| 1. |
- Anderson, Karen, et al.
(författare)
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Projektet God Informationsförvaltning
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Detta är den första publikationen i skriftserien Arkiv- och informationsvetenskap vid Mittuniversitetet producerad av Centrum för digital informationsförvaltning (CEDIF) vid Avdelningen för Arkiv- och Datavetenskap (ADV), Mittuniversitetet. Rapporten redovisar delar av det projektarbete som genomförts under namnet GoInfo (God Informationsförvaltning), under åren 2012-2015 med medel från Länsstyrelsen Västernorrland, Mittuniversitetet, Härnösands kommun och Riksarkivet Härnösand. Skriftserien är inspirerad av den tidigare rapportserien Arkiv-och informationsvetenskap vid Mitthögskolan, som utkom med sex nummer åren 1999-2000. I förordet till det första numret skrev redaktör Torbjörn Kjölstad “Det är vår förhoppning att rapportserien skall kunna förmedla en del av arkiv- och informationsvetenskapliga verksamheten vid Mitthögskolan. Vi har naturligtvis en strävan att presentera nya resultat inom detta mycket breda forskningsområde men också – och väl så viktigt – nya problemställningar och metodiska experiment”1. Vårt mål med den aktuella serien är densamma som i den tidigare: att dela med oss och sprida resultaten av vår forskning och kunskap.Ämnet arkivkunskap och dokumenthantering startade läsåret 1988/89 som en grundkurs vid Högskolan i Sundsvall/Härnösand, som senare blev Mitthögskolan. 1997 bedömde Högskoleverket att det uppfyllde kraven för magisterutbildning och magisterexamen och samma år ändrades benämningen till arkiv- och informationsvetenskap och år 2005 blev Mitthögskolan fullvärdigt universitet - Mittuniversitetet. Sedan universitet har fått ett allt större fokus på forskning så har också vårt ämne försökt att etablera en mer uttalad forskningsplattform. Det första större projekt ”Framtidens Arkiv” kom också att utgöra startskott för en rekrytering av en professur som tillsattes 2008. I Framtidens Arkiv rekryterades också ett par doktorander Erik Borglund och Lena-Maria Öberg som i anslutning till det projektet och via projekt som Bygga Villa och SMEdoc också disputerade.2 I slutet av 2009 beviljades medel till projekt CEDIF, som fick stöd av EU Europeiska regionala utvecklingsfond, Länsstyrelsen Västernorrland, Mittuniversitetet, Härnösands kommun och Sundsvalls kommun 2009-2012. Projektet syftade till att utveckla modeller för effektiv och långsiktig förvaltning av information inom framför allt offentlig sektor men även privat näringsliv. Inom detta projekt rekryterades doktorander Maria Kallberg och Proscovia Svärd. Maria Kallberg avslutade i december 2013 sin forskarutbildning inom GoInfo med avhandlingen ’The Emperor’s New Clothes’ - Recordkeeping in a New Context3, och samtidigt vinnare av Bureanska priset vid Mittuniversitetet. 2009 doktorerade Anneli Sundqvist med avhandlingen Search Processes, User Behaviour and Archival Representational Systems4.När detta skrivs är totalt tre doktorander aktiva vid avdelningen. Inom GoInfo har Ann-Sofie Klareld varit aktiv som doktorand. Ämnet arkiv- och informationsvetenskap har växt och mognat sedan starten 1988-1989. Utbildningen på grund- och masternivå har utökats med utbildning på forskarnivå och ett forskningsprogram.Sidorna som följer innehåller summeringar och reflektioner från GoInfo. Först ut är projektledaren Göran Samuelsson, som inleder med en övergripande beskrivning. Kapitlen som följer speglar GoInfos delprojekt och forskningsresultat. Ann-Sofie Klareld har skrivit om Arkivets roll inom e-förvaltningen. Sedan får vi insikter från Ann-Sofie Klareld och Annalena Olsson, (Riksarkivet i Härnösand) om Arkivmyndighetens roll i samarbets- och utvecklingsprojekt, utifrån Riksarkivets deltagande i flera projekt, inte minst e-ARD5, sponsrat av e-Delegationen. Karen Anderson och Göran Samuelsson presenterar i kapitlet Omvärldsanalys och