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2,922 results on '"HUSLAB"'

1. A Randomized Trial of Early Detection of Clinically Significant Prostate Cancer (ProScreen) (ProScreen)

Author: Helsinki University Hospital, Finland, Tampere University Hospital, Finland, Finnish Cancer Registry, Finland, University of Turku, Finland, Lund University, Fimlab Laboratories, Finland, Laboratory HUSLAB, Finland, University of Helsinki, Hospital District of Helsinki and Uusimaa, Clinical Research Institute HUCH Ltd, Finland, and Anssi Auvinen, Professor
Published: 2022

2. Photodynamic Therapy for Lentigo Maligna Using 5-aminolevulinic Acid Nanoemulsion as a Light Sensitizing Cream (LM PDT)

Author: Huslab, Finland and Tampere University
Published: 2018

3. Incidence of Fluoroquinolone Resistant Bacteria in Patients Undergoing Prostate Biopsy

Author: University of Helsinki, HUSLAB, and Kanerva Lahdensuo, MD
Published: 2017

4. Acute Upper Respiratory Tract Infection - When is Bacteria Involved?

Author: Finnish Defense Forces, The Central Hospital of Kajaani, Huslab, Clinical Microbiology, Virology and Immunology, and University of Oulu
Published: 2013

5. Development of liquid chromatography mass spectrometric methods for quantification of metabolites from cellular level to clinical biomarkers

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Laboratory services, HUSLAB, Tohmola, Niina, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Laboratory services, HUSLAB, and Tohmola, Niina
Abstract: Metabolites are low molecular weight compounds participating in different functions of cellular systems. Metabolites can be used as diagnostic biomarkers for numerous diseases. Liquid chromatography tandem mass spectrometry (LC-MS/MS) is a powerful tool in quantification of metabolites from various sample matrices. Good sensitivity and specificity are the main benefits of the technique. Mass spectrometry is commonly used in industry, drug research and clinical diagnostics. Extensive validation of newly developed analytical methods will construct the basis to a reliable assay, and it is significant especially when analysing e.g. patient samples. The aim of this study was to develop quantitative assays for metabolites from biological samples for biomedical research and clinical diagnostics. We designed and constructed an on-line high performance liquid chromatography (HPLC) equipment and validated an assay for direct quantification of extracellular metabolites from cell cultivation. Automated sampling for LC-MS/MS analysis of intracellular metabolites was connected to the on-line system. The on-line analysis improves the methodology and shortens the time of analysis. Furthermore, a frequent sampling data can provide valuable information about physiological indications in various cell cultivations. On-line HPLC is suitable for various biotechnological applications because of its ability to monitor and collect data during cell cultivation. We developed and validated LC-MS/MS assays for neuroendocrine tumor (NET) biomarkers 5-hydroxyindole acetic acid (5-HIAA) and vanillylmandelic acid (VMA) from human serum. Generally, urinary HPLC assays are used for the determination of NET markers. HPLC assays have certain limitations and 24-h urine collection is laborious. Our LC-MS/MS assays are specific, fast and well suited for diagnostics of NETs. Furthermore, guidelines for urine collection advise to refrain from serotonin-containing foods for three days before sample collectio, Metaboliitit ovat pienen molekyylipainon omaavia yhdisteitä, jotka osallistuvat erilaisiin toimintoihin solujen aineenvaihdunnassa. Eri metaboliitit toimivat myös useiden sairauksien merkkiaineina ja niiden pitoisuuden mittausta käytetään apuna sairauksien toteamisessa sekä seurannassa. Nestekromatografia (LC) yhdistettynä massaspektrometriaan (MS) on tehokas analyysitekniikka metaboliittien määritykseen. LC-MS -menetelmiä käytetään laajalti esimerkiksi teollisuudessa, lääketutkimuksessa sekä kliinisessä diagnostiikassa. Menetelmän validointi eli toimivuuden testaus on erittäin tärkeä vaihe uusien määritysmenetelmien kehityksessä. Validointi takaa, että menetelmä toimii halutulla tavalla ja että analyysitulokset ovat luotettavia, mikä on erityisen tärkeää varsinkin analysoitaessa potilasnäytteitä. Tämän työn tarkoituksena oli kehittää ja validoida kvantitatiivisia määritysmenetelmiä metaboliiteille käyttäen hyödyksi LC-MS -tekniikoita. Kyseisiä menetelmiä voidaan hyödyntää biolääketieteellisessä tutkimuksessa ja kliinisessä diagnostiikassa. Suunnittelimme ja valmistimme korkean erotuskyvyn nestekromatografia (HPLC) -laitteiston ja validoimme menetelmän solunulkoisten metaboliittien reaaliaikaiseen määritykseen suoraan solukasvatuksesta. Lisäksi keräsimme näytteitä solukasvatuksesta automaattisella näytteenottolaitteistolla ja määritimme kerätyistä näytteistä solun sisäisiä metaboliitteja LC-MS/MS -menetelmällä. Reaaliaikaisen mittauksen avulla saatiin lisää hyödyllistä tietoa solujen aineenvaihdunnasta. Metaboliitit 5-hydroksyyli-indoliasetaatti (5-HIAA) ja metoksihydroksimandelaatti (MOMA, VMA) ovat neuroendokriinisten kasvaimien merkkiaineita. Yleensä näitä merkkiaineita on määritetty potilaan vuorokausivirtsasta HPLC -menetelmällä yhdistettynä elektrokemialliseen tai flurometriseen detektioon. Nämä menetelmät ovat kuitenkin alttiita häiritseville yhdisteille, kuten lääkeaineille tai toisille metaboliiteille. Lisäksi vuorokausivirtsan keräys ja esikäsittely on han
Published: 2015

6. Merkel cell carcinoma : Epidemiological study with special reference to polyomavirus and vascular factors in pathogenesis

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, patologian laitos, HUSLAB, Kukko, Heli, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, patologian laitos, HUSLAB, and Kukko, Heli
Abstract: Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that occurs predominantly on sun exposed skin areas. A new polyomavirus (MCPyV) was identified in MCC tumor tissues in 2008 suggesting that a viral infection might be an etiological factor. A typical MCC is a rapidly growing painless purple nodule. In its early stage it can be misjudged by its appearance as a cyst or abscess. Recurrences are common and approximately half of the patients will develop lymph node metastases and third of the patents will have distant metastases. It affects mostly elderly persons at an average age of 70 at the time of diagnosis. MCC was first described in 1972 and the first MCC patient in Finland was identified in 1983. MCC has been poorly recognized, but increased awareness and better diagnostic accuracy has increased the incidence since the early years. In this study, all cases with a notation of MCC during 1979 2008 were obtained from the Finnish Cancer Registry. Based on this data, the incidence is 0.11 for men and 0.12 for women. It is similar than that of other Nordic countries, but lower than in the USA. For clinical series, the files of patients diagnosed with MCC during 1983 2004 were reviewed, and the tissue samples were re-evaluated, if available (n=181). Third of the patients were men, and the most common site of the primary tumor was the head and neck (53%). The majority of the patients (86%) presented with a clinically node-negative (Stage I or II) disease, but the disease recurred in 38% of them. The treatment schemes were heterogeneous. No additional benefit from a wide margin (≥2 cm) was found compared to a margin of 0.1-1.9 cm, but intralesional excision was more often associated with local recurrence. None of the patients with Stage I-II disease who had received postoperative radiotherapy had local recurrence during the follow-up period. The 5-year relative survival ratio for Stage I disease was 68%, for Stage II 67%, for Stage III 16%, and for Stage IV 0%. The, Merkelin solu karsinooma on harvinainen ihosyöpä, jota esiintyy ensisijaisesti aurinkoaltisteisilla iho-alueilla. Vuonna 2008 löydettiin uusi polyomavirus Merkelin solu kasvaimista ja arvellaan, että tauti on ainakin osittain virusperäinen. Merkelin solu karsinooma on tyypillisimmillään nopeasti kasvava ihon alainen punertava kivuton patti, jota varsinkin alkuvaiheessa voidaan pelkän kliinisen kuvan perusteella pitää ateroomana tai paiseena. Tauti uusii herkästi ja noin puolella kehittyy imusolmukemetastaasit ja kolmanneksella etäpesäkkeet. Tauti on yleisempi vanhusväestöllä; potilaiden keski-ikä on n.70 vuotta. Merkelin solu karsinooma tunnistettiin omaksi entiteetikseen vasta v.1972. Suomessa ensimmäinen Merkelin solu karsinooma todettiin v. 1983. Tauti oli alkuun varsin huonosti tunnettu ja tunnistettu, mutta lisääntyneen tietämyksen ja parantuneiden diagnostisten menetelmien myötä todettujen tautitapausten määrä on sittemmin lisääntynyt. Nykyään tautitapauksia todetaan Suomessa 10 20 vuosittain. Tutkimuksessa kartoitettiin kaikki Suomessa todetut Merkelin solu karsinooma tapaukset v. 1983 2008 perustuen Suomen Syöpärekisterin tietoaineistoon. Tämän perusteella taudin esiintyvyys Suomessa on samaa tasoa kuin muissa pohjoismaissa, mutta alhaisempi kuin USA:ssa. Kliininen potilassarja käsitti 1983 2004 diagnosoidut tautitapaukset. Tietoja taudista ja hoidosta täydennettiin sairaaloiden ja terveyskeskusten arkistoista. Kudosnäytteistä varmistettiin diagnoosi, kasvaimen koko ja poistomarginaali. Potilasta vajaa kolmannes oli miehiä, ja yli puolella tauti esiintyi pään tai kaulan alueella. Suurimmalla osalla potilaista tauti oli paikallinen toteamishetkellä, mutta yli kolmanneksella tauti uusiutui. Vakiintumattomista hoitokäytännöistä johtuen kirurgisen poiston laajuudessa ja liitännäishoidoissa oli suuria vaihteluja. Laajalla, > 2cm poistomarginaalilla ei todettu olevan etua verrattuna siihen, että kasvain oli poistettu kokonaan tervekudosmarginaalilla. Kenelläkään n
Published: 2011

7. Atrial Electric Signal During Sinus Rhythm in Lone Paroxysmal Atrial Fibrillation

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliininen laitos, Helsingfors universitet, medicinska fakulteten, institutionen för klinisk medicin, University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Division of Cardiology, BioMag Laboratory, HUSLAB, Helsinki University Central Hospital, Laboratory of Biomedical Engineering, Helsinki University of Technology, Jurkko, Raija, Helsingin yliopisto, lääketieteellinen tiedekunta, kliininen laitos, Helsingfors universitet, medicinska fakulteten, institutionen för klinisk medicin, University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Division of Cardiology, BioMag Laboratory, HUSLAB, Helsinki University Central Hospital, Laboratory of Biomedical Engineering, Helsinki University of Technology, and Jurkko, Raija
Abstract: Atrial fibrillation (AF) is the most common tachyarrhythmia and is associated with substantial morbidity, increased mortality and cost. The treatment modalities of AF have increased, but results are still far from optimal. More individualized therapy may be beneficial. Aiming for this calls improved diagnostics. Aim of this study was to find non-invasive parameters obtained during sinus rhythm reflecting electrophysiological patterns related to propensity to AF and particularly to AF occurring without any associated heart disease, lone AF. Overall 240 subjects were enrolled, 136 patients with paroxysmal lone AF and 104 controls (mean age 45 years, 75% males). Signal measurements were performed by non-invasive magnetocardiography (MCG) and by invasive electroanatomic mapping (EAM). High-pass filtering techniques and a new method based on a surface gradient technique were adapted to analyze atrial MCG signal. The EAM was used to elucidate atrial activation in patients and as a reference for MCG. The results showed that MCG mapping is an accurate method to detect atrial electrophysiologic properties. In lone paroxysmal AF, duration of the atrial depolarization complex was marginally prolonged. The difference was more obvious in women and was also related to interatrial conduction patterns. In the focal type of AF (75%), the root mean square (RMS) amplitudes of the atrial signal were normal, but in AF without demonstrable triggers the late atrial RMS amplitudes were reduced. In addition, the atrial characteristics tended to remain similar even when examined several years after the first AF episodes. The intra-atrial recordings confirmed the occurrence of three distinct sites of electrical connection from right to left atrium (LA): the Bachmann bundle (BB), the margin of the fossa ovalis (FO), and the coronary sinus ostial area (CS). The propagation of atrial signal could also be evaluated non-invasively. Three MCG atrial wave types were identified, each of which represe, Eteisvärinä on yleisin hoitoa vaativa rytmihäiriö ja siihen liittyy merkittävää sairastuvuutta, lisääntynyttä kuolleisuutta ja kustannuksia. Eteisvärinän hoitovaihtoehdot ovat lisääntyneet, mutta hoidon tulokset ovat huonosti ennakoitavissa eivätkä hoidot edelleenkään tehoa hyvin. Tässä tutkimuksessa selvitettiin eteisvärinän ilmentymän ja sähköfysiologisten piirteiden yhteyttä rakenteellisesti terveen sydämen kohtauksellisessa eteisvärinässä. Tavoitteena oli löytää kajoamattomasti mitattavia muuttujia, joita voitaisiin käyttää eteisvärinäsairauden kliinisten alaryhmien sähköfysiologisten piirteiden, kohtauksiin johtavien tekijöiden ja taudinkuvan tunnistamiseen. Tutkittavana oli 136 potilasta ja 104 tervettä koehenkilöä. Pääasiallisina menetelminä käytettiin kajoamatonta magnetokardiografiaa (MKG) ja sydämen sisäistä elektroanatomista kartoitusta. MKG mittaa sydämen sähköisen aktivaation aiheuttamia magneettikenttiä kehon pinnalta ja sen etuna sydänsähkökäyrään (EKG) verrattuna on mm. suurempi herkkyys kehon pinnan suuntaisille virroille. Pääosa käytetyistä signaalianalyysimenetelmistä kehitettiin tutkimuksen puitteissa. Tutkimuksessa osoitettiin ensimmäistä kertaa eroa eteissignaalin hienorakenteessa rakenteellisesti terveen sydämen eteisvärinän kliinisten alamuotojen välillä. Potilailla, joilla eteisvärinän alku liittyi eteislisälyöntisyyteen, ns. paikallisalkuinen eteisvärinä, normaalin rytmin aikainen eteissignaali oli lievästi pidentynyt, mutta sen korkeus oli normaali. Potilailla, joilla ei todettu lisälyöntisyyttä, eteissignaalin kesto oli normaali, mutta signaalin loppuosa oli madaltunut. Löydös viittaa siihen, että ei-paikallisalkuisessa eteisvärinässä eteiskudos saattaa olla alttiimpi eteisvärinälle kuin paikallisalkuisessa eteisvärinässä, jossa pääasiallinen rytmihäiriömekanismi olisi lisälyöntisyys. Tutkimuksessa todettiin myös, että naisilla eteisten aktivaatiosignaali oli potilailla selvästi pidempi kuin terveillä, mutta miehillä vastaava ero oli marg
Published: 2009

