clin, Hlth Data Sci Unit, DE-69120 Heidelberg, Germany;Heidelberg Univ, Inst Pharm & Mol Biotechnol & BioQuant, DE-69120 Heidelberg, Germany.
    Hess, Julian M.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    Hobolth, Asger
    Aarhus Univ, Dept Math, DK-8000 Aarhus, Denmark;Aarhus Univ, Bioinformat Res Ctr BiRC, DK-8000 Aarhus, Denmark.
    Hodzic, Ermin
    Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada.
    Hornshoj, Henrik
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Isaev, Keren
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada;Univ Toronto, Dept Med BioPhys, Toronto, ON M5S 1A8, Canada.
    Izarzugaza, Jose M. G.
    Tech Univ Denmark, DK-2800 Lyngby, Denmark.
    Johnson, Todd A.
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan.
    Juul, Malene
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Juul, Randi Istrup
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Kahles, Andre
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Swiss Fed Inst Technol, Dept Biol, CH-8093 Zurich, Switzerland;Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland;SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland;Univ Hosp Zurich, CH-8091 Zurich, Switzerland.
    Kahraman, Abdullah
    Swiss Inst Bioinformat, Clin Bioinformat, CH-1202 Geneva, Switzerland;Univ Hosp Zurich, Inst Pathol & Mol Pathol, CH-8091 Zurich, Switzerland;Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland.
    Kellis, Manolis
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;MIT, MIT Comp Sci & Artificial Intelligence Lab, Cambridge, MA 02139 USA.
    Khurana, Ekta
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10065 USA;Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA.
    Kim, Jaegil
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Kim, Jong K.
    Natl Canc Ctr Korea, Res Core Ctr, Goyangsi 410769, South Korea.
    Kim, Youngwook
    Sungkyunkwan Univ Sch Med, Dept Hlth Sci & Technol, Seoul 06351, South Korea;Samsung Genome Inst, Seoul 06351, South Korea.
    Komorowski, Jan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland.
    Korbel, Jan O.
    European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England;European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany.
    Kumar, Sushant
    European Bioinformat Inst EMBLEBI, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England;Univ Milano Bicocca, I-20052 Monza, Italy.
    Larsson, Erik
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA.
    Lawrence, Michael S.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    Lee, Donghoon
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Lehmann, Kjong-Van
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Swiss Fed Inst Technol, Dept Comp Sci, CH-8092 Zurich, Switzerland;SIB Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland;Univ Hosp Zurich, CH-8091 Zurich, Switzerland;Swiss Fed Inst Technol, Dept Biol, Wolfgang-Pauli-Str 27, CH-8093 Zurich, Switzerland.
    Li, Shantao
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Li, Xiaotong
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Lin, Ziao
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Univ, Cambridge, MA 02138 USA.
    Liu, Eric Minwei
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Mem Sloan Kettering Canc Ctr, New York, NY 10065 USA.
    Lochovsky, Lucas
    Jackson Lab Gen Med, Farmington, CT 06032 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, New Haven, CT 06520 USA.
    Lou, Shaoke
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Madsen, Tobias
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Marchal, Kathleen
    Univ Ghent, Dept Informat Technol, B-9000 Ghent, Belgium;Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium.
    Martincorena, Inigo
    Wellcome Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England.
    Martinez-Fundichely, Alexander
    Weill Cornell Med, Dept Physiol & BioPhys, New York, NY 10065 USA;Weill Cornell Med, Inst Computat BioMed, New York, NY 10021 USA;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10065 USA.
    Maruvka, Yosef E.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA;Massachusetts Gen Hosp Ctr Canc Res, Charlestown, MA 02129 USA.
    McGillivray, Patrick D.
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA.
    Meyerson, William
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Yale Univ, Yale Sch Med, New Haven, CT 06520 USA.
    Muinos, Ferran
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Mularoni, Loris
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Nakagawa, Hidewaki
    RIKEN Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan.
    Nielsen, Morten Muhlig
    Aarhus Univ Hosp, Dept Mol Med, Palle Juul-Jensens Blvd 99, DK-8200 Aarhus, Denmark.
    Paczkowska, Marta
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Park, Keunchil
    Sungkyunkwan Univ Sch Med, Samsung Med Ctr, Div Hematol Oncol, Seoul 06351, South Korea;Sungkyunkwan Univ Sch Med, Samsung Adv Inst Hlth Sci & Technol, Seoul 06351, South Korea.
    Park, Kiejung
    Sangmyung Univ, Cheonan Ind Acad Collaborat Fdn, Cheonan 31066, South Korea.
    Pich, Oriol
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Pons, Tirso
    Spanish Natl Canc Res Centre, E-28029 Madrid, Spain.
    Pulido-Tamayo, Sergio
    Univ Ghent, Dept Informat Technol, B-9000 Ghent, Belgium;Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium.
    Raphael, Benjamin J.
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA.
    Reimand, Juri
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada;Univ Toronto, Dept Med BioPhys, Toronto, ON M5S 1A8, Canada.
    Reyes-Salazar, Iker
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain.
    Reyna, Matthew A.
    Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA.
    Rheinbay, Esther
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Boston, MA 02115 USA;Massachusetts Gen Hosp, Boston, MA 02114 USA.
    Rubin, Mark A.
    Univ Bern, Dept BioMed Res, CH-3008 Bern, Switzerland;Weill Cornell Med, Meyer Canc Ctr, New York, NY 10065 USA;Univ Bern, Univ Hosp Bern, Bern Ctr Precis Med, CH-3008 Bern, Switzerland;Weill Cornell Med, Englander Inst Precis Med, New York, NY 10021 USA;NewYork Presbyterian Hosp, New York, NY 10021 USA;Weill Cornell Med Coll, Pathol & Lab, New York, NY 10021 USA.