teoretiska utgångspunkter de influenser som påverkat vår forskning, som bland annat haft en bas i den modell för informationsförsörjning som utvecklats av Göran Samuelsson. Kapitlet innehåller även några preliminära tankar om hur vi kan använda modellen i anslutning till de mer teoretiska modeller som används inom arkivvetenskap och praktik som; livscykelmodellen, Records Continuum modellen och OAIS-modellen. I kapitlet Myndighetsnätverket och GoInfo, rapporterar Ann-Sofie Klareld om hennes aktionsforskning och utmaningen att balansera rollen som forskare med förväntningar på verksamhetsutveckling. De följande tre kapitlen presentera mer konkreta forskning- och utvecklings ansatser i den kommunala miljön med ett stort fokus på GoInfos samverkans partner Härnösands kommun. Göran Samuelsson och Stefan Berggren ger ett Förslag till modell för strategiarbete för god informationsförvaltning, med användning av några av standarderna kring verksamhetsinformation bland annat ISO/SS 30300 och Riksarkivets RA FS 2009:16.Maria Kallberg skriver om Centraliserad diariefunktion, ett projekt som hon initierade i sin roll som kommunarkivarie i Härnösands kommun och sedan fortsatte att utforska som en del av sitt doktorandprojekt. Stefan Berggren, nuvarande kommunarkivarie i Härnösands kommun, och Göran Samuelsson beskriver sedan arbetet med hantera kommunens lönedata och hur man integrerar den nuvarande digitala hanteringen med äldre pappersbaserade informationen i kapitlet Lönedatafångst. I detta arbete har man försökt att praktiskt tillämpa de framtagna de förvaltningsgemensamma specifikationer för personalsystem (FGS Personal), som togs fram under e-ARD projektet. I ett avslutande avsnitt skriver Göran Samuelsson om Bevarande av geodata, ett alltmer viktigt område eftersom ’everything happens somewhere’ och att dessa data integreras med alltfler verksamhetssystem.Vår förhoppning är att du som läsarna ska kunna dra nytta av och även hämta kunskap från vår forskning, samt inspireras och utmanas att delta och bidra till den framtida arkiv- och informationsvetenskapliga forskningen.
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| 2. |
- Arnell, Sofie, 1984-
(författare)
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Elevers möten med matematik : En studie om elevers möten med matematik i förskoleklass och årskurs 1
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Många och positiva tidiga möten med matematik är betydelsefulla för barns och elevers matematiklärande. Avhandlingens syfte är att bidra med kunskap om elevers möten med matematik i förskoleklass och årskurs 1 genom att undersöka, analysera och beskriva dem. Ytterligare ett syfte är att redogöra för likheter och skillnader i elevers möten med matematik i förskoleklass och årskurs 1 för att bidra till ökad förståelse kring faktorer som kan påverka elevers möjligheter att utveckla förståelse för skolmatematiken. En empirisk studie genomfördes, där en elevgrupp och dess lärare följdes från höstterminen i förskoleklass till höstterminen i årskurs 1. Data samlades in genom deltagande observationer och informella samtal. Materialet analyserades sedan i två steg; först gjordes en empirinära analys och därefter en teoretisk analys utifrån begrepp hämtade från verksamhetsteorin. Resultatet visar att elevers möten med matematik i förskoleklass och årskurs 1 sker på en mängd olika sätt. Mötena kan relateras till tre olika typer av matematikverksamheter i både förskoleklassen och årskurs 1, vilka erbjuder eleverna olika lärandemöjligheter. Av dessa verksamheter framgår även att matematikundervisningen är mer formell i årskurs 1 än i förskoleklassen. Det visar sig i att eleverna har högre handlingsfrihet i förskoleklassen än i årskurs 1 och att det finns ett starkare fokus på matematiska begrepp och metoder i årskurs 1 än i förskoleklassen. Dessa skillnader kan vidare få negativa konsekvenser för kontinuiteten i elevernas matematiklärande.