8. Molecular profiling of malignant pleural mesothelioma and pulmonary fibrosis

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Department of Pathology, Haartman Institute and HUSLAB, Pulmonary Division, University of Helsinki, and Helsinki University Central Hospital, Department of Medicine, Pulmonary Division, Lindholm, Pamela, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Department of Pathology, Haartman Institute and HUSLAB, Pulmonary Division, University of Helsinki, and Helsinki University Central Hospital, Department of Medicine, Pulmonary Division, and Lindholm, Pamela
Abstract: Malignant mesothelioma (MM) is a rare, usually incurable, disease mainly caused by former exposure to asbestos. Even though MM has a strong etiological link, genetic factors may play a role, since not all cases can be linked to former asbestos exposure. This thesis focuses on lung diseases, mainly malignant mesothelioma (MM), and idiopathic pulmonary fibrosis (IPF), which resembles asbestosis. The specific asbestos-related pathways associated with malignant as well as non-malignant lung diseases, still need to be clarified. Since most patients diagnosed with MM or asbestosis/fibrosis have a dismal prognosis and few therapeutic options are available, early diagnosis and better understanding of the disease pathogenesis are of the utmost importance. The first objective of this thesis was to identify asbestos specific differentially expressed genes. This was approached by using high-resolution gene expression arrays, and three different human lung cell lines, as well as with three different bioinformatics approaches. Since the first study aimed to elucidate potential early changes, the second study was used to screen DNA copy number changes in MM tumour samples. This was performed using genome wide microarrays for identification of DNA copy number changes characterstic for MM. Study III focused on the role of gremlin in the regulation of bone morphogenetic protein (BMPs) in IPF. Further studies were conducted in asbestos-exposed cell cultures as well as in an asbestos-induced mouse model. Furthermore, GATA-6 was studied in MM and metastatic pleural adenocarcinoma. The GATA transcription factors are important during embryonic development, but their role in cancer is still unclear. GATA-6 is a co-factor/target of thyroid transcription factor 1 (TTF-1), which is used in differential diagnostics of pleural MM and adenocarcinoma. Bioinformatics probed the genes and biological processes ordered in terms of significance, clusters, and highly enriched chromosomal regions. The s, Asbestialtistukseen liittyy komplekseja, suurimmaksi osaksi parantumattomia ja edelleen ympäri maailmaa yleistyviä sairauksia. Pahanlaatuinen mesoteliooma (MM) on harvinainen keuhkopussin solukosta alkunsa saava syöpäsairaus, jonka syntyyn liittyy yleensä aikaisempi altistuminen asbestille. Idiopaattinen keuhkofibroosi (IPF) on progressiivinen keuhkokudossairaus, joka histologisesti muistuttaa asbestoosia. Sekä mesoteliooma- että keuhkofibroosipotilaiden hoitovaste heikko ja ennuste huono, mistä syystä varhaisdiagnostiikalle ja täsmällisemmille hoitomuodoille on erityinen tarve. Tautien patogeneesi ja etenemisreitit tulisi kuitenkin ymmärtää paremmin, jotta tehokkaita hoitomuotoja voitaisiin kehittää. Tutkimuksessa pyrittiin kartoittamaan asbestialtistukseen liittyviä geneettisiä ja molekulaarisia muutoksia keuhkopussin ja keuhkoparenkyymin sairauksissa. Asbestiin liittyvien biomarkkereiden kartoituksessa käytettiin geenien ilmentymistä ja DNA kopioiden määrää määrittäviä mikrosiruja sekä tutkittiin signalointireittejä, joihin asbestialtistus vaikuttaa. Ensimmäinen tavoite oli tunnistaa asbestisairauksille ominaisia varhaisia geenin ilmentymisen muutoksia käyttämällä mikrosiruja ja kolmea viljeltyä ihmisen keuhkosolulinjaa. Tutkimus paljasti useita jo aikaisemmin tunnistettuja kohdegeenejä sekä antoi uusia löydöksiä, jotka ovat mahdollisesti keskeisiä asbestialtistuksessa. Lisäksi saatiin täydentävää tietoa omia tuloksiaan ja teorioitaan tarkasteleville tutkijoille. Seuraavassa tutkimuksessa seulottiin DNA-kopioiden määrän muutoksia mesotelioomakasvaimista saaduissa kudosnäytteissä mikrosirujen avulla. Mesotelioomakasvaimissa havaittiin häviämiä kromosomialueissa 1p, 3p, 6q, 9p, 13, 14 ja 22, ja monistumia 17q:ssa. Transformoivan kasvutekijä- β (TGF-β) perheen proteiinit ovat tärkeitä kudosten ylläpidossa ja vaurioiden korjauksessa sekä epätasapaino TGF-β:n ja luun morfogeenisen proteiinin (BMP)-signaloinnissa saattaa johtaa IPF:n etenemiseen. Koska asbestoosin ja I
Published: 2009

9. Microarrays in Molecular Profiling of Ewing Sarcoma Family of Tumors and CDKN2A Aberrations

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Department of Pathology, HUSLAB, Helsinki University Central Hospital, Savola, Suvi, Helsingin yliopisto, lääketieteellinen tiedekunta, kliinisteoreettinen laitos, Helsingfors universitet, medicinska fakulteten, Haartman institutet, University of Helsinki, Faculty of Medicine, Haartman Institute, Department of Pathology, HUSLAB, Helsinki University Central Hospital, and Savola, Suvi
Abstract: Background: The Ewing sarcoma family of tumors (ESFT) are rare but highly malignant neoplasms that occur mainly in bone or but also in soft tissue. ESFT affects patients typically in their second decade of life, whereby children and adolescents bear the heaviest incidence burden. Despite recent advances in the clinical management of ESFT patients, their prognosis and survival are still disappointingly poor, especially in cases with metastasis. No targeted therapy for ESFT patients is currently available. Moreover, based merely on current clinical and biological characteristics, accurate classification of ESFT patients often fails at the time of diagnosis. Therefore, there is a constant need for novel molecular biomarkers to be applied in tandem with conventional parameters to further intensify ESFT risk-stratification and treatment selection, and ultimately to develop novel targeted therapies. In this context, a greater understanding of the genetics and immune characteristics of ESFT is needed. Aims: This study sought to open novel insights into gene copy number changes and gene expression in ESFT and, further, to enlighten the role of inflammation in ESFT. For this purpose, microarrays were used to provide gene-level information on a genomewide scale. In addition, this study focused on screening of 9p21.3 deletion sizes and frequencies in ESFT and, in another pediatric cancer, acute lymphocytic leukemia (ALL), in order to define more exact criteria for highrisk patient selection and to provide data for developing a more reliable diagnostic method to detect CDKN2A deletions. Results: In study I, 20 novel ESFT-associated suppressor genes and oncogenes were pinpointed using combined array CGH and expression analysis. In addition, interesting chromosomal rearrangements were identified: (1) Duplication of derivative chromosome der(22)(11;22) was detected in three ESFT patients. This duplication included the EWSR1-FLI1 fusion gene leading to increase in its copy number, Ewingin sarkooma on pahanlaatuinen luukasvain, jota esiintyy sen harvinaisuudesta huolimatta etenkin lapsilla ja murrosikäisillä. Ewingin sarkoomalle ominainen piirre on kromosomien 11 ja 22 välinen uudelleenjärjestäytyminen eli translokaatio, joka johtaa kimeerisen EWSR1-FLI1 -fuusiogeenin syntymisen ja muuttuneen geenien ilmentymisen kautta solujen pahanlaatuistumiseen. Koska kasvain lähettää aggressiivisesti etäpesäkkeitä, jää potilaiden eloonjääntiluku alhaiseksi uusista yhdistelmähoidoista huolimatta. Kun edelleenkään ei tunneta tarkkoja syitä näiden luukasvainten kehittymiselle ja etenemiselle, on potilaiden hoito haastavaa eikä tarpeeksi tehokasta ja spesifistä hoitoa ole annettavissa. Tämän takia tarve uusien kliinisesti merkittävien kohdegeenien löytymiselle Ewingin sarkoomassa on suuri, jotta taudin diagnosointi ja ennusteen määrittäminen helpottuisi sekä uusien kohdennettujen hoitomuotojen kehittäminen mahdollistuisi. Tutkimuksessa käytettiin mikrosirupohjaisia menetelmiä geenien kopiomäärän ja ilmentymisen muutosten kartoittamiseen koko perimän laajuisesti kliinisesti merkittävien kohdegeenien ja geneettisten muutosten löytämiseksi Ewingin sarkoomassa. Lisäksi mikrosirumenetelmää hyödynnettiin kasvurajoitegeeni-CDKN2A:n häviämien tutkimisessa, jotta saataisiin tietoa geenin häviämien koosta ja yleisyydestä Ewingin sarkoomassa sekä toisessa lasten syövässä, akuutissa lymfaattisessa leukemiassa (ALL). Ensimmäisessä osatyössä saimme tarkempaa tietoa mahdollisista Ewingin sarkooma -kasvaimen kehitykseen johtavista geneettisistä muutoksista yhdistämällä geenien kopiomäärä- ja ilmentymisprofiilit potilasnäytteissä. Tutkimuksemme osoitti 20 uutta potentiaalista onkogeeniä ja kasvurajoitegeeniä, jotka voivat osallistua kasvaimen kehittymiseen ja etenemiseen. Geenien kopiomäärätutkimuksessa havaitsimme kolmessa potilasnäytteessä myös derivatiivikromosomin der(22)(11;22) kahdentuman seurauksena EWSR1-FLI1 -fuusiogeenin kopiomäärän lisääntymisen. Lisäksi yhdessä po
Published: 2009

10. Molecular genetics of X-linked cone-rod dystrophy and Åland Island eye disease

Author: Helsingin yliopisto, lääketieteellinen tiedekunta, kliininen laitos, Helsingfors universitet, medicinska fakulteten, institutionen för klinisk medicin, University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Department of Obstetrics and Gynecology, Department of Clinical Genetics, HUSLAB, Helsinki University Central Hospital, Folkhälsan Institute of Genetics, Department of Medical Genetics, University of Helsinki, Jalkanen, Reetta, Helsingin yliopisto, lääketieteellinen tiedekunta, kliininen laitos, Helsingfors universitet, medicinska fakulteten, institutionen för klinisk medicin, University of Helsinki, Faculty of Medicine, Institute of Clinical Medicine, Department of Obstetrics and Gynecology, Department of Clinical Genetics, HUSLAB, Helsinki University Central Hospital, Folkhälsan Institute of Genetics, Department of Medical Genetics, University of Helsinki, and Jalkanen, Reetta
Abstract: Inherited retinal diseases are the most common cause of vision loss among the working population in Western countries. It is estimated that ~1 of the people worldwide suffer from vision loss due to inherited retinal diseases. The severity of these diseases varies from partial vision loss to total blindness, and at the moment no effective cure exists. To date, nearly 200 mapped loci, including 140 cloned genes for inherited retinal diseases have been identified. By a rough estimation 50% of the retinal dystrophy genes still await discovery. In this thesis we aimed to study the genetic background of two inherited retinal diseases, X-linked cone-rod dystrophy and Åland Island eye disease. X-linked cone-rod dystrophy (CORDX) is characterized by progressive loss of visual function in school age or early adulthood. Affected males show reduced visual acuity, photophobia, myopia, color vision defects, central scotomas, and variable changes in fundus. The disease is genetically heterogeneous and two disease loci, CORDX1 and CORDX2, were known prior to the present thesis work. CORDX1, located on Xp21.1-11.4, is caused by mutations in the RPGR gene. CORDX2 is located on Xq27-28 but the causative gene is still unknown. Åland Island eye disease (AIED), originally described in a family living in Åland Islands, is a congenital retinal disease characterized by decreased visual acuity, fundus hypopigmentation, nystagmus, astigmatism, red color vision defect, myopia, and defective night vision. AIED shares similarities with another retinal disease, congenital stationary night blindness (CSNB2). Mutations in the L-type calcium channel α1F-subunit gene, CACNA1F, are known to cause CSNB2, as well as AIED-like disease. The disease locus of the original AIED family maps to the same genetic interval as the CACNA1F gene, but efforts to reveal CACNA1F mutations in patients of the original AIED family have been unsuccessful. The specific aims of this study were to map the disease gene in a la, Perinnölliset verkkokalvorappeumat ovat suurin näkövammaisuuden aiheuttaja työikäisten keskuudessa teollistuneissa maissa. Retiniitikoita eli periytyvää verkkokalvon rappeumaa sairastavia ihmisiä arvioidaan olevan noin promille maailman väestöstä. Periytyvät verkkokalvorappeumat ovat itse asiassa suuri joukko sairauksia, joiden periytymismalli ja taudin kuva vaihtelevat suuresti. Näihin osittaiseen tai täydelliseen sokeuteen johtaviin tauteihin ei tunneta tehokasta hoitokeinoa. Vilkkaan geenitutkimuksen ansiosta viime vuosina on tunnistettu useita kymmeniä geenejä, joiden virheet johtavat verkkokalvorappeuman syntyyn. Tämän tutkimuksen tavoitteena oli selvittää kahden harvinaisen X-kromosomissa peittyvästi periytyvän verkkokalvorappeuman, tappi-sauvadystrofian ja Ahvenanmaan silmäsairauden, geneettistä taustaa. X-kromosomaalinen tappi-sauvadystrofia (CORDX) on etenevä, yleensä lapsuudessa alkava verkkokalvoa rappeuttava sairaus, joka ilmenee ainoastaan miehillä. Taudin tyypillisimpiä piirteitä ovat merkittävä näöntarkkuuden aleneminen, näkökentän puutokset, voimakas likinäköisyys ja värinäön häiriöt. Taudin kantajanaiset ovat useimmiten oireettomia. CORDX on geneettisesti monimuotoinen tauti ja taudin taustalla tiedetään olevan ainakin kahden eri geenin virheet. Ahvenanmaan silmäsairaus (AIED) kuvattiin ensimmäisen kerran vuonna 1964 yhden suomalaisen suvun miespotilailla. Taudin tyypillisimpiä piirteitä ovat alentunut näöntarkkuus, likinäköisyys, hajataitteisuus, silmävärve ja puutteellinen hämäränäkö. Alkuperäisen AIED-suvun lisäksi Suomessa ja ulkomailla on kuvattu perheitä, joiden potilailla on AIED:n kaltainen tauti (AIED-like). AIED-like potilaiden taudin taustalla on virheet solukalvon kalsiumkanavageenissä, CACNA1F. Alkuperäisen AIED-suvun tautigeeni on paikannettu X-kromosomiin samalle alueelle, jolla CACNA1F geeni sijaitsee, mutta geenitutkimuksissa ei ole löytynyt virheitä kyseisestä geenistä. Tutkimusaineistoomme kuului suuri suomalainen CORDX-suku sekä
Published: 2008

11. Immunogenomic Landscape of Hematological Malignancies

Author: Disha Malani, Satu Mustjoki, Olli Lohi, Matti Kankainen, Kirsi J. Granberg, Olli Dufva, Mikko A. I. Keränen, Markus Vähä-Koskela, Merja Heinäniemi, Bishwa Ghimire, Matti Nykter, Sirpa Leppä, Ashwini Kumar, Leo Meriranta, Pirkko Mattila, Petri Pölönen, Juha Mehtonen, Suvi-Katri Leivonen, Krister Wennerberg, Oscar Brück, Jay Klievink, Sanna Siitonen, Jani Huuhtanen, Caroline A. Heckman, Jenni Lahtela, University of Helsinki, Department of Clinical Chemistry and Hematology, University of Helsinki, HUS Comprehensive Cancer Center, University of Helsinki, Department of Oncology, University of Helsinki, Medicum, University of Helsinki, Institute for Molecular Medicine Finland, University of Helsinki, HUSLAB, University of Helsinki, Biosciences, University of Helsinki, Krister Wennerberg / Principal Investigator, University of Helsinki, Research Programs Unit, University of Helsinki, Faculty of Medicine, Department of Clinical Chemistry and Hematology, HUS Comprehensive Cancer Center, Department of Oncology, Hematologian yksikkö, TRIMM - Translational Immunology Research Program, Research Programs Unit, Digital Precision Cancer Medicine (iCAN), Medicum, Institute for Molecular Medicine Finland, Precision Systems Medicine, HUSLAB, Biosciences, Krister Wennerberg / Principal Investigator, ATG - Applied Tumor Genomics, Faculty of Medicine, Helsinki University Hospital Area, and Clinicum
Subjects: 0301 basic medicine, Cancer Research, Myeloid, CANCER-TESTIS ANTIGENS, medicine.medical_treatment, Epigenesis, Genetic, 0302 clinical medicine, HLA Antigens, DNA METHYLATION, GENE-EXPRESSION, 0303 health sciences, Myeloid leukemia, CLASS-II EXPRESSION, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Leukemia, medicine.anatomical_structure, Oncology, Leukemia, Myeloid, 030220 oncology & carcinogenesis, Acute Disease, Cancer/testis antigens, Immunotherapy, Lymphoma, Large B-Cell, Diffuse, Multiple Myeloma, TUMOR MICROENVIRONMENT, 3122 Cancers, Biology, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, MULTIPLE-MYELOMA, medicine, CIITA, Humans, 030304 developmental biology, INTERFERON-GAMMA, Gene Expression Profiling, Cell Biology, medicine.disease, PD-1 BLOCKADE, Immune checkpoint, 030104 developmental biology, COMPLEX CLASS-II, IMMUNE CELLS, Mutation, Cancer research, 1182 Biochemistry, cell and molecular biology, 3111 Biomedicine, Tumor Suppressor Protein p53
Abstract: Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and myelodysplasia-related changes in acute myeloid leukemia, and activated B cell-like phenotype and interferon-gamma response in lymphoma. CIITA methylation regulating antigen presentation, cancer type-specific immune checkpoints, such as VISTA in myeloid malignancies, and variation in cancer antigen expression further contributed to immune heterogeneity and predicted survival. Our study provides a resource linking immunology with cancer subtypes and genomics in hematological malignancies.
Published: 2020
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12. Endothelial Dysfunction is Associated With Early-Onset Cryptogenic Ischemic Stroke in Men and With Increasing Age

