Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia

The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients' CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.Peer reviewe

Introduction and Rapid Spread of SARS-CoV-2 Omicron Variant and Dynamics of BA.1 and BA.1.1 Sublineages, Finland, December 2021

Multiple introductions of SARS-COV-2 Omicron variant BA.1 and BA.1.1. lineages to Finland were detected in early December 2021. Within 3 weeks, Omicron overtook Delta as the most common variant in the capital region. Sequence analysis demonstrated the emergence and spread through community transmission of a large cluster of BA.1.1 virus.Peer reviewe

Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4(+) T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n=134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4(+) T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies. Chronic graft versus host disease (cGvHD) is a major cause of morbidity and mortality in allogeneic bone marrow transplantation. Here the authors identify a recurrent activating mTOR mutation in expanded donor T-cell clones of 3 cGvHD patients, which suggests somatic mutations may contribute to GvHD pathogenesis and opens avenues to targeted therapies.Peer reviewe

The phylodynamics of SARS-CoV-2 during 2020 in Finland

Finland has had a low incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infections as compared to most European countries. Here we report the origins and turnover of SARS-CoV-2 lineages circulating in Finland in 2020. SARS-CoV-2 introduced to Finland in January 2020 and spread rapidly across southern Finland during spring. We observed rapid turnover among Finnish lineages during this period. Clade 20C became the most prevalent among sequenced cases and was replaced by other strains in fall 2020. Bayesian phylogeographic reconstructions suggested 42 independent introductions into Finland during spring 2020, mainly from Italy, Austria, and Spain, which might have been the source for a third of cases. The investigations of the original introductions of SARS-CoV-2 to Finland during the early stages of the pandemic and of the subsequent lineage dynamics could be utilized to assess the role of transboundary movements and effects of early intervention and public health measures.Peer reviewe

Working people with type 1 diabetes in the Finnish population

Peer reviewe

Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4+ T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4+ T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.</p

Lääkehoito Jokilaakson Perhekodeissa: Lääkehoidon opas henkilökunnalle

Nuorten hyvinvointi ja mielenterveyden ongelmat ovat ajankohtainen ja puhuttava aihe, joka on ollut pinnalla viime vuosien aikana. Lääkehoito sosiaalialan palveluyksiköissä on yleistynyt ja sitä kautta tarvitaan myös enemmän lääkehoidon osaamista kyseisissä yksiköissä. Lastensuojeluyksiköissä useat lapset ja nuoret oireilevat psyykkisesti ja monilla heistä on käytössä psyykelääkkeitä. Tämän opinnäytetyön tilaajana oli sosiaalialan palveluita tuottava Jokilaakson perhekodit Oy, jonka henkilökunnalle toteutettiin kysely lääkehoidon toteutuksesta työyksiköissä. Tutkimuksen tarkoituksena oli kartoittaa Jokilaakson perhekodit Oy:n henkilökunnan lääkehoidon osaamista ja sen toteutuksen haasteita. Tutkimuksessa käytettiin sekä kvalitatiivisia että kvantitatiivisia menetelmiä. Kyselyn pohjalta henkilökunnan käyttöön laadittiin lääkehoidon opas, joka tulee käyttöön Jokilaakson perhekotien jokaiseen yksikköön. Aineisto kerättiin Webropolohjelman avulla ja kysely lähetettiin jokaiselle henkilökunnan vakituiselle tai pitkäaikaiselle jäsenelle (92 henkilöä). Kyselyn vastausprosentti oli 39,1 %. Kyselystä kävi ilmi, että suurimmat haasteet henkilökunnan mielestä olivat esimerkiksi lääkkeiden yhteisvaikutuksissa, sivuvaikutuksissa sekä yhteisvaikutuksissa lääkkeiden ja päihteiden välillä. Lisäksi kyselyn vastauksista koostui henkilökunnan mielestä tarve lääkehoidon ohjeiden ja käytänteiden selkeydestä. Näistä vastauksista saatiin informaatiota henkilökunnan lääkehoidon opasta varten ja tämä koostettiin tutkimustulosten pohjalta. Opinnäytetyön tuotoksena valmistui lääkehoidon opas Jokilaakson perhekotien henkilökunnalle ja se tulee tulevaisuudessa toimimaan henkilökunnan työkaluna lääkehoidon toteutuksessa. Lisäksi opas tulee osaksi Jokilaakson perhekotien uuden henkilökunnan perehdytysohjelmaa

Ennusteet auttavat näkemään pidemmälle

vokpka ks