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| 3. |
- Christensen, Mathilde Egelund, et al.
(författare)
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Monocytosis in primary care and risk of haematological malignancies
- 2023
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Ingår i: European Journal of Haematology. - : WILEY. - 0902-4441 .- 1600-0609. ; 110:4, s. 362-370
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Tidskriftsartikel (refereegranskat)abstract
- Monocytosis (>= 0.5 x 10(9)/L in peripheral blood) is the hallmark of chronic myelomonocytic leukaemia (CMML) but may be present in a spectrum of diseases including other haematological malignancies. In the primary care sector, monocytosis is a relatively common finding, but its predictive value for haematological malignancy is unknown. We included 663 184 adult primary care patients from the greater Copenhagen area with one or more differential cell counts registered between 2000 and 2016 and followed them in the extensive nationwide Danish health data registers for 3 years after blood sampling. We used logistic regression to model the risk of haematological malignancy and death following monocytosis. Monocytosis was associated with an increased risk of all types of haematological malignancy with the greatest relative risk increase observed in CMML with an OR of 105.22 (95% confidence interval: 38.27-289.30). Sustained monocytosis (at least two requisitions in 3 months) further increased CMML risk, although the diagnosis was still very rare, that is, observed in only 0.1% of these individuals. Outside the haematological setting, the absolute risk of haematological malignancy associated with monocytosis is low and haematological malignancy should mainly be suspected when monocytosis is sustained or the clinical presentation raises suspicion of malignancy.
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| 4. |
- Christesen, Henrik Thybo, et al.
(författare)
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Tissue variations of mosaic genome-wide paternal uniparental disomy and phenotype of multi-syndromal congenital hyperinsulinism
- 2020
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Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 63:1
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Tidskriftsartikel (refereegranskat)abstract
- Mosaic genome-wide paternal uniparental disomy (GW-pUPD) is a rarely recognised disorder. The phenotypic manifestations of multilocus imprinting defects (MLIDs) remain unclear. We report of an apparently non-syndromic infant with severe congenital hyperinsulinism (CHI) and diffuse pancreatic labelling by 18F*-DOPA-PET/CT leading to near-total pancreatectomy. The histology was atypical with pronounced proliferation of endocrine cells comprising >70% of the pancreatic tissue and a small pancreatoblastoma. Routine genetic analysis for CHI was normal in the blood and resected pancreatic tissue. At two years’ age, Beckwith-Wiedemann Syndrome (BWS) stigmata emerged, and at five years a liver tumour with focal nodular hyperplasia and an adrenal tumour were resected. pUPD was detected in 11p15 and next in the entire chromosome 11 with microsatellite markers. Quantitative fluorescent PCR with amplification of chromosome-specific DNA sequences for chromosomes 13, 18, 21 and X indicated GW-pUPD. A next generation sequencing panel with 303 SNPs on 21 chromosomes showed pUPD in both blood and pancreatic tissue. The mosaic distribution of GW-pUPD ranged from 31 to 35% in blood and buccal swap to 74% in the resected pancreas, 80% in a non-tumour liver biopsy, and 100% in the liver focal nodular hyperplasia and adrenal tumour. MLID features included transient conjugated hyperbilirubinaemia and lack of macrosomia from BWS (pUPD6); and behavioural and psychomotor manifestations of Angelman Syndrome (pUPD15) on follow-up. In conclusion, atypical pancreatic histology in apparently non-syndromic severe CHI patients may be the first clue to BWS and multi-syndromal CHI from GW-pUPD. Variations in the degree of mosaicism between tissues explained the phenotype.