Author: Titta Salopuro, Krishna Adeshara, Mika Lehto, Lauri Soinne, Jani Pirinen, Lotta Joutsi-Korhonen, Daniel Gordin, Sami Curtze, Juha Sinisalo, Jukka Putaala, Per-Henrik Groop, Turgut Tatlisumak, Ron Liebkind, Nicolas Martinez-Majander, Tiina Sairanen, Gerli Sibolt, HUS Neurocenter, Neurologian yksikkö, HUS Abdominal Center, Department of Medicine, Clinicum, Nefrologian yksikkö, HUSLAB, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, University of Helsinki, Kardiologian yksikkö, HUS Heart and Lung Center, Department of Neurosciences, Perttu Lindsberg / Principal Investigator, Research Programs Unit, Staff Services, Per Henrik Groop / Principal Investigator, University of Helsinki, HUS Neurocenter, University of Helsinki, HUS Abdominal Center, University of Helsinki, HUSLAB, University of Helsinki, Clinicum, University of Helsinki, HUS Medical Imaging Center, University of Helsinki, Department of Neurosciences, University of Helsinki, HUS Heart and Lung Center, and University of Helsinki, Staff Services
Subjects: Male, 030204 cardiovascular system & hematology, 0302 clinical medicine, Glycated albumin, endothelial function, REPRODUCIBILITY, YOUNG-ADULTS, risk factors, Prospective Studies, brain infarction, Age of Onset, Young adult, Endothelial dysfunction, Finland, Original Research, Early onset, Incidence, Arteries, TRIGGERS, Middle Aged, ETIOLOGY, Stroke, Vasodilation, Brain infarction, RELIABILITY, Cardiology, cryptogenic stroke, Female, Cardiology and Cardiovascular Medicine, Vascular function, Adult, young adults, medicine.medical_specialty, Adolescent, microcirculation, DIAGNOSIS, Risk Assessment, Fingers, Young Adult, 03 medical and health sciences, Sex Factors, Internal medicine, EXPLANATIONS, medicine, ischemic stroke, Humans, GLYCATED ALBUMIN, Sex Distribution, business.industry, medicine.disease, Case-Control Studies, 3121 General medicine, internal medicine and other clinical medicine, Ischemic stroke, Etiology, Endothelium, Vascular, business, PERIPHERAL ARTERIAL TONOMETRY, VASCULAR FUNCTION, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: Background The aim of this study was to assess the association between endothelial function and early‐onset cryptogenic ischemic stroke (CIS), with subgroup analyses stratified by sex and age groups. Methods and Results We prospectively enrolled 136 consecutive patients aged 18 to 49 years (median age, 41 years; 44% women) with a recent CIS and 136 age‐ and sex‐matched (±5 years) stroke‐free controls. Endothelial function was measured with an EndoPAT 2000 device and analyzed as tertiles of natural logarithm of reactive hyperemia index with lower values reflecting dysfunction. We used conditional logistic regression adjusting for age, education, hypertension, diabetes mellitus, dyslipidemia, current smoking, heavy drinking, obesity, and diet score to assess the independent association between endothelial function and CIS. Patients in the lowest tertile of natural logarithm of reactive hyperemia index were more often men and they more frequently had a history of dyslipidemia; they were also more often obese, had a lower diet score, and lower high‐density lipoprotein cholesterol. In the entire cohort, we found no association in patients with endothelial function and CIS compared with stroke‐free controls. In sex‐ and age‐specific analyses, endothelial dysfunction was associated with CIS in men (adjusted odds ratio [OR], 3.50 for lowest versus highest natural logarithm of reactive hyperemia index tertile; 95% CI, 1.22–10.07) and in patients ≥41 years (OR, 5.78; 95% CI, 1.52–21.95). These associations remained significant when dyslipidemia was replaced with the ratio of total to high‐density lipoprotein cholesterol. Conclusions Endothelial dysfunction appears to be an independent player in early‐onset CIS in men and patients approaching middle age.
Published: 2021

13. High miR-30 Expression Associates with Improved Breast Cancer Patient Survival and Treatment Outcome

Author: Maral Jamshidi, Rainer Fagerholm, Taru A. Muranen, Sippy Kaur, Swapnil Potdar, Sofia Khan, Eliisa Netti, John-Patrick Mpindi, Bhagwan Yadav, Johanna I. Kiiski, Kristiina Aittomäki, Päivi Heikkilä, Jani Saarela, Ralf Bützow, Carl Blomqvist, Heli Nevanlinna, University of Helsinki, HUS Gynecology and Obstetrics, University of Helsinki, Faculty Common Matters, University of Helsinki, Institute for Molecular Medicine Finland, University of Helsinki, Helsinki Institute of Life Science HiLIFE, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, University of Helsinki, Medicum, University of Helsinki, HUSLAB, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Helsinki University Hospital Area, Faculty Common Matters (Faculty of Biology and Environmental Sciences), Clinicum, Medicum, Department of Pathology, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, INDIVIDRUG - Individualized Drug Therapy, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, HUS Diagnostic Center, HUS Comprehensive Cancer Center, and Department of Oncology
Subjects: p53, PROTEIN EXPRESSION, MICRORNAS, education, INVASION, 3122 Cancers, SUPPRESS, chemotherapy, anthracycline, survival, doxorubicin, Article, PROGNOSTIC-FACTORS, breast cancer, 3123 Gynaecology and paediatrics, metastasis, miR-30, BRCA2 MUTATIONS, lapatinib, skin and connective tissue diseases, RC254-282, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, EPITHELIAL-MESENCHYMAL TRANSITION, HER-2, HYBRIDIZATION, RESISTANCE
Abstract: Deregulated miRNA expression has been suggested in several stages of breast cancer pathogenesis. We have studied the miR-30 family, in particular miR-30d, in relation to breast cancer patient survival and treatment outcomes. With tumor specimens from 1238 breast cancer patients, we analyzed the association of miR-30d expression with tumor characteristics with the 5-year occurrence of breast cancer-specific death or distant metastasis (BDDM), and with 10-year breast cancer survival (BCS). We conducted a two-stage drug-screen to investigate the impact of miR-30 family members (miR-30a-30e) on sensitivity to doxorubicin and lapatinib in six breast cancer cell lines HCC1937, HCC1954, MDA-MB-361, MCF7, MDA-MB-436 and CAL-120, using drug sensitivity scores (DSS) to compare the miR-30 family mimics to their specific inhibitors. The study was complemented with Ingenuity Pathway Analysis (IPA) with the METABRIC data. We found that while high miR-30d expression is typical for aggressive tumors, it predicts better metastasis-free (pBDDM = 0.035, HR = 0.63, 95% CI = 0.4–0.9) and breast cancer-specific survival (pBCS = 0.018, HR = 0.61, 95% CI = 0.4–0.9), especially in HER2-positive (pBDDM = 0.0009), ER-negative (pBDDM = 0.003), p53-positive (pBDDM = 0.011), and highly proliferating (pBDDM = 0.0004) subgroups, and after adjuvant chemotherapy (pBDDM = 0.035). MiR-30d predicted survival independently of standard prognostic markers (pBDDM = 0.0004). In the drug-screening test, the miR-30 family sensitized the HER2-positive HCC1954 cell line to lapatinib (p &lt, 10−2) and HCC1937, MDA-MB-361, MDA-MB-436 and CAL120 to doxorubicin (p &lt, 10−4) with an opposite impact on MCF7. According to the pathway analysis, the miR-30 family has a suppressive effect on cell motility and metastasis in breast cancer. Our results suggest prognostic and predictive potential for the miR-30 family, which warrants further investigation.
Published: 2021

14. Lapsuuden mitokondriotaudit - yhden soluelimen toimintaviasta kymmeniä erilaisia sairauksia

Author: Isohanni, Pirjo, Wartiovaara, Anu, Helsingin yliopisto, HUS Lasten ja nuorten sairaudet, Helsingin yliopisto, HUSLAB, HUS Lasten ja nuorten sairaudet, Tutkimusohjelmayksikkö, Anu Wartiovaara / Vastuullinen tutkija, Clinicum, Lastenklinikka, Lastenneurologian yksikkö, Lääketieteellinen tiedekunta, Helsingin yliopisto, HUSLAB, Stem Cells and Metabolism Research Program, and Neurotieteiden osasto
Subjects: +drug therapy, Mitochondrial Diseases, +diagnosis, +genetics, Mitochondrial Myopathies, Kearns-Sayre Syndrome, Lipid Metabolism, Inborn Errors, DNA Polymerase gamma, 3123 Naisten- ja lastentaudit, Status Epilepticus, Muscular Diseases, +therapy, MELAS Syndrome, Congenital Bone Marrow Failure Syndromes, Leigh Disease, Child, Retinitis Pigmentosa
Abstract: Vertaisarvioitu. English abstract. Lapsuudessa alkavat mitokondriotaudit ovat useimmiten eteneviä aivo- tai lihastauteja, joihin voi liittyä muiden elimien, kuten maksan, sydämen, munuaisten ja aistinelinten toiminnanhäiriöitä. Mitokondriotaudit ovat yksi yleisimmistä periytyvistä aineenvaihduntatautiryhmistä, ja niiden mahdollisuus tulisi pitää mielessä, kun lapsella on tunnistamaton, etenevä sairaus. Diagnosointi on vaativaa kliinisen kuvan monimuotoisuuden, laboratoriotutkimusten epäspesifisyyden ja joidenkin tarkennettujen tutkimusten, kuten lapsilta nukutuksessa otettavan lihaskudosnäytteen, kajoavan luonteen vuoksi. Uudet genominlaajuiset tutkimusmenetelmät ovat osoittautuneet arvokkaiksi lasten mitokondriotautien diagnostiikassa. Vain yksittäisiin mitokondriotauteihin on toistaiseksi täsmähoitoja. Kaikki potilaat tarvitsevat kuitenkin yksilöllistä hoitoa, kuntoutusta ja pysyviä hoitosuhteita, perheet puolestaan sekä perinnöllisyysneuvontaa että pitkäjänteistä tukea.
Published: 2021

15. Detrended fluctuation analysis in the presurgical evaluation of parietal lobe epilepsy patients

Author: Juha Wilenius, Maria Peltola, Sami Auno, J. Matias Palva, Sampsa Vanhatalo, Leena Lauronen, University of Helsinki, Neuroscience Center, University of Helsinki, HUS Medical Imaging Center, University of Helsinki, HUSLAB, University of Helsinki, Matias Palva / Principal Investigator, Neuroscience Center, University of Helsinki, Helsinki University Hospital Area, HUS Medical Imaging Center, HUS Children and Adolescents, Kliinisen neurofysiologian yksikkö, Clinicum, BioMag Laboratory, HUSLAB, Department of Neurosciences, Matias Palva / Principal Investigator, Biosciences, Helsinki Institute of Life Science HiLIFE, Department of Neuroscience and Biomedical Engineering, Aalto-yliopisto, and Aalto University
Subjects: DYNAMICS, Male, Drug Resistant Epilepsy, Pilot Projects, Electroencephalography, Cohort Studies, Epilepsy, 0302 clinical medicine, Parietal Lobe, Parietal lobe epilepsy, Epilepsy surgery, EEG, Child, MEG, NEURONAL AVALANCHES, medicine.diagnostic_test, 05 social sciences, Magnetoencephalography, Magnetic Resonance Imaging, Sensory Systems, PHASE SYNCHRONIZATION, 3. Good health, medicine.anatomical_structure, Neurology, Long-range temporal correlation, Child, Preschool, Detrended fluctuation analysis, Female, Adolescent, 050105 experimental psychology, SCALING BEHAVIOR, 03 medical and health sciences, Young Adult, Physiology (medical), Preoperative Care, medicine, OSCILLATIONS, Humans, 0501 psychology and cognitive sciences, Ictal, Retrospective Studies, business.industry, 3112 Neurosciences, REMISSION, Cortical dysplasia, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Lobe, RANGE TEMPORAL CORRELATIONS, PATTERNS, Neurology (clinical), business, Nuclear medicine, 030217 neurology & neurosurgery
Abstract: Funding Information: This work was supported by Helsinki University Hospital, Neuroscience Center (HiLIFE; Univ. Helsinki), Aivosäätiö, Finnish Pediatric Foundation/ Lastentautiensäätiö (SV), Sigrid Juselius Foundation, and Academy of Finland (SV, 313242, 288220, 3104450). Funding Information: This work was supported by Helsinki University Hospital, Neuroscience Center (HiLIFE; Univ. Helsinki), Aivos??ti?, Finnish Pediatric Foundation/ Lastentautiens??ti? (SV), Sigrid Juselius Foundation, and Academy of Finland (SV, 313242, 288220, 3104450). Publisher Copyright: © 2021 International Federation of Clinical Neurophysiology Objective: To examine the usability of long-range temporal correlations (LRTCs) in non-invasive localization of the epileptogenic zone (EZ) in refractory parietal lobe epilepsy (RPLE) patients. Methods: We analyzed 10 RPLE patients who had presurgical MEG and underwent epilepsy surgery. We quantified LRTCs with detrended fluctuation analysis (DFA) at four frequency bands for 200 cortical regions estimated using individual source models. We correlated individually the DFA maps to the distance from the resection area and from cortical locations of interictal epileptiform discharges (IEDs). Additionally, three clinical experts inspected the DFA maps to visually assess the most likely EZ locations. Results: The DFA maps correlated with the distance to resection area in patients with type II focal cortical dysplasia (FCD) (p
Published: 2020

16. Effect of High-Dose Esomeprazole on CYP1A2, CYP2C19, and CYP3A4 Activities in Humans: Evidence for Substantial and Long-lasting Inhibition of CYP2C19

