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

Role of MAPT mutations and haplotype in frontotemporal lobar degeneration in Northern Finland

<p>Abstract</p> <p>Background</p> <p>Frontotemporal lobar degeneration (FTLD) consists of a clinically and neuropathologically heterogeneous group of syndromes affecting the frontal and temporal lobes of the brain. Mutations in microtubule-associated protein tau (<it>MAPT</it>), progranulin (<it>PGRN</it>) and charged multi-vesicular body protein 2B (<it>CHMP2B</it>) are associated with familial forms of the disease. The prevalence of these mutations varies between populations. The H1 haplotype of <it>MAPT </it>has been found to be closely associated with tauopathies and with sporadic FTLD. Our aim was to investigate <it>MAPT </it>mutations and haplotype frequencies in a clinical series of patients with FTLD in Northern Finland.</p> <p>Methods</p> <p><it>MAPT </it>exons 1, 2 and 9–13 were sequenced in 59 patients with FTLD, and <it>MAPT </it>haplotypes were analysed in these patients, 122 patients with early onset Alzheimer's disease (eoAD) and 198 healthy controls.</p> <p>Results</p> <p>No pathogenic mutations were found. The H2 allele frequency was 11.0% (<it>P </it>= 0.028) in the FTLD patients, 9.8% (<it>P </it>= 0.029) in the eoAD patients and 5.3% in the controls. The H2 allele was especially clustered in patients with a positive family history (<it>P </it>= 0.011) but did not lower the age at onset of the disease. The ApoE4 allele frequency was significantly increased in the patients with eoAD and in those with FTLD.</p> <p>Conclusion</p> <p>We conclude that although pathogenic <it>MAPT </it>mutations are rare in Northern Finland, the <it>MAPT </it>H2 allele may be associated with increased risks of FTLD and eoAD in the Finnish population.</p

Treponema denticola chymotrypsin-like protease as associated with HPV-negative oropharyngeal squamous cell carcinoma

BACKGROUND: An opportunistic oral pathogen, Treponema denticola (Td), has been linked to orodigestive carcinogenesis, but its role in oropharyngeal squamous cell carcinoma (OPSCC) has remained open. We evaluated the presence of Td chymotrypsin-like protease (Td-CTLP) in a series of 201 unselected consecutive OPSCC patients, and the relation of the Td-CTLP to human papillomavirus (HPV) status, to expression of toll-like receptors (TLR) 5, 7, and 9, and to clinical parameters and patient outcome. METHODS: Clinicopathological data came from hospital registries. The expression of cell surface-bound Td-CTLP was evaluated by immunohistochemistry. Immunoexpression of TLRs 5, 7, and 9, and HPV status we studied earlier in this patient series. RESULTS: We detected Td-CTLP in 81% of the OPSCC, and especially in HPV-negative tumours (48% of all OPSCCs). Among the HPV-positive tumours (52% of all OPSCCs), low Td-CTLP expression associated with low TLR 5 and high TLR 7 expression. Among those HPV-negative, higher TLR 5 and lower TLR 7 expression associated with high Td-CTLP expression. Strong Td-CTLP expression associated with poor disease-specific survival, but no similar association among HPV-positive and HPV-negative subgroups emerged. CONCLUSIONS: Td-CTLP was highly expressed in OPSCC and was associated with the HPV status of tumour tissue.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

Interaction of climate change with effects of conspecific and heterospecific density on reproduction