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| 5. |
- Elander, Johanna, et al.
(författare)
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Extended genetic diagnostics for children with profound sensorineural hearing loss by implementing massive parallel sequencing. Diagnostic outcome, family experience and clinical implementation
- 2022
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Ingår i: International Journal of Pediatric Otorhinolaryngology. - : Elsevier BV. - 0165-5876. ; 159
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: The aim of this study was to investigate genetic outcomes, analyze the family experience, and describe the process of implementing genetic sequencing for children with profound sensorineural hearing loss (SNHL) at a tertial audiological center in southern Sweden. Design: This is a prospective pilot study including eleven children with profound bilateral SNHL who underwent cochlear implant surgery. Genetic diagnostic investigation was performed with whole exome sequencing (WES) complemented with XON-array to identify copy number variants, using a manually curated gene panel incorporating 179 genes associated with non-syndromic and syndromic SNHL. Mitochondrial DNA (mtDNA) from blood was examined separately. A patient reported experience measures (PREM) questionnaire was used to evaluate parental experience. We also describe here the process of implementing WES in an audiology department. Results: Six female and five male children (mean 3.4 years, SD 3.5 years), with profound bilateral SNHL were included. Genetic variants of interest were found in six subjects (55%), where three (27%) could be classified as pathogenic or likely pathogenic. Among the six cases, one child was found to have a homozygous pathogenic variant in MYO7A and two children had homozygous likely pathogenic variants in SLC26A4 and PCDH15, respectively. One was carrying a compound heterozygote frameshift variant of uncertain significance (VUS) on one allele and in trans, a likely pathogenic deletion on the other allele in PCDH15. Two subjects had homozygous VUS in PCDH15 and ADGRV1, respectively. In five of the cases the variants were in genes associated with Usher syndrome. For one of the likely pathogenic variants, the finding was related to Pendred syndrome. No mtDNA variants related to SNHL were found. The PREM questionnaire revealed that the families had difficulty in fully understanding the results of the genetic analysis. However, the parents of all eleven (100%) subjects still recommended that other families with children with SNHL should undergo genetic testing. Specifically addressed referrals for prompt complementary clinical examination and more individualized care were possible, based on the genetic results. Close clinical collaboration between different specialists, including physicians of audiology, audiologists, clinical geneticists, ophthalmologists, pediatricians, otoneurologists, physiotherapists and hearing habilitation teams was initiated during the implementation of the new regime. For all professionals involved, a better knowledge of the diversity of the genetic background of hearing loss was achieved. Conclusions: Whole exome sequencing and XON-array using a panel of genes associated with SNHL had a high diagnostic yield, added value to the families, and provided guidance for further examinations and habilitation for the child. Great care should be taken to thoroughly inform parents about the genetic test result. Collaborations between departments were intensified and knowledge of hearing genomics was increased among the staff.