    Rubio-Perez, Carlota
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain;Vall Hebron Inst Oncol VHIO, E-08035 Barcelona, Spain.
    Sabarinathan, Radhakrishnan
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain;Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, India.
    Sahinalp, S. Cenk
    Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada;Indiana Univ, Bloomington, IN 47405 USA;Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada.
    Saksena, Gordon
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Salichos, Leonidas
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Sander, Chris
    Mem Sloan Kettering Canc Ctr, Computat Biol Ctr, New York, NY 10065 USA;Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA;Dana Farber Canc Inst, Boston, MA 02215 USA;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
    Schumacher, Steven E.
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
    Shackleton, Mark
    Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic 3052, Australia;Univ Melbourne, Melbourne, Vic 3000, Australia;Peter MacCallum Canc Inst, Melbourne, Vic 3000, Australia.
    Shapira, Ofer
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA.
    Shen, Ciyue
    Harvard Med Sch, Dana Farber Canc Inst, cBio Ctr, Boston, MA 02115 USA;Harvard Med Sch, Dept Cell Biol, Boston, MA 02115 USA.
    Shrestha, Raunak
    Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada.
    Shuai, Shimin
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada;Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Sidiropoulos, Nikos
    Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark;Univ Copenhagen, Finsen Lab, DK-2200 Copenhagen, Denmark.
    Sieverling, Lina
    Heidelberg Univ, Fac Biosci, DE-69120 Heidelberg, Germany;Univ Porto, Res Ctr Biodivers & Genet Resources, CIBIO InBIO, P-4485601 Vairao, Portugal.
    Sinnott-Armstrong, Nasa
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA;Stanford Univ Sch Med, Dept Genet, Stanford, CA 94305 USA.
    Stein, Lincoln D.
    Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada;Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Stuart, Joshua M.
    Univ Calif, BioMol Engn Dept, Santa Cruz, CA 95064 USA.
    Tamborero, David
    Barcelona Inst Sci & Technol, Inst Res BioMed IRB Barcelona, E-8003 Barcelona, Spain;Univ Pompeu Fabra, Res Program BioMed Informat, E-08002 Barcelona, Spain.
    Tiao, Grace
    Broad Inst MIT & Harvard, Cambridge, MA 02142 USA.
    Tsunoda, Tatsuhiko
    RIKEN Ctr Integrat Med Sci, Lab Med Sci Math, Yokohama, Kanagawa 2300045, Japan;Japan Sci & Technol Agcy, CREST, Tokyo, Tokyo 1130033, Japan;Tokyo Med & Dent Univ, Med Res Inst, Dept Med Sci Math, Bunkyo Ku, Tokyo 1138510, Japan;Univ Tokyo, Grad Sch Sci, Dept Biol Sci, Lab Med Sci Math,Bunkyo Ku, Tokyo 1130033, Japan.
    Umer, Husen Muhammad
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Karolinska Inst, Dept Oncol & Pathol, Sci Life Lab, S-17121 Stockholm, Sweden.
    Uuskula-Reimand, Liis
    Tallinn Univ Technol, Dept Gene Technol, EE-12616 Tallinn, Estonia;Hosp Sick Children, SickKids Res Inst, Genet & Genome Biol Program, Toronto, ON M5G 1X8, Canada.
    Valencia, Alfonso
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Inst Catalana Recerca & Estudis Avancats ICREA, E-08010 Barcelona, Spain.
    Vazquez, Miguel
    Barcelona SuperComp Ctr, E-08034 Barcelona, Spain;Norwegian Univ Sci & Technol, Fac Med & Hlth Sci, Dept Clin & Mol Med, N-7030 Trondheim, Norway.
    Verbeke, Lieven P. C.
    Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9000 Ghent, Belgium;Univ Ghent, Dept Informat Technol, Interuniv Microelectron Centrum IMEC, B-9000 Ghent, Belgium.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Wadi, Lina
    Ontario Inst Canc Res, Computat Biol Program, Toronto, ON M5G 0A3, Canada.
    Wang, Jiayin
    Xi'an Jiaotong Univ, Sch Comp Sci & Technol, Xian 710048, Peoples R China;Xi'an Jiaotong Univ, Sch Elect & Informat Engn, Xian 710048, Peoples R China;McDonnell Genome Inst Washington Univ, St. Louis, MO 63108 USA.
    Warrell, Jonathan
    Yale Univ, Dept Mol BioPhys & Biochem, New Haven, CT 06520 USA;Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Waszak, Sebastian M.
    European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany.
    Weischenfeldt, Joachim
    European Mol Biol Lab EMBL, Genome Biol Unit, DE-69117 Heidelberg, Germany;Univ Copenhagen, Biotech Res & Innovat Ctr BRIC, DK-2200 Copenhagen, Denmark;Univ Copenhagen, Finsen Lab, DK-2200 Copenhagen, Denmark;Charite Univ Med Berlin, Dept Urol, DE-10117 Berlin, Germany.
    Wheeler, David A.
    Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA.
    Wu, Guanming
    Oregon Hlth & Sci Univ, Portland, OR 97239 USA.
    Yu, Jun
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China;Second Mil Med Univ, Shanghai 200433, Peoples R China.
    Zhang, Jing
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA.
    Zhang, Xuanping
    Xi'an Jiaotong Univ, Sch Comp Sci & Technol, Xian 710048, Peoples R China;Univ Texas Hlth Sci Ctr Houston, Houston, TX 77030 USA.
    Zhang, Yan
    Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT 06520 USA;Ohio State Univ, Coll Med, Dept BioMed Informat, Columbus, OH 43210 USA;Ohio State Univ Comprehens Canc Ctr OSUCCC James, Columbus, OH 43210 USA.
    Zhao, Zhongming
    Univ Texas Hlth Sci Ctr Houston, Sch BioMed Informat, Houston, TX 77030 USA.
    Zou, Lihua
    Northwestern Univ, Feinberg Sch Med, Dept Biochem & Mol Genet, Chicago, IL 60637 USA.
    von Mering, Christian
    Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;Univ Zurich, Swiss Inst Bioinformat, CH-8057 Zurich, Switzerland.
    Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis2020Inngår i: COMMUNICATIONS BIOLOGY, ISSN 2399-3642, Vol. 3, nr 1, artikkel-id 56Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Joana Carlevaro-Fita, Andres Lanzos et al. present the Cancer LncRNA Census (CLC), a manually curated dataset of 122 long noncoding RNAs (lncRNAs) with experimentally-validated functions in cancer based on data from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. CLC lncRNAs have unique gene features, and a number display evidence for cancer-driving functions that are conserved from humans to mice. Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.