We studied the relationship between temperature and the coexistence of great titParus majorand blue titCyanistes caeruleus, breeding in 75 study plots across Europe and North Africa. We expected an advance in laying date and a reduction in clutch size during warmer springs as a general response to climate warming and a delay in laying date and a reduction in clutch size during warmer winters due to density-dependent effects. As expected, as spring temperature increases laying date advances and as winter temperature increases clutch size is reduced in both species. Density of great tit affected the relationship between winter temperature and laying date in great and blue tit. Specifically, as density of great tit increased and temperature in winter increased both species started to reproduce later. Density of blue tit affected the relationship between spring temperature and blue and great tit laying date. Thus, both species start to reproduce earlier with increasing spring temperature as density of blue tit increases, which was not an expected outcome, since we expected that increasing spring temperature should advance laying date, while increasing density should delay it cancelling each other out. Climate warming and its interaction with density affects clutch size of great tits but not of blue tits. As predicted, great tit clutch size is reduced more with density of blue tits as temperature in winter increases. The relationship between spring temperature and density on clutch size of great tits depends on whether the increase is in density of great tit or blue tit. Therefore, an increase in temperature negatively affected the coexistence of blue and great tits differently in both species. Thus, blue tit clutch size was unaffected by the interaction effect of density with temperature, while great tit clutch size was affected in multiple ways by these interactions terms.Peer reviewe

Variation in clutch size in relation to nest size in birds

Peer reviewe

Endometriosis patients’ experiences of the counseling they need from the nurses through the digital care pathway:a qualitative descriptive study

Abstract Endometriosis is a chronic disease associated with severe, life-impacting pain symptoms and impaired fertility that can affect relationships, sexuality, family life, social relationships, and working life. The aim of the present study was to describe endometriosis patients’ experiences of the counseling they need from the nurses through the digital care pathway. A qualitative descriptive study was conducted; 14 Finnish women with endometriosis were interviewed. Content analysis revealed four main categories related to counseling provided through the digital care pathway: counseling on endometriosis and its role in life; counseling on how to live with endometriosis; comprehensive support for self-care; and patient-oriented counseling. Nurses should provide counseling at different stages of the disease, because the symptoms of endometriosis can change rapidly in a short period of time, and these are the moments when the patient needs support and advice from the nurses. The digital care pathway can provide reliable information to patients at the right time of disease progression. The study was planned and reported using the Consolidated Criteria for Reporting Qualitative Research Checklist

Mikroyrittäjien kokemuksia työterveyshuollon palvelujen järjestämisestä ja niiden kehittämistarpeista

Tiivistelmä Tutkimuksen tarkoitus: Kuvailla mikroyrittäjien työterveyshuoltopalveluja sekä kokemuksia niiden järjestämisestä ja kehittämistarpeista. Aineisto ja menetelmät: Kyselyaineistosta ristiintaulukoitiin työterveyshuoltopalvelut taustamuuttujien suhteen sukupuolittain. Tilastollista merkitsevyyttä mitattiin Χ² testillä. Mikroyrittäjien haastatteluaineisto (n=30) analysoitiin aineistolähtöisellä sisällönanalyysilla. Aineistot kerättiin vuonna 2018. Tulokset: Mikroyrittäjistä (N=1245) työterveyshuoltopalvelut itselleen oli järjestänyt 38 % naisista ja 56 % miehistä. Yrittäjien koulutustasolla, iällä tai koetulla terveydentilalla ei ollut tähän vaikutusta. Yrittäjät, jotka eivät pystyneet säännöllisesti maksamaan palkkaa itselleen, olivat harvemmin järjestäneet työterveyshuoltopalvelut. Mikroyrittäjät kokivat työterveyshuollon järjestämisen kalliina tai tarpeettomana. Palvelujen ei koettu huomioivan yrittäjyyden tai työn vaatimuksia. Myönteiset kokemukset liittyivät nopeaan hoitoon pääsyyn, hyvään ohjaukseen ja ennaltaehkäisevään terveydenhuoltoon. Ennaltaehkäisevien, yksilöllisten, yrittäjyyden ja työn vaatimukset huomioivien palvelujen kehittäminen ja tiedottaminen koettiin tärkeiksi. Päätelmät: Mikroyrittäjille suunnatuissa työterveyshuoltopalveluissa tulee kehittää ennaltaehkäiseviä palveluja. Mikroyrittäjyyden vaatimusten ja aikutusten tuntemusta tulee lisätä koulutuksessa. Mikroyrittäjät tarvitsevat lisää tiedottamista työterveyshuoltopalveluista.Abstract Aim: To describe microentrepreneurs’ occupational health services (OHS) and microentrepreneurs’ experiences how OHS need to be developed. Data and methods: The data of questionnaires was analyzed by using crosstabulations of OHS services with background variables separately by gender. Statistical significancy was measured by using Χ²-test. The interviews (n=30) were analyzed by using inductive content analysis. The data was collected in year 2018. Results: Among microentrepreneurs (N=1245), 38 % of women and 56 % of men has OHS services. Education, age or perceived health had not effect on OHS. They who has not possibility to pay salary to themselves, has also more seldom OHS. The microentrepreneurs felt that OHS were expensive, that they had no any need for OHS services, and that OHS did not take into account the nature of entrepreneurship or the demands of entrepreneurs’ work. Positive experiences were related to quick access to OHS, good quality guidance and health promotion services. Development of individual, holistic health promotion services that take into account entrepreneurship and the demands of entrepreneurs’ work were considered important. Conclusions: In microentreprenurs’ OHS, health promotion services need to be developed in future. Knowledge on demands and effects of entrepreneurship and entrepreneurs’ work should be increased in education of occupational health nurses. Microentrepreneurs need more information about OHS in future