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| 6. |
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Global hälsa : en praktisk guide
- 2023. - 2
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Introduktion: Behovet av ett globalt perspektiv på hälsa.Det har gått fem år sedan Global Hälsa – En praktisk guide släpptes. Sedan dess har världen förändrats. Covid-19-pandemin har i grunden påverkat förutsättningarna för den global hälsan och visar på hur svårt det är att isolera sig från globala hälsohot. Hälsokonsekvenserna av klimatförändringarna, liksom hälso- och sjukvårdens klimatpåverkan har tydliggjorts. Fler väpnade konflikter, inklusive kriget i Ukraina, riskerar många år av folkhälsoarbete. I kriser drabbas de fattigaste hårdast. Detta gäller globalt såväl som i Sverige.I årets halvtidsgenomgång av världens utvecklingsagenda, Agenda 2030 och de globala målen, konstateras att många viktiga framsteg har gjorts, men att dessa hotas av det förändrade världsläget. Ett förnyat fokus på globala hälsofrågor krävs och här är svensk kunskap viktig. Många av de utmaningar som Sverige står inför delar vi dessutom med andra länder, såsom till exempel personalbrist, som leder till stängda vårdplatser och för låg täckning i primärvården. Här kan vi lära av varandra.Svenska Läkaresällskapet har sedan 2013 aktivt arbetat med globala hälsofrågor, med övertygelsen om att större medvetenhet om global hälsa kan minska konsekvenserna från världens gemensamma utmaningar. Sedan den förra guiden kom ut har läkaresällskapet bidragit till mobilisering och kunskapsspridning om Covid-19 under pandemin, en hybridkonferens om planetär hälsa har hållits med världsledande forskare, och svensk hälso- och sjukvårds möjligheter att stötta den ukrainska befolkningen under pågående krig har lyfts i en webinarie-serie.Liksom förra gången är guiden framtagen av läkarstudenter och läkare tidigt i karriären under handledning av kommittén för global hälsa. Den är tänkt som ett handfast stöd för de som vill engagera sig för global hälsa – genom klinik, forskning eller folkhälsoarbete och berör bland annat hälso- och sjukvårdens utmaningar i omställningen till ett klimatneutralt samhälle.Fältets ambition om att skapa alltmer jämlika samarbeten, genom att ifrågasätta äldre beslutsstrukturer, berörs också som en röd tråd genom guiden.Därför vill vi rikta ett stort tack till de studenter och yngre läkare som med vägledning av projektledarna har möjliggjort denna nya och förbättrade upplaga av guiden!Tillsammans kan vi verka för förbättrad hälsa, här hemma och utomlands!
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| 7. |
- Ilinca, Andreea, et al.
(författare)
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A stroke gene panel for whole-exome sequencing
- 2019
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 27:2, s. 317-324
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Tidskriftsartikel (refereegranskat)abstract
- Extensive analyses of known monogenic causes of stroke by whole-exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of stroke for use in clinical and research situations. We systematically searched the publically available database Online Mendelian Inheritance in Man, and validated the entries against original peer-reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with stroke, and classified the stroke phenotype for each gene into eight subgroups: (1) large artery atherosclerotic, (2) large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection, occlusion), (3) cerebral small-vessel diseases, (4) cardioembolic (arrhythmia, heart defect, cardiomyopathy), (5) coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), (6) intracerebral hemorrhage, (7) vascular malformations (cavernoma, arteriovenous malformations), and (8) metabolism disorders. Second, we selected other genes that may plausibly cause stroke through diseases related to stroke, but without any documented stroke patient description. A third section comprised SNPs associated with stroke in genome-wide association studies (GWAS). We identified in total 214 genes: 120 associated with stroke, 62 associated with diseases that may cause stroke, and 32 stroke-related genes from recent GWAS. We describe these 214 genes and the clinical stroke subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic stroke. Based on the panel’s clinical phenotype description, the pathogenicity of novel variants in these genes may be evaluated in specific situations.
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| 8. |
- Ilinca, Andreea, et al.
(författare)
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MAP3K6 Mutations in a Neurovascular Disease Causing Stroke, Cognitive Impairment, and Tremor
- 2021
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Ingår i: Neurology: Genetics. - 2376-7839. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.Methods: We studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.Results: Fifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.Conclusions: Our data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.
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| 9. |
- Ilinca, Andreea, et al.
(författare)
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Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
- 2020
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Ingår i: Stroke. - 1524-4628. ; 51:4, s. 1056-1063
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Tidskriftsartikel (refereegranskat)abstract
- Backgrounds and Purpose- Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods- We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results- Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions- Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
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| 10. |
- Klareld, Ann-Sofie, 1981-, et al.
(författare)
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Fem röster om projektet GoInfo
- 2015
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Ingår i: Arkiv. - : Svensk arkivtidskrift. - 2001-1555. ; , s. 14-15
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Tidskriftsartikel (populärvet., debatt m.m.)
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| 11. |
- Malmberg, Erik, et al.