Author: Aleksi Tornio, Tuija Tapaninen, Janne T. Backman, Terhi Launiainen, Nina Isoherranen, Taavi J. K. Kaartinen, Mikko Niemi, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, University of Helsinki, HUSLAB, University of Helsinki, Helsinki University Hospital Area, INDIVIDRUG - Individualized Drug Therapy, HUSLAB, Helsinki University Hospital Area, Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Research Programs Unit, Medicum, Janne Backman / Principal Investigator, and Clinicum
Subjects: Male, Pharmacogenomic Variants, Administration, Oral, BREATH TEST, Pharmacology, 030226 pharmacology & pharmacy, STEREOSELECTIVE PHARMACOKINETICS, Esomeprazole, chemistry.chemical_compound, 0302 clinical medicine, Cytochrome P-450 CYP3A, Pharmacology (medical), Pantoprazole, Omeprazole, DRUG-INTERACTION, Paraxanthine, Cross-Over Studies, OMEPRAZOLE, Cytochrome P-450 CYP1A2 Inducers, Healthy Volunteers, 3. Good health, 317 Pharmacy, 030220 oncology & carcinogenesis, Female, Caffeine, medicine.drug, PROTON PUMP INHIBITOR, Midazolam, METABOLISM, Models, Biological, 03 medical and health sciences, Pharmacokinetics, Cytochrome P-450 CYP1A2, medicine, Humans, PH PROFILES, CYTOCHROME-P450, IN-VITRO, Drug interaction, Cytochrome P-450 CYP2C19, chemistry, Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP3A Inhibitors, 3111 Biomedicine, DEPENDENT INHIBITOR
Abstract: In vitro, esomeprazole is a time-dependent inhibitor of CYP2C19. Additionally, racemic omeprazole induces CYP1A2 and omeprazole and its metabolites inhibit CYP3A4 in vitro. In this 5-phase study, 10 healthy volunteers ingested 20 mg pantoprazole, 0.5 mg midazolam, and 50 mg caffeine as respective index substrates for CYP2C19, 3A4, and 1A2 before and 1, 25, 49 (pantoprazole only), and 73 hours after an 8-day pretreatment with 80 mg esomeprazole twice daily. The area under the plasma concentration-time curve (AUC) of R-pantoprazole increased 4.92-fold (90% confidence interval (CI) 3.55-6.82), 2.31-fold (90% CI 1.85-2.88), and 1.33-fold (90% CI 1.06-1.68) at the 1-hour, 25-hour, and 73-hour phases, respectively, consistent with a substantial and persistent inhibition of CYP2C19. The AUC of midazolam increased up to 1.44-fold (90% CI 1.22-1.72) and the paraxanthine/caffeine metabolic ratio up to 1.19-fold (90% CI 1.04-1.36), when the index substrates were taken 1 hour after esomeprazole. Based on the recovery of R-pantoprazole oral clearance, the turnover half- life of CYP2C19 was estimated to average 53 hours. Pharmacokinetic simulation based on the observed concentrations of esomeprazole and its metabolites as well as their published CYP2C19 inhibitory constants was well in line with the observed changes in R-pantoprazole pharmacokinetics during the course of the study. Extrapolations assuming linear pharmacokinetics of esomeprazole suggested weak to moderate inhibition at 20 and 40 mg twice daily dosing. In conclusion, high-dose esomeprazole can cause strong inhibition of CYP2C19, but only weakly inhibits CYP3A4 and leads to minor induction of CYP1A2. The enzymatic activity of CYP2C19 recovers gradually in similar to 3-4 days after discontinuation of esomeprazole treatment.
Published: 2020

17. Prediction of the aggressiveness of non-functional pancreatic neuroendocrine tumors based on the dual-tracer PET/CT

Author: Camilla Schalin-Jäntti, Jari Sundström, Hanna Seppänen, Harri Mustonen, Jukka Kemppainen, Jukka Schildt, Susanna Majala, Saila Kauhanen, Risto Gullichsen, Tiina Vesterinen, Johanna Arola, University of Helsinki, CAN-PRO - Translational Cancer Medicine Program, University of Helsinki, HUS Abdominal Center, University of Helsinki, HUS Medical Imaging Center, University of Helsinki, HUSLAB, CAN-PRO - Translational Cancer Medicine Program, HUS Abdominal Center, Faculty of Medicine, University of Helsinki, University Management, Endokrinologian yksikkö, HUS Medical Imaging Center, Department of Diagnostics and Therapeutics, Clinicum, Department of Surgery, HUSLAB, Institute for Molecular Medicine Finland, Department of Pathology, and Helsinki Institute of Life Science HiLIFE
Subjects: lcsh:Medical physics. Medical radiology. Nuclear medicine, medicine.medical_specialty, lcsh:R895-920, education, 18F-FDG-PET/CT, Neuroendocrine tumors, surgical management, Asymptomatic, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Biopsy, medicine, Radiology, Nuclear Medicine and imaging, Lymph node, Cardiac imaging, Original Research, PET-CT, biology, medicine.diagnostic_test, business.industry, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, medicine.anatomical_structure, NF-PNET, 68Ga-DOTANOC-PET/CT, 030220 oncology & carcinogenesis, Ki-67, biology.protein, Histopathology, medicine.symptom, Nuclear medicine, business, prospective study
Abstract: Background Predicting the aggressive behavior of non-functional pancreatic neuroendocrine tumors (NF-PNET) remains controversial. We wanted to explore, in a prospective setting, whether the diagnostic accuracy can be improved by dual-tracer functional imaging 68Ga-DOTANOC and 18F-FDG-PET/CT in patients with NF-PNETs. Methods Thirty-one patients with NF-PNET (90% asymptomatic) underwent PET-imaging with 18F-FDG and 68Ga-DOTANOC, followed by surgery (n = 20), an endoscopic ultrasonography and fine-needle biopsy (n = 2) or follow-up (n = 9). A focal activity on PET/CT greater than the background that could not be identified as physiological activity was considered to indicate tumor tissue. The imaging results were compared to histopathology. The mean follow-up time was 31.3 months. Results Thirty-one patients presented a total of 53 lesions (40 histologically confirmed) on PET/CT. Thirty patients had a 68Ga-DOTANOC-positive tumor (sensitivity 97%) and 10 patients had an 18F-FDG-positive tumor. In addition, one 68Ga-DOTANOC-negative patient was 18F-FDG-positive. 18F-FDG-PET/CT was positive in 19% (3/16) of the G1 tumors, 63% (5/8) of the G2 tumors and 1/1 of the well-differentiated G3 tumor. 68Ga-DOTANOC-PET/CT was positive in 94% of the G1 tumors, 100% of the G2 tumors and 1/1 of the well-differentiated G3 tumor. Two out of six (33%) of the patients with lymph node metastases (LN+) were 18F-FDG-positive. The 18F-FDG-PET/CT correlated with tumor Ki-67 (P = 0.021). Further, the Krenning score correlated with tumor Ki-67 (P = 0.013). 18F-FDG-positive tumors were significantly larger than the 18F-FDG-negative tumors (P = 0.012). 18F-FDG-PET/CT showed a positive predictive value of 78% in the detection of potentially aggressive tumors (G2, G3, or LN + PNETs); the negative predictive value was 69%. Conclusions 18F-FDG-PET/CT is useful to predict tumor grade but not the LN+ of NF-PNETs. Patients with 18F-FDG-avid NF-PNETs should be referred for surgery. The 68Ga-DOTANOC-PET/CT also has prognostic value since the Krenning score predicts the histopathological tumor grade. Trial registration The study has been registered at ClinicalTrials.gov; Non-functional Pancreatic NET and PET imaging, NCT02621541.
Published: 2019

18. Disturbances in complement recognition and control in human disease - An editorial to a special issue on 'Complement Regulation'

Author: Meri, Seppo, HUSLAB, Seppo Meri / Principal Investigator, Department of Bacteriology and Immunology, University of Helsinki, TRIMM - Translational Immunology Research Program, Research Programs Unit, and University of Helsinki, HUSLAB
Subjects: education, 3111 Biomedicine
Abstract: Non
Published: 2019

19. Aseptic meningitis outbreak associated with echovirus 4 in Northern Europe in 2013–2014

Author: Arthur Löve, Maija Lappalainen, Teemu Smura, Alexander Lukasev, Susanne Gjeruldsen Dudman, Mia Brytting, Sindy Böttcher, Sofie Midgley, Sabine Diedrich, Thea Kølsen Fischer, Elenor Hauzenberger, Isabelle Schuffenecker, Carita Savolainen-Kopra, Anne J. Jääskeläinen, Olga Ivanova, Bruno Lina, Soile Blomqvist, Pekka Kolehmainen, Petri Susi, HUSLAB, University of Helsinki, Helsinki University Hospital Area, Department of Virology, Clinicum, Medicum, Viral Zoonosis Research Unit, University of Helsinki, HUSLAB, University of Helsinki, Department of Virology, and University of Helsinki, Medicum
Subjects: 0301 basic medicine, Echovirus, Picornavirus, SAMPLES, Northern Europe, medicine.disease_cause, Disease Outbreaks, 0302 clinical medicine, Germany, PICORNAVIRUS, Meningitis, Aseptic, 030212 general & internal medicine, Diagnostic screening, Finland, Phylogeny, 11832 Microbiology and virology, biology, Norway, Human parechovirus, ENTEROVIRUSES, Aseptic meningitis, Enterovirus B, Human, 3. Good health, Europe, Infectious Diseases, Adolescent, 030106 microbiology, Echovirus Infections, Viremia, TYPE-3, Young Adult, 03 medical and health sciences, CEREBROSPINAL-FLUID, Virology, medicine, Humans, Sweden, IDENTIFICATION, HUMAN PARECHOVIRUS INFECTIONS, SPAIN, Outbreak, biology.organism_classification, medicine.disease, Central nervous system, Parechovirus, Echovirus 4, 3111 Biomedicine
Abstract: Picornaviruses (family Picornaviridae) are small, nonenveloped, positive-sense, single-stranded RNA viruses. The members of this family are currently classified into 47 genera and 110 species. Of picornaviruses, entero-and parechoviruses are associated with aseptic meningitis. They are transmitted via fecal-oral and respiratory routes, and occasionally, these viruses may cause a brief viremia and gain access to central nervous system (CNS). During the diagnostic screening of entero-and parechovirus types in Finland in year 2013-14, we detected a cluster of echovirus 4 (E4) infections in young adults and adolescents. As E4 is infrequently detected in Finland, we contacted several Northern and Central European laboratories that conduct routine surveillance for enteroviruses and, for those who have had E4 cases, we send a query for E4 sequences and data. Here we report CNS infections caused by E4 in Finland, Sweden, Norway, Denmark, Iceland and Germany in 2013 and 2014, and show that the E4 detected in these countries form a single lineage. In contrast, E4 strains circulating in these countries preceding the year 2013, and those circulating elsewhere in Europe during 2013-2014, formed several independent clusters.
Published: 2020
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20. The angiopoietin receptor Tie2 is atheroprotective in arterial endothelium

Author: Andrey Anisimov, Shentong Fang, Karthik Amudhala Hemanthakumar, Tiit Örd, Kristof van Avondt, Raphael Chevre, Anu Toropainen, Prosanta Singha, Huda Gilani, Su D. Nguyen, Sinem Karaman, Emilia A. Korhonen, Ralf H. Adams, Hellmut G. Augustin, Katariina Öörni, Oliver Soehnlein, Minna U. Kaikkonen, Kari Alitalo, CAN-PRO - Translational Cancer Medicine Program, Doctoral Programme in Biomedicine, Kivelä Lab, Department of Agricultural Sciences, Staff Services, Medicum, INDIVIDRUG - Individualized Drug Therapy, Organotypic Vasculature Lab, Doctoral Programme in Integrative Life Science, Research Programs Unit, Molecular and Integrative Biosciences Research Programme, Biosciences, Doctoral Programme in Clinical Veterinary Medicine, HUSLAB, and Kari Alitalo / Principal Investigator
Subjects: 3121 General medicine, internal medicine and other clinical medicine
Abstract: Leukocytes and resident cells in the arterial wall contribute to atherosclerosis, especially at sites of disturbed blood flow. Expression of endothelial Tie1 receptor tyrosine kinase is enhanced at these sites, and attenuation of its expression reduces atherosclerotic burden and decreases inflammation. However, Tie2 tyrosine kinase function in atherosclerosis is unknown. Here we provide genetic evidence from humans and from an atherosclerotic mouse model to show that TIE2 is associated with protection from coronary artery disease. We show that deletion of Tie2, or both Tie2 and Tie1, in the arterial endothelium promotes atherosclerosis by increasing Foxo1 nuclear localization, endothelial adhesion molecule expression and accumulation of immune cells. We also show that Tie2 is expressed in a subset of aortic fibroblasts, and its silencing in these cells increases expression of inflammation-related genes. Our findings indicate that unlike Tie1, the Tie2 receptor functions as the dominant endothelial angiopoietin receptor that protects from atherosclerosis.
Published: 2023
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21. Optimal sampling and analysis methods for clinical diagnostics of vaginal microbiome

Author: Katja Kero, Niina Hieta, Teemu Kallonen, Anne Ahtikoski, Hanna K. Laine, Jaana Rautava, Eveliina Munukka, Department of Oral and Maxillofacial Diseases, University of Helsinki, Research Programs Unit, HUS Head and Neck Center, Department of Pathology, HUS Diagnostic Center, and HUSLAB
Subjects: 11832 Microbiology and virology, Microbiology (medical), Infectious Diseases, Microbial diagnostics sampling, 3121 General medicine, internal medicine and other clinical medicine, Next-generation sequencing, Vaginal microbiota, General Medicine, Vaginal microbiome, Bacterial 16S rRNA gene
Abstract: Next-generation sequencing-based microbiological analysis is a complex way to profile vaginal microbiome samples since each step affects the results gained. Methodologies for sample collection lack golden standards. We compared Puritan DNA/RNA swab (PS) and Copan FLOQ swab (CS) and provided consistent and reliable microbiome profiles analyzed by 16S rRNA gene sequencing. We collected two consecutive vaginal samples utilizing PS with room temperature storing and CS with instant freezing from 26 women. Variable region 4 of bacterial 16S rRNA gene was amplified with single PCR by custom-designed dual-indexed primers and sequenced with Illumina MiSeq system. Read quality control, operational taxonomic unit tables, and alpha and beta diversities analysis were performed, and community richness, diversity, and evenness were evaluated and compared between the two samplings and tests. Nineteen sample pairs produced detectable, intact DNA during the extraction protocol and/or further microbial profiles. Alpha bacterial diversity indices were independent on the collection protocol. No significant statistical differences were found in the measured beta diversity metrics between the collection methods. Of the women, 43% had Lactobacillus-dominated vaginal microbiome profile despite of collection method. Previously reported important vaginal microbiome phyla Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were present in the sample set although their relative abundances varied among individuals. PS and CS enable constant vaginal microbiota sampling. The PS method with no need for instant freezing is suitable for on-site collections at clinics. Furthermore, it seems to be possible to take two samples instead of one with constant microbiological results.
Published: 2023
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22. Automated image analysis of keratin 7 staining can predict disease outcome in primary sclerosing cholangitis