    Fulltekst (pdf)
    FULLTEXT01
  • 48.
    Castillejo-Lopez, Casimiro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Abalo, Xesus M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Sidibeh, Cherno O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Kamble, Prasad G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    FKBP51 ablation using CRISPR/Cas-9 impairs adipocyte differentiation2018Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S11-S12Artikkel i tidsskrift (Annet vitenskapelig)
  • 49.
    Castillejo-Lopez, Casimiro
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pjanic, Milos
    Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA.
    Pirona, Anna Chiara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. German Canc Res Ctr, Heidelberg, Germany.
    Hetty, Susanne
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Wabitsch, Martin
    Univ Ulm, Dept Pediat & Adolescent Med, Div Pediat Endocrinol & Diabet, Ulm, Germany.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Quertermous, Thomas
    Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA.
    Arner, Erik
    RIKEN, Lab Appl Regulatory Genom Network Anal, Ctr Integrat Med Sci, Yokohama, Kanagawa 2300045, Japan.
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Stanford Univ, Dept Med, Div Cardiovasc Med, Sch Med, Stanford, CA 94305 USA;Stanford Univ, Stanford Cardiovasc Inst, Stanford, CA 94305 USA;Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA.
    Detailed Functional Characterization of a Waist-Hip Ratio Locus in 7p15.2 Defines an Enhancer Controlling Adipocyte Differentiation2019Inngår i: ISCIENCE, ISSN 2589-0042, Vol. 20, s. 42-59Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We combined CAGE sequencing in human adipocytes during differentiation with data from genome-wide association studies to identify an enhancer in the SNX10 locus on chromosome 7, presumably involved in body fat distribution. Using reporter assays and CRISPR-Cas9 gene editing in human cell lines, we characterized the role of the enhancer in adipogenesis. The enhancer was active during adipogenesis and responded strongly to insulin and isoprenaline. The allele associated with increased waist-hip ratio in human genetic studies was associated with higher enhancer activity. Mutations of the enhancer resulted in less adipocyte differentiation. RNA sequencing of cells with disrupted enhancer showed reduced expression of established adipocyte markers, such as ADIPOQ and LPL, and identified CHI3L1 on chromosome 1 as a potential gene involved in adipocyte differentiation. In conclusion, we identified and characterized an enhancer in the SNX10 locus and outlined its plausible mechanisms of action and downstream targets.