(författare)
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Minimal residual disease assessed with deep sequencing of NPM1 mutations predicts relapse after allogeneic stem cell transplant in AML
- 2019
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 60:2, s. 409-417
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in NPM1 can be used for minimal residual disease (MRD) analysis in acute myeloid leukemia (AML). We here applied a newly introduced method, deep sequencing, allowing for simultaneous analysis of all recurrent NPM1 insertions and thus constituting an attractive alternative to multiple PCRs for the clinical laboratory. We retrospectively used deep sequencing for measurement of MRD pre- and post-allogeneic hematopoietic stem cell transplantation (alloHCT). For 29 patients in morphological remission at the time of alloHCT, the effect of deep sequencing MRD on outcome was assessed. MRD positivity was defined as variant allele frequency ≥0.02%. Post-transplant MRD status was significantly and independently associated with clinical outcome; 3-year relapse-free survival 20% vs 85% (p <.001), HR 45 (95% CI 2–1260), and overall survival 20% vs 89% (p <.001), HR 49 (95% CI 2–1253). Thus, the new methodology deep sequencing is an applicable and predictive tool for MRD assessment in AML.
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| 12. |
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| 13. |
- Malmberg, Erik, et al.
(författare)
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Patient-tailored analysis of minimal residual disease in acute myeloid leukemia using next-generation sequencing
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 98:1, s. 26-37
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Tidskriftsartikel (refereegranskat)abstract
- Next-generation sequencing techniques have revealed that leukemic cells in acute myeloid leukemia often are characterized by a limited number of somatic mutations. These mutations can be the basis for the detection of leukemic cells in follow-up samples. The aim of this study was to identify leukemia-specific mutations in cells from patients with acute myeloid leukemia and to use these mutations as markers for minimal residual disease. Leukemic cells and normal lymphocytes were simultaneously isolated at diagnosis from 17 patients with acute myeloid leukemia using fluorescence-activated cell sorting. Exome sequencing of these cells identified 240 leukemia-specific single nucleotide variations and 22 small insertions and deletions. Based on estimated allele frequencies and their accuracies, 191 of these mutations qualified as candidates for minimal residual disease analysis. Targeted deep sequencing with a significance threshold of 0.027% for single nucleotide variations and 0.006% for NPM1 type A mutation was developed for quantification of minimal residual disease. When tested on follow-up samples from a patient with acute myeloid leukemia, targeted deep sequencing of single nucleotide variations as well as NPM1 was more sensitive than minimal residual disease quantification with multiparameter flow cytometry. In conclusion, we here describe how exome sequencing can be used for identification of leukemia-specific mutations in samples already at diagnosis of acute myeloid leukemia. We also show that targeted deep sequencing of such mutations, including single nucleotide variations, can be used for high-sensitivity quantification of minimal residual disease in a patient-tailored manner.
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| 14. |
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| 15. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
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| 16. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
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| 17. |
- Valind, Anders, et al.
(författare)
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ZMIZ1-associated neurodevelopmental disorder and Hirschsprung disease
- 2021
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Ingår i: Journal of Pediatric Surgery Case Reports. - : Elsevier BV. - 2213-5766. ; 71
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Tidskriftsartikel (refereegranskat)abstract
- De novo mutations in the gene encoding transcription factor ZMIZ1, located on chromosome 10q22, were recently found to be associated with a novel neurodevelopmental syndrome [1]. In this case report we present a patient with developmental delay and Hirschsprung disease, who carries a de novo mutation in ZMIZ1. Utilizing public gene expression data from mouse we confirm that ZMIZ1 is indeed expressed in progenitors of the enteric nervous system (ENS) as well as in a subpopulation of ENS neurons in the adult mouse and based on this we then propose that ZMIZ1 is a novel putative risk gene for HD.
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| 18. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
- 2023
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Ingår i: JCO Precision Oncology (JCO PO). - : American Society of Clinical Oncology. - 2473-4284. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 19. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer
- 2023
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Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; :7
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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