Author: Nelli Sjöblom, Sonja Boyd, Anniina Manninen, Sami Blom, Anna Knuuttila, Martti Färkkilä, Johanna Arola, HUSLAB, Department of Pathology, HUS Helsinki and Uusimaa Hospital District, Clinicum, Centre of Excellence in Complex Disease Genetics, HUS Abdominal Center, Department of Medicine, and Gastroenterologian yksikkö
Subjects: Artificial intelligence, Infectious Diseases, Hepatology, Primary sclerosing cholangitis, 3111 Biomedicine, Surrogate marker, Ductular reaction, Liver histology
Abstract: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease that obstructs the bile ducts and causes liver cirrhosis and cholangiocarcinoma. Efficient surrogate markers are required to measure disease progression. The cytokeratin 7 (K7) load in a liver specimen is an independent prognostic indicator that can be measured from digitalized slides using artificial intelligence (AI)-based models.A K7-AI model 2.0 was built to measure the hepatocellular K7 load area of the parenchyma, portal tracts, and biliary epithelium. K7-stained PSC liver biopsy specimens (n = 295) were analyzed. A compound endpoint (liver transplantation, liver-related death, and cholangiocarcinoma) was applied in Kaplan-Meier survival analysis to measure AUC values and positive likelihood ratios for each histological variable detected by the model.The K7-AI model 2.0 was a better prognostic tool than plasma alkaline phosphatase-ALP, fibrosis stage evaluated by Nakanuma classification, or K7 score evaluated by a pathologist based on the AUC values of measured variables. A combination of parameters, such as portal tract volume and area of K7-positive hepatocytes analyzed by the model, produced an AUC of 0.81 for predicting the compound endpoint. Portal tract volume measured by the model correlated with the histological fibrosis stage.The K7-staining of histological liver specimens in PSC provides significant information on disease outcomes through objective and reproducible data, including variables that cannot be measured by a human pathologist. The K7-AI model 2.0 could serve as a prognostic tool for clinical endpoints and as a surrogate marker in drug trials. This article is protected by copyright. All rights reserved.
Published: 2022
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23. Drug response profiles in patient-derived cancer cells across histological subtypes of ovarian cancer: real-time therapy tailoring for a patient with low-grade serous carcinoma

Author: Astrid Murumägi, Daniela Ungureanu, Suleiman Khan, Mariliina Arjama, Katja Välimäki, Aleksandr Ianevski, Philipp Ianevski, Rebecka Bergström, Alice Dini, Anna Kanerva, Riitta Koivisto-Korander, Johanna Tapper, Heini Lassus, Mikko Loukovaara, Andrus Mägi, Akira Hirasawa, Daisuke Aoki, Vilja Pietiäinen, Teijo Pellinen, Ralf Bützow, Tero Aittokallio, Olli Kallioniemi, Institute for Molecular Medicine Finland, Precision Systems Medicine, University of Helsinki, Helsinki Institute of Life Science HiLIFE, ATG - Applied Tumor Genomics, Research Programs Unit, Department of Computer Science, Computational Systems Medicine, HUS Gynecology and Obstetrics, Akseli Eetu Hemminki / Principal Investigator, Clinicum, Department of Obstetrics and Gynecology, Digital Precision Cancer Medicine (iCAN), Department of Pathology, HUSLAB, Helsinki Institute for Information Technology, Tero Aittokallio / Principal Investigator, Bioinformatics, Karolinska Institutet, University of Tartu, Okayama University, Keio University, Aalto-yliopisto, and Aalto University
Subjects: Cancer Research, Sensitivity, Oncology, Reprogrammed cells, 3122 Cancers, Resistant
Abstract: Funding Information: This study was supported by grants from the Academy of Finland (grants 278741, 313267, 326238, 333583, 313267, 326238, and 344698), Academy of Finland Centre of Excellence for Translational Cancer Biology (grant 271845), Cancer Society of Finland (grants 140114, 160080, 170112), Sigrid Jusélius Foundation. OK was also supported by Vetenskaprådet, Knut and Alice Wallenberg Foundation, Swedish Foundation for Strategic Research and Vinnova. Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. Funding Information: OK is a co-founder and a board member of Medisapiens and Sartar Therapeutics and has received royalty on patents licensed by Vysis-Abbot. His research group has a Vinnova-funded collaborative programme with Astra-Zeneca, Labcyte, Takara Biosciences and Pelago. VP has received a grant from UPM-Kymmene. Other authors did not disclose any potential conflicts of interest. Publisher Copyright: © 2022, The Author(s). Many efforts are underway to develop novel therapies against the aggressive high-grade serous ovarian cancers (HGSOCs), while our understanding of treatment options for low-grade (LGSOC) or mucinous (MUCOC) of ovarian malignancies is not developing as well. We describe here a functional precision oncology (fPO) strategy in epithelial ovarian cancers (EOC), which involves high-throughput drug testing of patient-derived ovarian cancer cells (PDCs) with a library of 526 oncology drugs, combined with genomic and transcriptomic profiling. HGSOC, LGSOC and MUCOC PDCs had statistically different overall drug response profiles, with LGSOCs responding better to targeted inhibitors than HGSOCs. We identified several subtype-specific drug responses, such as LGSOC PDCs showing high sensitivity to MDM2, ERBB2/EGFR inhibitors, MUCOC PDCs to MEK inhibitors, whereas HGSOCs showed strongest effects with CHK1 inhibitors and SMAC mimetics. We also explored several drug combinations and found that the dual inhibition of MEK and SHP2 was synergistic in MAPK-driven EOCs. We describe a clinical case study, where real-time fPO analysis of samples from a patient with metastatic, chemorefractory LGSOC with a CLU-NRG1 fusion guided clinical therapy selection. fPO-tailored therapy with afatinib, followed by trastuzumab and pertuzumab, successfully reduced tumour burden and blocked disease progression over a five-year period. In summary, fPO is a powerful approach for the identification of systematic drug response differences across EOC subtypes, as well as to highlight patient-specific drug regimens that could help to optimise therapies to individual patients in the future.
Published: 2022
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24. Prognostic Role ofPorphyromonas gingivalisGingipain Rgp and Matrix Metalloproteinase 9 in Oropharyngeal Squamous Cell Carcinoma

Author: ANNA KAISA KYLMÄ, TIMO SORSA, LAURI JOUHI, HARRI K. MUSTONEN, HESHAM MOHAMED, REIJA RANDÉN-BRADY, ANTTI MÄKITIE, TIMO ATULA, JAANA HAGSTRÖM, CAJ HAGLUND, HUSLAB, Department of Pathology, Helsinki University Hospital Area, HUS Head and Neck Center, Department of Oral and Maxillofacial Diseases, Korva-, nenä- ja kurkkutautien klinikka, Clinicum, HUS Abdominal Center, Department of Surgery, Research Programs Unit, Research Program in Systems Oncology, Medicum, CAN-PRO - Translational Cancer Medicine Program, Faculty of Medicine, and II kirurgian klinikka
Subjects: Matrix metalloproteinase, Human papillomavirus, Cancer Research, Oncology, Opscc, Rgp, 3122 Cancers, General Medicine, Survival analysis, Oropharyngeal squamous cell carcinoma, Porphyromonas gingivalis, Gingipain
Abstract: Background/Aim: The oral bacteria involved in the development of periodontitis alter the tissue conditions and modify immune responses in a way that may also influence tumor development. We investigated the prevalence of R gingipain (Rgp), a key virulence factor of the oral pathobiont Porphyromonas gingivalis, and the tissue-destructive enzymes matrix metalloproteinase 8 (MMP-8) and 9 (MMP-9) in 202 unselected consecutive oropharyngeal squamous cell carcinoma
Published: 2022
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25. Moderate hyperuricaemia ameliorated kidney damage in a low‐renin model of experimental renal insufficiency

Author: Venla Kurra, Arttu Eräranta, Timo Paavonen, Teemu Honkanen, Juhani Myllymäki, Asko Riutta, Ilkka Tikkanen, Päivi Lakkisto, Jukka Mustonen, Ilkka Pörsti, HUS Abdominal Center, Department of Medicine, Clinicum, Medicum, Helsinki University Hospital Area, University of Helsinki, Nefrologian yksikkö, HUSLAB, Department of Clinical Chemistry and Hematology, Tampere University, Clinical Medicine, and Department of Internal medicine
Subjects: BLOOD-PRESSURE, Hyperuricemia, URIC-ACID, kidney morphology, 3121 Internal medicine, Kidney, Toxicology, Nephrectomy, GLOMERULOSCLEROSIS, hyperuricaemia, Renin, Animals, Renal Insufficiency, oxonic acid, OXIDATIVE STRESS, ARTERY TONE, Inflammation, Pharmacology, experimental renal insufficiency, NITRIC-OXIDE, HYPERTENSION, HIGH-CALCIUM, General Medicine, Fibrosis, Rats, Uric Acid, 317 Pharmacy, 3121 General medicine, internal medicine and other clinical medicine, Kidney Diseases, MAST-CELL ACTIVATION, EXTRACELLULAR-SUPEROXIDE DISMUTASE
Abstract: Background: Hyperuricemia may predispose to renal damage, but in end-stage renal disease lower uric acid concentrations have been associated with higher mortality. In experimental studies, uric acid has promoted renal fibrosis and inflammation, but some studies have shown nephroprotective effects probably due to alleviated oxidative stress. We studied the influence of moderate hyperuricemia on kidney morphology in 5/6 nephrectomized rats.Methods: Three weeks after subtotal nephrectomy or sham-operation, rats were put on 2.0% oxonic acid (uricase inhibitor) diet for 9 weeks. Blood pressure was monitored using tail-cuff. At close of the study, blood, urine, and kidney samples were taken, and renal histology, mast cell count, and oxidative stress markers were determined. Kidney tissue inflammation and fibrosis were evaluated using RT‑PCR and immunohistochemistry.Results: Oxonic acid diet increased plasma uric acid levels by >80 µmol/l without influencing blood pressure. Creatinine clearance was reduced by ~60% in both remnant kidney groups, and by ~30% in hyperuricemic sham-operated rats. In remnant kidney rats with suppressed plasma renin activity, moderate hyperuricemia decreased glomerulosclerosis, tubulointerstitial damage, and kidney mast cell count, but did not influence the fibrosis marker collagen I mRNA content. In both hyperuricemic groups, the mast-cell product 11-epi-prostaglandin-F2α excretion to the urine and kidney tissue COX‑2 levels were decreased.Conclusions: Hyperuricemic remnant kidney rats displayed improved kidney morphology and reduced markers of oxidative stress and inflammation. Thus, moderately increased plasma uric acid had beneficial effects on the kidney in this low-renin model of experimental chronic renal insufficiency.
Published: 2022
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26. Clinically relevant germline variants in allogeneic hematopoietic stem cell transplant recipients

Author: Atte K. Lahtinen, Jessica Koski, Jarmo Ritari, Kati Hyvärinen, Satu Koskela, Jukka Partanen, Kim Vettenranta, Minna Koskenvuo, Riitta Niittyvuopio, Urpu Salmenniemi, Maija Itälä-Remes, Kirsi Jahnukainen, Outi Kilpivaara, Ulla Wartiovaara-Kautto, Research Programs Unit, University of Helsinki, Statskunskap med förvaltning, ATG - Applied Tumor Genomics, Medicum, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Clinicum, Children's Hospital, Lastentautien yksikkö, HUS Children and Adolescents, HUS Comprehensive Cancer Center, Hematologian yksikkö, HUSLAB, and HUS Diagnostic Center
Subjects: Adult, Risk, Transplantation, 3122 Cancers, Hematopoietic Stem Cell Transplantation, Predisposition, Hematology, Guidelines, Hematologic Diseases, Management, Humans, Transplantation, Homologous, Child, Malignancies, Breast-cancer
Abstract: Allogeneic hematopoietic stem cell transplantation (HSCT) provides patients with severe hematologic disease a well-established potential for curation. Incorporation of germline analyses in the workup of HSCT patients is not a common practice. Recognizing rare harmful germline variants may however affect patients’ pre-transplantation care, choice of the stem cell donor, and complication risks. We analyzed a population-based series of germline exome data of 432 patients who had undergone HSCT. Our aim was to identify clinically relevant variants that may challenge the outcome of the HSCT. We focused on genes predisposing to hematological diseases, or solid tumors, and genes included in the American College of Medical Genetics secondary findings list v3.0. As population-specific controls, we used GnomAD non-cancer Finns (n = 10,816). We identified in our population-based analysis rare harmful germline variants in disease-predisposing or actionable toxicity-increasing genes in 17.8% of adult and pediatric patients that have undergone HSCT (15.1% and 22.9%, respectively). More than half of the patients with a family member as a donor had not received genetic diagnosis prior to the HSCT. Our results encourage clinicians to incorporate germline genetic testing in the HSCT protocol in the future in order to reach optimal long-term outcome for the patients.
Published: 2022
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27. IgG4-positive plasma cells in nonspecific sialadenitis and sialolithiasis

Author: Elin Peuraharju, Jaana Hagström, Jussi Tarkkanen, Caj Haglund, Timo Atula, Department of Oral and Maxillofacial Diseases, HUS Head and Neck Center, HUSLAB, Medicum, Department of Pathology, HUS Abdominal Center, II kirurgian klinikka, Department of Surgery, Clinicum, CAN-PRO - Translational Cancer Medicine Program, and Korva-, nenä- ja kurkkutautien klinikka
Subjects: Salivary Gland Calculi, SUBMANDIBULAR-GLAND, Plasma Cells, Submandibular Gland, CHRONIC SCLEROSING SIALADENITIS, Sialadenitis, DISEASE, CLASSIFICATION, Pathology and Forensic Medicine, Immunoglobulin G, Humans, Immunoglobulin G4-Related Disease, KUTTNER TUMOR, 3111 Biomedicine
Abstract: Chronic sclerosing sialadenitis is commonly regarded as a manifestation of IgG4-related disease. We previously found that a high IgG4 expression or IgG4-related disease could accompany nonspecific sialadenitis, whereas chronic sclerosing sialadenitis was not directly associated with IgG4-related disease. Our previous findings lead us to hypothesize that these inflammatory conditions of the submandibular gland signify a continuous progression of disease rather than different disease entities. We, therefore, aimed to determine the presence of IgG4-positivity and genuine IgG4-related disease in a cohort of 165 submandibular gland specimens from patients who underwent surgery due to chronic nonspecific sialadenitis or sialolithiasis. To do so, we re-evaluated histopathological features and divided samples into three groups: (A) nonspecific sialadenitis without known sialolithiasis, (B) sialadenitis with sialolithiasis, and (C) sialolithiasis without sialadenitis. We performed immunohistochemical staining for IgG4, IgG, and CD31, and assessed the Boston consensus statement criteria for IgG4-related disease in IgG4-positive samples. We also reviewed patient records and supplemented follow-up data with a questionnaire among patients with IgG4-positive samples. IgG4-positive plasma cells (range 1-344) were found in 131 samples. Among these, 19 samples were classified as IgG4-positive (>= 70 IgG4-positive plasma cells/high-power field). Two IgG4-positive samples were histologically highly suggestive of IgG4-related disease, but only one had a clinically confirmed diagnosis of IgG4-related disease. Our results indicate that patients with sialadenitis and sialolithiasis often present with IgG4-positive lymphoplasmacytic infiltrates, but exceedingly rarely present with genuine IgG4-related disease. In sialolithiasis without sialadenitis, IgG4-positive plasma cells are often absent or appear in small numbers. These results support our hypothesis of a continuum of disease, and indicate that progressive inflammation of the submandibular gland leads to the development of more specific pathological features over time.
Published: 2022
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28. Germline ERCC excision repair 6 like 2 ( <scp> ERCC6L2 </scp> ) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment

Author: Hannah Armes, Findlay Bewicke‐Copley, Ana Rio‐Machin, Doriana Di Bella, Céline Philippe, Anna Wozniak, Hemanth Tummala, Jun Wang, Teresa Ezponda, Felipe Prosper, Inderjeet Dokal, Tom Vulliamy, Outi Kilpivaara, Ulla Wartiovaara‐Kautto, Jude Fitzgibbon, Kevin Rouault‐Pierre, Department of Medical and Clinical Genetics, ATG - Applied Tumor Genomics, Research Programs Unit, University of Helsinki, HUSLAB, Medicum, HUS Comprehensive Cancer Center, Clinicum, Helsinki University Hospital Area, and Hematologian yksikkö
Subjects: mesenchymal cells, DNA Repair, FAILURE SYNDROME, 3122 Cancers, DNA Helicases, progenitor cells, Hematology, Haematopoietic stem, Niche and bone marrow microenvironment, Germ Cells, HEMATOPOIETIC STEM, Familial leukaemia, Bone Marrow, DNA-REPAIR, Humans, Erythropoiesis, ANEMIA, acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), Germ-Line Mutation
Abstract: Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2-silenced and patient-derived cells ex vivo. Here, we show for the first time that ERCC6L2-deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA-sequencing deconvolution performed on ERCC6L2-silenced erythroid-committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2-deficiency are not limited to HSPCs, as we observe a striking phenotype in patient-derived and ERCC6L2-silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment.
Published: 2022
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29. Antibodies Recognizing Yersinia enterocolitica Lipopolysaccharides of Various Chemotypes in Synovial Fluids From Patients With Juvenile Idiopathic Arthritis