National MEDigi project:systematic implementation of digitalization to undergraduate medical and dental education in Finland

Abstract MEDigi is a nationwide Finnish project that aims to develop and implement digital teaching, learning and assessment solutions and to provide possibilities for national harmonization of undergraduate medical and dental education in Finland. The MEDigi project will investigate the options and feasibility of a common national digital online platform and produce digital content and solutions for medical education. Furthermore, tools and support system for digital pedagogy training will be created to ensure that the teaching staff will achieve and retain appropriate digipedagogical skills. The project aims also to increase the competence related to the digital tools used in clinical practice (eHealth, digital health) of physicians and dentists. Furthermore, academic research will be carried out on various aspects of the project. All the universities in Finland that offer the Licentiate Degree in Medicine and Dentist programmes are involved: Universities of Eastern Finland, Helsinki, Oulu, Tampere and Turku. The project is coordinated by the University of Oulu. The project is carried out in close collaboration with the Finnish Medical Society Duodecim and the Finnish Dental Society Apollonia. The project lifespan is until the end of May 2021. MEDigi project is financed by the Finnish Ministry of Culture and Education and its total budget is over 4 million euros

Effectiveness of training in guideline-oriented biopsychosocial management of low-back pain in occupational health services:a cluster randomized controlled trial

Abstract Objective: This study aimed to investigate the effectiveness of brief training in the guideline-oriented biopsychosocial management of low-back pain (LBP) in occupational health services using a cluster-randomized design. A small sample of physiotherapists and physicians from the intervention units (N=12) were given three- to seven-day training focusing on the biopsychosocial management of LBP, while professionals in the control units (N=15) received no such training. Methods: Eligible patients with LBP, with or without radicular pain, aged 18–65, were invited to participate. A web-based questionnaire was sent to all recruited patients at baseline, three months and one year. The primary outcome measure was disability (Oswestry Disability Index, ODI) over one year. Between-group differences were analyzed using linear and generalized linear mixed models adjusted for baseline-response delay as well as variables showing between-group imbalance at baseline. Results: The final study sample comprised 234 and 81 patients in the intervention and control groups, respectively at baseline, and 137 and 47 patients, respectively, at one year. At baseline, the mean duration of pain was longer in the intervention group (P=0.017), and pain-related fear concerning physical activity was lower (P=0.012). We observed no significant difference between the groups’ primary outcome measure (adjusted one-year mean difference in the ODI: 2.3; 95% confidence interval -1.0–5.7; P=0.175) or most secondary outcomes. Conclusions: Brief training in guideline-oriented biopsychosocial management of LBP for occupational health professionals did not appear to be effective in reducing patients’ symptom over one-year follow-up compared to treatment as usual