    Fulltekst (pdf)
    FULLTEXT01
  • 50.
    Cavalli, Marco
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Baltzer, Nicholas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Pan, Gang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Walls, Jose Ramon Barcenas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Garbulowska, Karolina Smolinska
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik.
    Kumar, Chanchal
    AstraZeneca, Gothenburg, Sweden.
    Skrtic, Stanko
    AstraZeneca, Gothenburg, Sweden.
    Komorowski, Jan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Beräkningsbiologi och bioinformatik. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Wadelius, Claes
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Studies of liver tissue identify functional gene regulatory elements associated to gene expression, type 2 diabetes, and other metabolic diseases2019Inngår i: HUMAN GENOMICS, ISSN 1473-9542, Vol. 13, artikkel-id 20Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background:

    Genome-wide association studies (GWAS) of diseases and traits have found associations to gene regions but not the functional SNP or the gene mediating the effect. Difference in gene regulatory signals can be detected using chromatin immunoprecipitation and next-gen sequencing (ChIP-seq) of transcription factors or histone modifications by aligning reads to known polymorphisms in individual genomes. The aim was to identify such regulatory elements in the human liver to understand the genetics behind type 2 diabetes and metabolic diseases.

    Methods:

    The genome of liver tissue was sequenced using 10X Genomics technology to call polymorphic positions. Using ChIP-seq for two histone modifications, H3K4me3 and H3K27ac, and the transcription factor CTCF, and our established bioinformatics pipeline, we detected sites with significant difference in signal between the alleles.

    Results:

    We detected 2329 allele-specific SNPs (AS-SNPs) including 25 associated to GWAS SNPs linked to liver biology, e.g., 4 AS-SNPs at two type 2 diabetes loci. Two hundred ninety-two AS-SNPs were associated to liver gene expression in GTEx, and 134 AS-SNPs were located on 166 candidate functional motifs and most of them in EGR1-binding sites.

    Conclusions:

    This study provides a valuable collection of candidate liver regulatory elements for further experimental validation.

    Fulltekst (pdf)
    FULLTEXT01
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