Author: Katarzyna Kasperkiewicz, Anna S. Świerzko, Mateusz Michalski, Łukasz Eppa, Mikael Skurnik, Zbigniew Żuber, Maciej Cedzyński, HUMI - Human Microbiome Research, Helsinki One Health (HOH), Research Programs Unit, Mikael Skurnik / Principal Investigator, HUSLAB, Department of Bacteriology and Immunology, and University of Helsinki
Subjects: Serum, Virulence, Article Subject, Cells, Immunology, O-3, Immunology and Allergy, Pathogenesis, 3111 Biomedicine, General Medicine, Enterobacterial common antigen
Abstract: Yersinia enterocolitica O:3 (YeO3) is considered to be associated with reactive arthritis (ReA), and its lipopolysaccharide (LPS) has been detected in synovial fluids from patients. Interestingly, YeO3 wild-type LPS was processed by host cells, resulting in truncated LPS molecules presenting the core region. Previously, we reported the immunogenicity but not adjuvanticity of YeO3 LPSs of wild (S) type, Ra, Rd, or Re chemotypes in mice. Here, we demonstrate the presence of YeO3 LPS chemotype-specific antibodies in all analyzed synovial fluids (SF) from patients with juvenile idiopathic arthritis (JIA). Interestingly, the high titer of antibodies specific for the Kdo-lipid A region was found in most tested SF. In contrast, only a few were positive for antibodies recognizing O-specific polysaccharides. Western blot analysis revealed the presence of antibodies reacting with fast-migrating LPS fractions and enterobacterial common antigen (ECA) in synovial fluid samples. Our data also suggest the importance of LPS-associated ECA for the antigenicity of endotoxin. Furthermore, we confirmed in vitro that Yersinia LPS processing leads to the exposure of its core region and enhanced potency of complement lectin pathway activation.
Published: 2022
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30. Natural history and biomarkers of retinal dystrophy caused by the biallelic TULP1 variant c.148delG

Author: Anna Majander, Eeva‐Marja Sankila, Aura Falck, Laura Kristiina Vasara, Sanna Seitsonen, Maarit Kulmala, Anna‐Kaisa Haavisto, Kristiina Avela, Joni A. Turunen, HUS Head and Neck Center, Department of Ophthalmology and Otorhinolaryngology, Clinicum, University of Helsinki, Silmäklinikka, HUSLAB, Department of Medical and Clinical Genetics, and Medicum
Subjects: Ophthalmology, RECESSIVE RETINITIS-PIGMENTOSA, TUBBY-LIKE PROTEIN-1, MUTATIONS, early-onset inherited retinal dystrophy, TULP1, LEBER CONGENITAL AMAUROSIS, 3125 Otorhinolaryngology, ophthalmology, General Medicine, PHENOTYPE, INDIAN FAMILIES, tubby-like protein 1, nystagmus
Abstract: Purpose To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby-like protein 1 (TULP1) gene. Methods A retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral-domain optical coherence tomography (SD-OCT) were assessed. A meta-analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference. Results The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra-foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD-OCT images. The horizontal width of the foveal EZ showed significant regression with the best-corrected visual acuity (BCVA) of the eye (p < 0.0001, R-2 = 0.541, F = 26.0), the age of the patient (p < 0.0001, R-2 = 0.433, F = 16.8), and mild correlation with the foveal OPL-ONL thickness (p = 0.014, R-2 = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants. Conclusions This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL-ONL layers could serve as biomarkers of the disease stage.
Published: 2022
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31. Clinical features and spectrum of NOTCH3 variants in Finnish patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Author: Saana Mönkäre, Liina Kuuluvainen, Johanna Schleutker, Liisa Myllykangas, Minna Pöyhönen, HUSLAB, Department of Medical and Clinical Genetics, HUS Diagnostic Center, Department of Pathology, Helsinki University Hospital Area, Minna Pöyhönen / Principal Investigator, and University of Helsinki
Subjects: Arthrogryposis, Receptors, Notch, phenotype, MUTATIONS, genotype, Finnish, 3112 Neurosciences, CADASIL, General Medicine, Magnetic Resonance Imaging, 3124 Neurology and psychiatry, PREVALENCE, Neurology, Leukoencephalopathies, NOTCH3, Humans, Neurology (clinical), mutation, Receptor, Notch3, Finland, Retrospective Studies
Abstract: Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by pathogenic variants in the NOTCH3 gene. In Finland, the majority of CADASIL patients carry the pathogenic founder variant c.397C>T, (p.Arg133Cys), but the spectrum of other NOTCH3 variants has not been investigated previously. The aim of the study was to investigate the spectrum and prevalence of NOTCH3 variants Finnish CADASIL patients and to examine the clinical features associated with them. Materials and Methods The spectrum of NOTCH3 variants and the clinical features associated with them were retrospectively examined in 294 Finnish CADASIL patients tested during January 1996 to October 2021 in the Medical Genetics laboratory of Department of Genomics of Turku University Hospital, where practically all samples of patients with suspected CADASIL in Finland are investigated. Results The most common NOTCH3 variants in the study cohort were c.397C>T, (p.Arg133Cys) (68%) and c.3206A>G p.(Tyr1069Cys) (18%), but other less common NOTCH3 variants were detected in as many as 14% of the patients. Eight of the detected NOTCH3 variants were novel: c.520T>A,p.(Cys174Ser), c.836A>G,p.(Gln279Arg), c.1369T>G,p.(Cys457Gly), c.1338C>G,p.(Cys446Trp), c.1564T>G,p.(Cys522Gly), c.2848T>G,p.(Cys950Gly), c.6102dup,p.(Gly2035Argfs*60), and c.2410+6C>G. Other NOTCH3 variants than p.Arg133Cys and p.Tyr1069Cys were more often associated with more severe clinical features. Conclusion This study revealed the genetic and clinical spectrum of CADASIL in the Finnish population. Sequencing of the whole NOTCH3 gene performing a gene-panel or exome sequencing is recommended when suspecting CADASIL.
Published: 2022
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32. A germline exome analysis reveals harmful POT1 variants in multiple myeloma patients and families

Author: Marja Hakkarainen, Jessica R. Koski, Caroline A. Heckman, Pekka Anttila, Raija Silvennoinen, Juha Lievonen, Outi Kilpivaara, Ulla Wartiovaara‐Kautto, Department of Oncology, ATG - Applied Tumor Genomics, Department of Medical and Clinical Genetics, HUS Comprehensive Cancer Center, Hematologian yksikkö, Research Programs Unit, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Digital Precision Cancer Medicine (iCAN), Clinicum, HUS Diagnostic Center, and HUSLAB
Subjects: 3122 Cancers
Published: 2022
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33. Survival trends in patients diagnosed with colon and rectal cancer in the nordic countries 1990–2016: The NORDCAN survival studies

Author: Frida E. Lundberg, Helgi Birgisson, Tom B. Johannesen, Gerda Engholm, Anni Virtanen, David Pettersson, Elínborg J. Ólafsdóttir, Mats Lambe, Paul C. Lambert, Lina S. Mørch, Anna L.V. Johansson, Therese M.-L. Andersson, HUSLAB, University of Helsinki, Department of Pathology, and HUS Diagnostic Center
Subjects: Male, FLEXIBLE PARAMETRIC MODELS, Cancer Research, Survival, Colon, Colonic neoplasms, RELATIVE SURVIVAL, 3122 Cancers, Rectal neoplasms, Comparison, Scandinavian and Nordic Countries, Age Distribution, REGISTRIES, Risk Factors, Nordic cancer registries, MANAGEMENT, Humans, Rectal cancer, Child, NORDCAN, Incidence, DEATH, PATHWAYS, Survival Analysis, TIME, Survival Rate, colon cancer, Oncology, DENMARK, END, Female, 3111 Biomedicine
Abstract: Background: Survival of patients with colon and rectal cancer has improved in all Nordic countries during the past decades. The aim of this study was to further assess survival trends in patients with colon and rectal cancer in the Nordic countries by age at diagnosis and to present additional survival measures. Methods: Data on colon and rectal cancer cases diagnosed in the Nordic countries between 1990 and 2016 were obtained from the NORDCAN database. Relative survival was estimated using flexible parametric models. Both age-standardized and age-specific measures for women and men were estimated from the models, as well as reference-adjusted crude probabilities of death and life-years lost. Results: The five-year age-standardized relative survival of colon and rectal cancer patients continued to improve for women and men in all Nordic countries, from around 50% in 1990 to about 70% at the end of the study period. In general, survival was similar across age and sex. The largest improvement was seen for Danish men and women with rectal cancer, from 41% to 69% and from 43% to 71%, respectively. The age-standardized and reference-adjusted five-year crude probability of death in colon cancer ranged from 30% to 36% across countries, and for rectal cancer from 20% to 33%. The average number of age-standardized and reference-adjusted life-years lost ranged between six and nine years. Conclusion: There were substantial improvements in colon and rectal cancer survival in all Nordic countries 1990-2016. Of special note is that the previously observed survival disadvantage in Denmark is no longer present. (C) 2022 The Author(s). Published by Elsevier Ltd.
Published: 2022
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34. Evaluation of in vitro and in vivo personalized cancer treatment assays for oral squamous cell carcinoma

Author: Wafa Wahbi, Katja Korelin, Meri Sieviläinen, Peeter Karihtala, Tommy Wilkman, Jussi Tarkkanen, Tuula Salo, Ahmed Al-Samadi, Department of Oral and Maxillofacial Diseases, HUS Head and Neck Center, Clinicum, Department of Oncology, Helsinki University Hospital Area, Faculty Common Matters (Faculty of Medicine), HUSLAB, Department of Pathology, Faculty of Medicine, and TRIMM - Translational Immunology Research Program
Subjects: Microfluidic chip, Cancer Research, Oncology, Oral cancer, 3122 Cancers, Myogel, Personalized medicine, Zebrafish
Abstract: Publisher Copyright: © 2023 Background: Oral squamous cell carcinoma (OSCC) is a common cancer with a high heterogeneity and few approved treatments. OSCC is one of the least explored areas for precision oncology. In this study, we aimed to test the reliability of our three established rapid cancer systemic treatment-testing assays: human tumour-derived matrix (Myogel)-coated well-plates, zebrafish xenografts, and 3D microfluidic chips. Methods: Chemo-, radio- and targeted-therapy testing in Myogel-coated wells and zebrafish xenografts was conducted nine times using five samples; two primary and three metastatic lymph node samples from three OSCC patients. Peripheral blood mononuclear cells (PBMNCs) were isolated from the patients’ blood. The response of the tumour cells to radio-, chemo-, and targeted therapy was tested using Myogel-coated wells and zebrafish larvae xenografts. The tumour cells’ response to immunotherapy was tested using 3D microfluidic chips. The cells’ sensitivity to the treatments was compared with the patients’ clinical response. Primary and metastatic lymph node tissue-derived DNA samples from two patients underwent whole exome sequencing to compare the mutational profiles of the samples. Results: Test results were in line with patients’ responses in 7/9 (77%) zebrafish xenograft assays and 5/9 (55%) Myogel-coated wells assays. Immunotherapy testing was done using one metastatic patient sample which matched the patients’ response. Differences in responses to treatments between primary and metastatic samples of the same patient were detected in 50% of the zebrafish larvae assays. Conclusions: Our results show the potential of using personalized cancer treatment testing assays – specifically zebrafish xenografts that revealed promising results – in OSCC patient samples.
Published: 2023

35. Long-term outcome of vestibular function and hearing in children with congenital cytomegalovirus infection : a prospective cohort study

Author: Eeva Kokkola, Riina Niemensivu, Maija Lappalainen, Maarit Palomäki, Tea Nieminen, Suresh Boppana, Harri Saxèn, Laura Puhakka, HUS Children and Adolescents, Children's Hospital, HUS Head and Neck Center, Korva-, nenä- ja kurkkutautien klinikka, Clinicum, HUSLAB, Department of Virology, HUS Diagnostic Center, HUS Medical Imaging Center, and Department of Diagnostics and Therapeutics
Subjects: Sensorineural hearing loss, Otorhinolaryngology, Congenital cytomegalovirus infection, The video head impulse test, General Medicine, 3125 Otorhinolaryngology, ophthalmology, Vestibular dysfunction
Abstract: Purpose Congenital cytomegalovirus infection (cCMV) is the most frequent nonhereditary cause for sensorineural hearing loss (SNHL) in children. Data on vestibular function in children with cCMV are, however, scarce, although some evidence for cCMV-associated vestibular dysfunction exists. In this prospective cohort study, we evaluated long-term vestibular function and hearing outcomes in a cohort of children with cCMV. Methods Participants were 6–7-year-old children with cCMV from a large population-based screening study. Controls were age and gender matched healthy children, who were CMV-negative at birth. Hearing was examined with pure tone audiometry. Definition of hearing loss was pure-tone average > 20 dB. Vestibular function was assessed using the video head impulse test that provides a measure of semicircular canal function. Definition of vestibular dysfunction was lateral semicircular canal gain Results Vestibular dysfunction occurred in 7/36 (19.4%) of children with cCMV and in 1/31 (3.2%) of controls (p = 0.060). SNHL was recorded in 4/38 (10.5%) of children with cCMV and in 0/33 of controls (p = 0.118). Hearing loss was unilateral in all cases. In cCMV group, the two children with bilateral vestibular dysfunction also had SNHL, whereas those with unilateral vestibular dysfunction (n = 5) had normal hearing. Conclusions In this cohort of children with cCMV identified using newborn screening, vestibular dysfunction was more common than SNHL at 6 years of age. Vestibular dysfunction occurred both in children with and without SNHL. Based on these data, inclusion of vestibular tests in follow-up protocol of cCMV should be considered.
Published: 2023

36. The roles of proteases in prostate cancer : , Mount Sinai Hospital

Author: Koistinen, Hannu, Kovanen, Ruusu-Maaria, Hollenberg, Morley D., Dufour, Antoine, Radisky, Evette S., Stenman, Ulf-Håkan, Batra, Jyotsna, Clements, Judith, Hooper, John D., Diamandis, Eleftherios, Schilling, Oliver, Rannikko, Antti, Mirtti, Tuomas, Research Programs Unit, Department of Clinical Chemistry and Hematology, Helsinki University Hospital Area, Medicum, HUS Abdominal Center, Clinicum, Urologian yksikkö, Department of Surgery, Research Program in Systems Oncology, HUSLAB, Department of Pathology, and HUS Diagnostic Center
Subjects: Notch, Prostate cancer, Protease-activated receptor, Mmp, Fibroblast activation protein, Klk, Fap, CUB domain-containing protein 1, Proteases, Androgen, Kallikrein-related peptidases, Matrix metalloproteinase, Androgen receptor, Tmprss2, Hepsin, Cdcp1, uPA, 1182 Biochemistry, cell and molecular biology, Trypsin, Urokinase-type plasminogen activator, Par, Peptidases, Matriptase, Ar
Abstract: Since the proposition of the pro-invasive activity of proteolytic enzymes over 70 years ago, several roles for proteases in cancer progression have been established. About half of the 473 active human proteases are expressed in the prostate and many of the most well-characterized members of this enzyme family are regulated by androgens, hormones essential for development of prostate cancer. Most notably, several kallikrein-related peptidases, including KLK3 (prostate-specific antigen, PSA), the most well-known prostate cancer marker, and type II transmembrane serine proteases, such as TMPRSS2 and matriptase, have been extensively studied and found to promote prostate cancer progression. Recent findings also suggest a critical role for proteases in the development of advanced and aggressive castration-resistant prostate cancer (CRPC). Perhaps the most intriguing evidence for this role comes from studies showing that the protease-activated transmembrane proteins, Notch and CDCP1, are associated with the development of CRPC. Here, we review the roles of proteases in prostate cancer, with a special focus on their regulation by androgens.
Published: 2023

37. Maternal SSRI use during pregnancy and offspring depression or anxiety disorders : A review of the literature and description of a study protocol for a register-based cohort study

Author: Upadhyaya, Subina, Brown, Alan, Cheslack-Postava, Keely, Gissler, Mika, Gyllenberg, David, Heinonen, Emmi, Laitinen, Joonas, McKeague, Ian, Hinkka-Yli-Salomäki, Susanna, Sourander, Andre, Tornio, Aleksi, Malm, Heli, HUS Children and Adolescents, Lastenpsykiatria, Children's Hospital, HUSLAB, HUS Emergency Medicine and Services, Department of Diagnostics and Therapeutics, Clinicum, Research Programs Unit, and INDIVIDRUG - Individualized Drug Therapy
Subjects: Offspring, Depression, Pregnancy, 3123 Gynaecology and paediatrics, Ssri, Maternal, Anxiety, 3124 Neurology and psychiatry
Abstract: Previous studies examining the relationship between in utero exposure to selective serotonin reuptake inhibitors (SSRI) and long-term offspring depressive or anxiety behaviors are inconclusive. We aimed to critically review the findings of previous studies and describe a new study protocol to investigate the association of prenatal SSRI exposure and offspring depression or anxiety using data from several Finnish national registers. The study includes 1,266,473 mothers and their live-born singleton offspring, born in 1996-2018. The study cohorts include the prenatally SSRI exposed group and three comparison groups: 1) depression exposed/antidepressants unexposed, 2) unexposed to antidepressants or antipsychotics and depression, and 3) discordant siblings. We aim to examine whether depression in prenatally SSRI exposed children is more common or severe than depression in the offspring of mothers with depression but without SSRI exposure. We aim to disambiguate the effects of maternal SSRI from the effects of maternal depression, severity of maternal depression and familial loading history of psychiatric disorders by including data from first-degree relatives of prenatally SSRI exposed and unexposed children. Associations between exposure and outcome are assessed by statistical modeling, accounting for within-family correlation. The study has potential public health significance and in guiding clinicians in considering treatment options for pregnant women.
Published: 2023

38. Changing Immunochemistry Platforms: Thyroid Function Test Comparison and Reference Intervals Based on Clinical Needs

Author: Jonna Pelanti, Tea Lamberg, Titta Salopuro, Christel Pussinen, Janne Suvisaari, Lotta Joutsi-Korhonen, Camilla Schalin-Jäntti, Outi Itkonen, Mikko Anttonen, Department of Diagnostics and Therapeutics, Helsinki University Hospital Area, HUSLAB, Clinicum, University of Helsinki, HUS Abdominal Center, and Endokrinologian yksikkö
Subjects: Thyroxine, Thyroid Hormones, FREE-THYROXINE, Immunochemistry, Humans, Thyrotropin, HORMONES, 3111 Biomedicine, General Medicine, Thyroid Function Tests
Abstract: Background Diagnosis of thyroid dysfunction relies on thyroid stimulating hormone (TSH), free thyroxine (FT4), and free tri-iodothyronine (FT3) tests against valid reference intervals (RIs). We changed the immunoassay platform from Abbott Architect to Siemens Atellica and aimed to establish Atellica RIs based on laboratory information system (LIS) patient data. Methods Atellica thyroid hormone immunoassays were verified against those of Architect. Real-life patient results were retrieved from LIS. A single result per patient dataset was used to establish the RIs by the indirect method. Results Atellica and Architect assays correlated well but Atellica showed a positive bias between 13% and 53%, the largest for FT4. Variations of the Atellica assays were ≤4%. The 95% Atellica RIs were 0.4–3.8 mU/L for TSH, 0.9–1.6 ng/dL for FT4, and 227–416 pg/dL for FT3. Considering the accumulating clinical experience with Atellica, the RIs for clinical use were adjusted as 0.5–4.0 mU/L, 0.9–1.8 ng/dL, and 169–409 pg/dL, respectively. Conclusions We verified thyroid hormone RIs for Atellica by the indirect method for the first time. Our model proved reliable for selecting results of presumably healthy individuals from LIS data. Critical review of the RIs with local endocrinologists is essential.
Published: 2022
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39. Cardiac sarcoidosis and giant cell myocarditis after COVID‐19 infection

Author: Entela Bollano, Christian Lars Polte, Mikko I. Mäyränpää, Anders Oldfors, Niklas Bergh, Jukka Lehtonen, Riina Kandolin, HUSLAB, Department of Pathology, Helsinki University Hospital Area, HUS Heart and Lung Center, Kardiologian yksikkö, and Clinicum
Subjects: Cardiac sarcoidosis, Giant cell myocarditis, 3121 General medicine, internal medicine and other clinical medicine, COVID-19, Heart failure, Cardiology and Cardiovascular Medicine
Abstract: Patients infected with SARS-CoV-2 have varying manifestations of cardiac involvement. We report four patients presenting with symptomatic cardiac sarcoidosis (CS) or giant cell myocarditis (GCM) 1-8 months after mild COVID-19. All patients received immunosuppressive therapy and improved gradually within the following months. The possible temporal association between the CS/GCM and COVID-19 infection might suggest that COVID-19 could be a trigger for granulomatous myocarditis.
Published: 2022
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40. Maternal early-pregnancy body mass index-associated metabolomic component and mental and behavioral disorders in children

Author: Polina Girchenko, Marius Lahti-Pulkkinen, Jari Lipsanen, Kati Heinonen, Jari Lahti, Ville Rantalainen, Esa Hämäläinen, Hannele Laivuori, Pia M. Villa, Eero Kajantie, Katri Räikkönen, Department of Psychology and Logopedics, Developmental Psychology Research Group, Teachers' Academy, Medicum, HUSLAB, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, HUS Gynecology and Obstetrics, Children's Hospital, Lastentautien yksikkö, HUS Children and Adolescents, Tampere University, Welfare Sciences, Clinical Medicine, and Department of Gynaecology and Obstetrics
Subjects: Risk, Mothers, PROFILE, 3124 Neurology and psychiatry, Body Mass Index, SUPPLEMENTATION, DIET, Cellular and Molecular Neuroscience, INFLAMMATION, 3123 Gynaecology and paediatrics, Pregnancy, Humans, OXIDATIVE STRESS, AUTISM, Child, Molecular Biology, OUTCOMES, Mental Disorders, 3112 Neurosciences, RISKS, Psychiatry and Mental health, OBESITY, 1182 Biochemistry, cell and molecular biology, Female, HEALTH, 3111 Biomedicine
Abstract: Maternal pre-pregnancy obesity and/or higher body mass index (BMI) have been associated with neurodevelopmental and mental health adversities in children. While maternal metabolomic perturbations during pregnancy may underpin these associations, the existing evidence is limited to studying individual metabolites, not capturing metabolic variation specific to maternal BMI, and not accounting for the correlated nature of the metabolomic measures. By using multivariate supervised analytical methods, we first identified maternal early-pregnancy BMI-associated metabolomic component during pregnancy. We then examined whether this component was associated with mental and behavioral disorders in children, improved the prediction of the child outcomes over maternal BMI, and what proportion of the effect of maternal BMI on the child outcomes this component mediated. Early-pregnancy BMI of 425 mothers participating in the PREDO study was extracted from the national Medical Birth Register. During pregnancy, mothers donated up to three blood samples, from which a targeted panel of 68 metabolites were measured. Mental and behavioral disorders in children followed-up from birth until 8.4–12.8 years came from the Care Register for Health Care. Of the 68 metabolites averaged across the three sampling points, 43 associated significantly with maternal early-pregnancy BMI yielding a maternal early-pregnancy BMI-associated metabolomic component (total variance explained, 55.4%; predictive ability, 52.0%). This metabolomic component was significantly associated with higher hazard of any mental and behavioral disorder [HR 1.45, 95%CI(1.15, 1.84)] and relative risk of having a higher number of co-morbid disorders [RR 1.43, 95%CI(1.12, 1.69)] in children. It improved the goodness-of-model-fit over maternal BMI by 37.7–65.6%, and hence the predictive significance of the model, and mediated 60.8–75.8% of the effect of maternal BMI on the child outcomes. Maternal BMI-related metabolomic perturbations during pregnancy are associated with a higher risk of mental and behavioral disorders in children. These findings may allow identifying metabolomic targets for personalized interventions.
Published: 2022
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41. Clever-1 positive macrophages in breast cancer

Author: Minna Mutka, Reetta Virtakoivu, Kristiina Joensuu, Maija Hollmén, Päivi Heikkilä, Department of Pathology, HUSLAB, University of Helsinki, and Medicum
Subjects: EXPRESSION, Cancer Research, Macrophages, Tumor-associated macrophages, 3122 Cancers, Breast Neoplasms, CD8-Positive T-Lymphocytes, Prognosis, Tumor infiltrating lymphocytes, Lymphocytes, Tumor-Infiltrating, Breast cancer, Oncology, RECEPTOR STABILIN-1, SURVIVAL, Humans, Female, Tumor stroma, TUMOR-INFILTRATING LYMPHOCYTES, Clever-1, Lymphatic Vessels
Abstract: Purpose Common Lymphatic Endothelial and Vascular Endothelial Receptor 1 (Clever-1) is expressed by a subset of immunosuppressive macrophages and targeting the receptor with therapeutic antibodies has been shown to activate T-cell-mediated anti-cancer immunity. The aim of this research was to study Clever-1 expression in breast cancer. Specifically, how Clever-1 + macrophages correlate with clinicopathologic factors, Tumor Infiltrating Lymphocytes (TILs) and prognosis. Methods Tissue microarray blocks were made from 373 primary breast cancer operation specimens. Hematoxylin and Eosin (H&E-staining) and immunohistochemical staining with Clever-1, CD3, CD4 and CD8 antibodies were performed. Differences in quantities of Clever-1 + macrophages and TILs were analyzed. Clever-1 + cell numbers were correlated with 25-year follow-up survival data and with breast cancer clinicopathologic parameters. Results Low numbers of intratumoral Clever-1 + cells were found to be an independent adverse prognostic sign. Increased numbers of Clever-1 + cells were found in high grade tumors and hormone receptor negative tumors. Tumors that had higher amounts of Clever-1 + cells also tended to have higher amounts of TILs. Conclusion The association of intratumoral Clever-1 + macrophages with better prognosis might stem from the function of Clever as a scavenger receptor that modulates tumor stroma. The association of Clever-1 + macrophages with high number of TILs and better prognosis indicates that immunosuppression by M2 macrophages is not necessarily dampening adaptive immune responses but instead keeping them in control to avoid excess inflammation.
Published: 2022
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42. Characteristics of Patients in SPCG-15—A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer

Author: Magdalena Gongora, Johan Stranne, Eva Johansson, Matteo Bottai, Camilla Thellenberg Karlsson, Klaus Brasso, Steinbjørn Hansen, Henrik Jakobsen, Fredrik Jäderling, Henriette Lindberg, Wolfgang Lilleby, Peter Meidahl Petersen, Tuomas Mirtti, Mats Olsson, Antti Rannikko, Martin Andreas Røder, Per Henrik Vincent, Olof Akre, Research Program in Systems Oncology, HUSLAB, Department of Pathology, University of Helsinki, Digital Precision Cancer Medicine (iCAN), HUS Abdominal Center, Clinicum, Urologian yksikkö, and Department of Surgery
Subjects: Quality of life, Cancer och onkologi, Curative treatment, Radiotherapy, Urology, Randomized, NATIONWIDE, 3126 Surgery, anesthesiology, intensive care, radiology, Radical prostatectomy, Locally advanced prostate cancer, Cancer and Oncology, Urologi och njurmedicin, SURVIVAL, Urology and Nephrology, Prostatic neoplasms, Androgen deprivation
Abstract: Background: There is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. Objective: To describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design, setting, and participants: This study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. Intervention: Radical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysis: Cause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitations: The distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45-75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. Conclusions: We have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summary: This study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology.
Published: 2022
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43. Glutamine synthetase in human carotid plaque macrophages associates with features of plaque vulnerability: An immunohistological study

Author: Pia Sorto, Mikko I. Mäyränpää, Jani Saksi, Krista Nuotio, Petra Ijäs, Jarno Tuimala, Pirkka Vikatmaa, Lauri Soinne, Petri T. Kovanen, Perttu J. Lindsberg, Helsinki University Hospital Area, Department of Neurosciences, HUSLAB, Department of Pathology, HUS Neurocenter, Neurologian yksikkö, Research Programs Unit, Perttu Lindsberg / Principal Investigator, Clinicum, HUS Abdominal Center, and Verisuonikirurgian yksikkö
Subjects: EXPRESSION, Iron, Glutamate-Ammonia ligase, METABOLISM, 3124 Neurology and psychiatry, DISEASE, Glutamine synthetase, ACTIVATION, Carotid atherosclerosis, Humans, Carotid Stenosis, RNA, Messenger, RISK, Endarterectomy, Carotid, Macrophages, 3112 Neurosciences, PATHWAYS, Atherosclerosis, Fibrosis, Plaque, Atherosclerotic, APOPTOSIS, Stroke, Fibrous cap, GLUL, CELLS, Cardiology and Cardiovascular Medicine, Heme Oxygenase-1
Abstract: Publisher Copyright: © 2022 The Authors Background and aims: Glutamine synthetase (GLUL), the sole generator of glutamine, is a metabolic nexus molecule also involved in atherosclerosis. We recently demonstrated a 2.2-fold upregulation of GLUL mRNA in stroke-causing carotid plaques when compared with plaques from asymptomatic patients. Here we compared in the same cohort GLUL mRNA expression with plaque gross morphology, and the colocalization of immunodetectable GLUL protein with histopathological changes and molecular and mechanical mediators linked to plaque development. Methods: Endarterectomy specimens from 19 asymptomatic and 24 stroke patients were sectioned longitudinally and immunostained for GLUL, CD68, α-smooth muscle actin, iron, heme oxygenase-1 and CD163, and graded semiquantitatively in every 1 mm2. The amounts of cholesterol clefts and erythrocytes were graded. The fibrous cap thickness within each 1 mm2 area was measured. The association between the local pathological findings was analyzed by a hierarchical mixed modelling approach. Results: The previously found correlation between GLUL mRNA and clinical symptomatology was supported by the increased GLUL mRNA in diseased tissue and increased local GLUL immunoreactivity in areas with multiple different atherosclerotic changes. A longer symptom-to-operation time correlated with lower GLUL mRNA (Rs = −0.423, p=0.050) but few outliers had a significantly higher GLUL mRNA levels, which persisted throughout the post-symptomatic period. Plaque ulceration associated with 1.8-fold higher GLUL mRNA (p=0.006). Macrophages were the main GLUL immunoreactive cells. GLUL immunostaining colocalized with erythrocytes, iron, CD163, and heme oxygenase-1. The correlations between local variables were consistent in both asymptomatic and stroke-causing plaques. An inverse correlation was found between the fibrous cap thickness and local GLUL immunoreactivity (p=0.012). Considerable variability in interplaque expression pattern of GLUL was present. Conclusions: Our results link connect macrophage GLUL expression with carotid plaque features characterizing plaque vulnerability.
Published: 2022
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44. Human papillomavirus self‐sampling with <scp>mRNA</scp> testing benefits routine screening

Author: Eeva Auvinen, Pekka Nieminen, Jukka Pellinen, Joakim Dillner, Jussi Tarkkanen, Anni Virtanen, Medicum, Eeva Auvinen / Principal Investigator, HUSLAB, Department of Virology, University of Helsinki, HUS Diagnostic Center, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, and Department of Pathology
Subjects: Vaginal Smears, HPV, Cancer Research, Aptima, mRNA, Papillomavirus Infections, PARTICIPATION, 3122 Cancers, Uterine Cervical Neoplasms, opt-in, self-sampling, WOMEN, Alphapapillomavirus, Uterine Cervical Dysplasia, COVERAGE, Specimen Handling, ATTENDANCE, Oncology, Humans, Mass Screening, Female, RNA, Messenger, Papillomaviridae, Early Detection of Cancer
Abstract: High risk human papillomavirus (hrHPV) based screening provides the possibility of vaginal self-sampling as a tool to increase screening attendance. In order to evaluate the impact and feasibility of opt-in self-sampling in the Finnish setting, we invited a randomized population of 5350 women not attending screening after age group invitation or after reminder, to attend HPV self-sampling-based screening in the autumn of 2018 in Helsinki. Out of those, 1282 (24.0%) expressed their interest and ordered the sampling package. Eventually 787 women (14.7% of the total invited population) took part in screening, 770 women by providing a vaginal sample within 2 months from invitation and 17 by providing a pap smear in the laboratory. Self-taken samples were collected in Aptima Multitest vials and tested using the Aptima HPV mRNA assay. A high proportion, 158/770 (20.5%) of the samples were positive in the Aptima HPV assay. One hundred and forty-one samples were further submitted to Aptima HPV Genotyping and extended genotyping by a Luminex based assay. Of those, 23 samples (16.3%) were HPV 16 positive and 7 (5.0%) were positive for HPV 18/45; extended genotyping revealed multiple high-risk and low-risk HPV genotypes. At follow-up seven cases of high-grade squamous intraepithelial lesion (HSIL) were diagnosed, which represents 4.4% of HPV positive women and 0.9% of screened women, whereas the rate was 0.5% in routine screening. Our findings suggest that self-sampling with HPV mRNA testing is a feasible approach to improve screening efficacy in a high-risk population among original nonattendees.
Published: 2022
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45. TCGA molecular classification in endometriosis-associated ovarian carcinomas: Novel data on clear cell carcinoma

Author: Jonna Similä-Maarala, Piret Soovares, Annukka Pasanen, Terhi Ahvenainen, Pia Vahteristo, Ralf Bützow, Heini Lassus, HUSLAB, Department of Pathology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, University of Helsinki, ATG - Applied Tumor Genomics, Medicum, Department of Medical and Clinical Genetics, Digital Precision Cancer Medicine (iCAN), Biosciences, and Clinicum
Subjects: Ovarian Neoplasms, Endometrioid, p53, 3122 Cancers, Endometriosis, Obstetrics and Gynecology, MMR, Endometrial Neoplasms, Oncology, 3123 Gynaecology and paediatrics, Mutation, POLE, Biomarkers, Tumor, Humans, Female, Tumor Suppressor Protein p53, Ovarian carcinoma, Carcinoma, Endometrioid, Clear cell, Adenocarcinoma, Clear Cell
Abstract: Publisher Copyright: © 2022 The Authors Background: Clear cell and endometrioid ovarian carcinomas (OCC and OEC, respectively) have a presumed origin in endometriosis and share molecular alterations with each other and with their endometrial counterparts. The Cancer Genome Atlas (TCGA)-based molecular classification stratifies endometrial carcinomas into four categories: POLE mutated (POLEmut), mismatch repair deficient (MMRd), p53 abnormal (p53abn) and no specific molecular profile (NSMP) with divergent prognoses. The subsequent studies are indicative that this TCGA classification has some value in OEC, but the knowledge related to OCC is limited. Methods: Endometrial carcinoma molecular classification was evaluated and compared in a large series of OCCs (n = 115) and OECs (n = 158). POLE mutation analysis and tissue microarray-based immunohistochemistry for mismatch repair and p53 proteins were performed. Results: The distribution to the molecular groups was as follows: POLEmut 0.9%/3.2%, MMRd 3.5%/6.3%, p53abn 20%/30%, and NSMP 76%/60% in OCCs/OECs, respectively. The proportion of NSMP tumors was the largest in both histological types and significantly higher in OCC than OEC (p = 0.009). The molecular classification correlated significantly with DSS in both OCCs and OECs (p < 0.001 and p = 0.009, respectively), and with DFS in OCCs (p = 0.001). POLEmut and MMRd OCCs carried excellent prognosis, whereas MMRd OECs presented with poorer outcome. The p53abn group was associated with the poorest prognosis in both tumor types, particularly emphasized in OCCs. Conclusions: TCGA molecular classification associated with patient outcome in both histotypes, and the difference in prognosis between the molecular groups was even more marked in OCC. The large amount of NSMP tumors highlights the need for further studies.
Published: 2022
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46. X‐linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus

Author: Laura M. Tanner, Olli Tynninen, Kirsi Piippo, Antti M. Puhakka, Department of Medical and Clinical Genetics, Medicum, HUS Diagnostic Center, HUS Helsinki and Uusimaa Hospital District, HUSLAB, Department of Pathology, Pregnancy and Genes, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: 3123 Gynaecology and paediatrics, Spectrum, Obstetrics and Gynecology, Genetics (clinical)
Abstract: We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities.
Published: 2023
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47. Female doping: observations from a data lake study in the Hospital District of Helsinki and Uusimaa, Finland

Author: Vauhkonen, Paula Katriina, Laajala, Teemu Daniel, Lindroos, Katarina Mercedes, Mäyränpää, Mikko Ilari, Faculty of Medicine, HUSLAB, Department of Pathology, and HUS Helsinki and Uusimaa Hospital District
Subjects: Substance abuse, Reproductive Medicine, Specialized health care, Doping, Obstetrics and Gynecology, Women, General Medicine, Anabolic androgenic steroids, Morbidity, 3142 Public health care science, environmental and occupational health
Abstract: Background Doping is a well-recognized risk factor for several potentially severe health effects. Scientific literature concerning the need for medical treatment for such adversities is still sparse. This is especially true for women, due to lower doping use prevalence compared to men. Our study explored the nature of medical contacts and deviance in red blood cell parameters of female patients with doping use in Finnish specialized health care. Methods This was a retrospective register study. The study sample was gathered from the Hospital District of Helsinki and Uusimaa, Finland (HUS) Datalake. An exhaustive search for doping related terms was performed to find patients with doping use documentation within free-text patient records. Medical record data was supplemented with laboratory data and medical diagnoses covering a total observation time of two decades. Statistical analysis included Fisher's Exact Test and one-way ANOVA. Results We found 39 female patients with history of doping use and specialized health care contacts in the HUS-area between 2002–2020. At initial contact (i.e., the first documentation of doping use), the mean age of these patients was 33.6 years (min 18.1, max 63.5, SD 10.6). The most frequently used doping agents were anabolic androgenic steroids (AAS). The initial contacts were significantly more often acute in nature among patients with active doping use than among patients with only previous use (no use within one year; p = 0.002). Psychiatric and substance use disorder (SUD) morbidity was high (46.2% and 30.8%, respectively). Eight patients (20.5%) had received specialized health care for acute poisoning with alcohol or drugs, and nine (23.1%) for bacterial skin infections. Less than 45% of patients with active AAS use presented with off-range red blood cell parameters. Conclusions Our findings suggest that female patients with a history of doping use encountered in specialized health care may exhibit high psychiatric and SUD related morbidity. Also, majority of patients with AAS use had red blood cell parameters within-range. Further studies are required to assess the generalizability of these findings to patients within primary health care services, and to determine the usefulness of hematological parameters as indicators of AAS use in female patients.
Published: 2023
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48. Persistent oral mucosal lesions preceding diagnosis of Crohn's disease and primary sclerosing cholangitis

Author: Karita Nylund, Jaana Helenius‐Hietala, Fredrik Åberg, Jaana Hagström, Hellevi Ruokonen, HUS Head and Neck Center, Department of Oral and Maxillofacial Diseases, Helsinki University Hospital Area, Clinicum, HUS Abdominal Center, IV kirurgian klinikka, HUSLAB, Medicum, Research Programs Unit, and Department of Pathology
Subjects: Gastroenterology and hepatology, Dentistry, 3121 General medicine, internal medicine and other clinical medicine, Oral medicine, General Medicine, inflammatory bowel disease (IBD)
Abstract: Oral mucosal lesions may persist years before symptoms or diagnosis of inflammatory bowel disease (IBD) and subsequent primary sclerosing cholangitis (PSC). Since a dental practitioner may be the first clinician to suspect IBD with extraintestinal manifestations (EIMs), early referral, and close collaboration with a gastroenterologist are recommended.
Published: 2023
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49. SARS-CoV-2 Infection of Human Neurons Is TMPRSS2 Independent, Requires Endosomal Cell Entry, and Can Be Blocked by Inhibitors of Host Phosphoinositol-5 Kinase

Author: Pinja Kettunen, Angelina Lesnikova, Noora Räsänen, Ravi Ojha, Leena Palmunen, Markku Laakso, Šárka Lehtonen, Johanna Kuusisto, Olli Pietiläinen, Saber H. Saber, Merja Joensuu, Olli P. Vapalahti, Jari Koistinaho, Taisia Rolova, Giuseppe Balistreri, Neuroscience Center, Helsinki Institute of Life Science HiLIFE, Department of Virology, Research Programs Unit, Veterinary Biosciences, Veterinary Microbiology and Epidemiology, Helsinki One Health (HOH), Viral Zoonosis Research Unit, HUSLAB, Olli Pekka Vapalahti / Principal Investigator, and Division of Pharmacology and Pharmacotherapy
Subjects: 11832 Microbiology and virology, iPSC, SARS-CoV-2, Immunology, Brain, Neuron, Microbiology, Apilimod, Virology, Insect Science, Pik5, Covid-19, Astrocyte, long COVID, Central nervous system infections
Abstract: 2019 coronavirus disease (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition to respiratory illness, COVID-19 patients exhibit neurological symptoms lasting from weeks to months (long COVID). It is unclear whether these neurological manifestations are due to an infection of brain cells. We found that a small fraction of human induced pluripotent stem cell (iPSC)-derived neurons, but not astrocytes, were naturally susceptible to SARS-CoV-2. Based on the inhibitory effect of blocking antibodies, the infection seemed to depend on the receptor angiotensin-converting enzyme 2 (ACE2), despite very low levels of its expression in neurons. The presence of double-stranded RNA in the cytoplasm (the hallmark of viral replication), abundant synthesis of viral late genes localized throughout infected cells, and an increase in the level of viral RNA in the culture medium (viral release) within the first 48 h of infection suggested that the infection was productive. Productive entry of SARS-CoV-2 requires the fusion of the viral and cellular membranes, which results in the delivery of the viral genome into the cytoplasm of the target cell. The fusion is triggered by proteolytic cleavage of the viral surface spike protein, which can occur at the plasma membrane or from endosomes or lysosomes. We found that SARS-CoV-2 infection of human neurons was insensitive to nafamostat and camostat, which inhibit cellular serine proteases, including transmembrane serine protease 2 (TMPRSS2). Inhibition of cathepsin L also did not significantly block infection. In contrast, the neuronal infection was blocked by apilimod, an inhibitor of phosphatidyl-inositol 5 kinase (PIK5K), which regulates early to late endosome maturation.IMPORTANCE COVID-19 is a disease caused by the coronavirus SARS-CoV-2. Millions of patients display neurological symptoms, including headache, impairment of memory, seizures, and encephalopathy, as well as anatomical abnormalities, such as changes in brain morphology. SARS-CoV-2 infection of the human brain has been documented, but it is unclear whether the observed neurological symptoms are linked to direct brain infection. The mechanism of virus entry into neurons has also not been characterized. Here, we investigated SARS-CoV-2 infection by using a human iPSC-derived neural cell model and found that a small fraction of cortical-like neurons was naturally susceptible to infection. The productive infection was ACE2 dependent and TMPRSS2 independent. We also found that the virus used the late endosomal and lysosomal pathway for cell entry and that the infection could be blocked by apilimod, an inhibitor of cellular PIK5K.
Published: 2023

50. A comprehensive assessment of four whole blood stabilizers for flow-cytometric analysis of leukocyte populations

Author: Ngoc Anh Nguyen, Xiaobo Huang, Luz E. Cabrera, Pirkka T. Pekkarinen, Kirsten Nowlan, Tomas Strandin, Anu Kantele, Olli Vapalahti, Santtu Heinonen, Eliisa Kekäläinen, TRIMM - Translational Immunology Research Program, Department of Bacteriology and Immunology, Viral Zoonosis Research Unit, University of Helsinki, Department of Virology, Research Programs Unit, Anestesiologian yksikkö, HUS Perioperative, Intensive Care and Pain Medicine, Department of Medicine, HUS Inflammation Center, Clinicum, HUMI - Human Microbiome Research, Infektiosairauksien yksikkö, Helsinki One Health (HOH), HUSLAB, Veterinary Microbiology and Epidemiology, Veterinary Biosciences, Olli Pekka Vapalahti / Principal Investigator, HUS Diagnostic Center, Children's Hospital, Faculty of Medicine, Helsinki University Hospital Area, HUS Children and Adolescents, and Medicum
Subjects: MONONUCLEAR-CELLS, Histology, flow cytometry, whole blood, whole blood stabilizer, COVID-19, Cell Biology, CRYOPRESERVATION, Pathology and Forensic Medicine, ACTIVATION, immunophenotyping, method, VISUALIZATION, 1182 Biochemistry, cell and molecular biology, FIXATION, INACTIVATION, FORMALDEHYDE, 3111 Biomedicine, GRANULOCYTE, RESPONSES
Abstract: Though cryopreservation of cell fractions is widely used in flow cytometry studies, whole blood cryopreservation is more challenging due to the presence of erythrocytes and effects of fixatives commonly used for preservation. Here, we evaluated and compared head-to-head the performance of four commercial whole blood cryopreservation kits; (1) Cytodelics, (2) Stable-Lyse V2 and Stable-Store V2 (SLSS-V2), (3) Proteomic stabilizer (PROT-1), and (4) Transfix. We found that PROT-1, Transfix, and Cytodelics maintained the distribution of major leukocyte subsets-granulocytes, T cells, natural killer cells, and B cells, on a comparable level to unpreserved samples, despite the attenuation of fluorescence intensities in flow cytometric assays. Moreover, these three stabilizers also maintained the activated phenotypes of neutrophils upon stimulation with N-formylmethionyl-leucyl-phenylalanine and lipopolysaccharides. The upregulation of adhesion molecules (CD11b), Fc receptors (CD16), and granule proteins (CD66b), as well as the shedding of surface L-selectin (CD62L), was conserved most efficiently in PROT-1 and Cytodelics when compared to samples only treated with erythrocyte lysing. However, none of the stabilizers provided a reliable detection of CCR7 for accurate quantification of T cell maturation stages. We also evaluated the performance of Cytodelics in longitudinal clinical samples obtained from acute COVID-19 patients, where it allowed reliable detection of lymphopenia and granulocyte expansion. These results support the feasibility of whole blood cryopreservation for immunophenotyping by flow cytometry, particularly in longitudinal studies. In conclusion, the performance of different stabilizers is variable and therefore the choice of stabilizers should depend on cell type of interest, as well as antibody clones and experimental design of each study.
Published: 2023

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