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Introduction: The oncoprotein Bcr-Abl has two major isoforms, depending on the breakpoint in BCR gene, p190 and p210. While p210 is the hallmark of chronic myeloid leukemia (CML), p190 occurs in the majority of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients. p190 occurs as a sole transcript in 1-2% CML patients, associated with distinct features like monocytosis and frequent additional cytogenetic abnormalities (ACA) at diagnosis. It also confers a risk of treatment failure and progression in chronic phase (CP) CML patients. However, the underlying mechanisms are largely unknown. Here we explore the characteristics of p190 and p210 in CML and ALL patients using next generation sequencing, phospho-flowcytometry and high throughput drug testing. Patients and methods: Peripheral blood mononuclear cells (PMNC) were collected at diagnosis from four CP-CML patients harboring p190 isoform from Helsinki University Hospital. Genetic alterations were identified by whole exome sequencing. RNA sequencing was employed to analyze transcriptional profiles of p190 CML (n=3) in contrast to p210 CML patients (n=4). A thorough transcriptional, phosphorylation and drug sensitivity profiling were applied to five p190- and three p210-expressing Ph+ALL patients. Expression alterations were further characterized in two cell line models mimicking BCR-ABL positive leukemia (Ba/F3 and HPCLSK). Phosphorylation profiles were analyzed by flowcytometry and phospho-array (Tyrosine Phosphorylation ProArray, Full Moon Biosystems). For drug sensitivity and resistance testing (DSRT), a custom plate set comprising 75 approved and investigational oncology drugs was used for patient samples and more extensive 528-drugs plates were used for the cell lines. Results: CML patients with p190 had a median age of 72.5 years at the diagnosis (range: 50-80) and all received imatinib as a frontline treatment. Only one patient achieved a fluctuating major molecular response (MMR) by 12 months while the rest of the patients showed primary resistance to treatment and were shifted to a 2nd line TKI, nilotinib (n=2) or proceeded to HSCT (n=1). By exome sequencing we identified 26 variants in p190-CML samples (median per patient=7, range: 2-10), including variants in ASXL1, DNMT3A and KDM4D genes. RNA-sequencing analysis identified 19 and 97 dysregulated genes (Q Conclusions: In CML, p190 isoform of BCR-ABL1 is associated with distinct features and should be considered as a high-risk group. Combining clinical, genomic, phosphorylation and drug sensitivity data, we demonstrated that p190 activates specific cancer pathways, notably Src signaling and interferon pathways. Data also suggests that CML patients with p190 could benefit from broad spectrum TKI with Src inhibiting activity or combination of TKI with MDM2- or IAP-inhibitors. Disclosures Heckman: Orion Pharma: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding. Porkka:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Mustjoki:Novartis: Research Funding; Pfizer: Research Funding; BMS: Honoraria, Research Funding.

Acute myeloid leukemia (AML) is an aggressive disease of clonal hematopoietic progenitor cells. Here, we applied ex-vivo drug sensitivity and resistance testing on AML patient cells with 362 emerging and 153 approved cancer drugs together with genomic and transcriptomic profiling to identify and tailor therapies for patients with advanced disease. Ex-vivo testing with freshly isolated patient cells revealed cancer-specific efficacies of approved drugs in 97% of the 164 patient cases, including 47% of the cases with no actionable driver mutations. We identified 142 statistically significant associations between drug responses and somatic mutations, including increased sensitivity to JAK inhibitors in patients with NPM1 mutations. Transcriptomic profiles predicted drug responses better than genomics and helped to identify additional response markers, especially beyond mutations. For example, overexpression of HOX family genes was associated with sensitivity to JAK inhibitors in patients with NPM1 mutation. In a prospective study, we translated the functional drug response and molecular profile data to the clinic and suggested tailored therapy with targeted drugs for 26 relapsed or refractory AML patients. In an observational intervention study, acting on these recommendations resulted in a temporary complete clinical remission or leukemia-free state in 39% of the cases. In summary, we conclude that ex-vivo testing of drugs on patient AML cells i) revealed clinically actionable drug efficacies in almost all AML patients, including patients with no actionable mutations, ii) predicted cases with actionable driver mutations with no pharmacological dependency on the target, and iii) enabled real-time tailoring of therapy with 39% clinical response rate in chemorefractory advanced AML. Taken together, we believe this real-time systems medicine approach could become a powerful strategy for tailoring therapies for individual patients in the future. Citation Format: Disha Malani, Ashwni Kumar, Bhagwan Yadav, Mika Kontro, Swapnil Potdar, Oscar Bruck, Säri Kytölä, Jani Saarela, Samuli Eldfors, Riikka Karjalainen, Muntasir M. Majumder, Imre Västrik, Pekka Ellonen, Matti Kankainen, Minna Suvela, Siv Knappila, Alun Parson, Aino Palva, Pirkko Mattila, Evgeny Kulesskiy, Laura Turunen, Karoliina Laamanen, Elina Lehtinen, Maria Nurmi, Katja Suomi, Astrid Muruimägi, Bjorn T. Gjertsen, Satu Mustjoki, Simon Anders, Maija Wolf, Tero Aittokallio, Krister Wennerberg, Caroline Heckman, Kimmo Porkka, Olli Kallioniemi. Precision systems medicine in acute myeloid leukemia: real-time translation of tailored therapeutic opportunities arising from ex-vivo drug sensitivity testing and molecular profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 458.

The aim of the study was to detect mutations of BRAF oncogene in colorectal cancer and to use this information to identify Lynch syndrome patients. Consecutive cases of primary colorectal cancer (n = 137) were analyzed for MLH1 protein expression using immunohistochemistry (IHC). BRAF V600E mutation was detected by IHC using a specific monoclonal antibody (VE1) and by qPCR. All MLH1 protein-negative cases were subjected to microsatellite instability analysis and MLH1 promoter methylation assay. MLH1 protein expression deficiency and high microsatellite instability (MSI-H) were detected in 18 of the 137 (13.1 %) consecutive colorectal cancer specimens. Detection of the BRAF V600E mutation by IHC was 100 % sensitive and specific as compared to qPCR, and this mutation was frequently present in the MSI-H group (77.8 %; 14/18) and less frequently in the microsatellite-stable group (7.6 %; 9/118). All BRAF V600E mutated cases of the MSI-H group presented with a MLH1 promoter methylation (14/14) as detected by methylation-specific multiplex ligation-dependent probe amplification. When BRAF was wild type in the MSI-H group, only one MLH1 promoter methylation was detected (1/4), and of the remaining three cases without MLH1 methylation, two were identified to harbor an MLH1 mutation consistent with Lynch syndrome. Finally, 11 previously confirmed Lynch syndrome cases were analyzed for BRAF V600E mutation, and all of them were wild type. In conclusion, detection of BRAF V600E in colorectal cancer specimens by IHC is sensitive and specific and may help to identify Lynch syndrome patients.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant familial cancer syndrome characterized by parathyroid, pancreatic, and anterior pituitary tumors. The MEN1 locus has been previously localized to chromosome 11q13, and a 2-Mb gene-rich region flanked by D11S1883 and D11S449 has been defined. We have pursued studies to facilitate identification of the MEN1 gene by narrowing this critical region to a 900-kb interval between the VRF and D11S1783 loci through meiotic mapping. This was achieved by investigating 17 cosmids for microsatellite polymorphisms, which defined two novel polymorphisms at the VRF and A0138 loci, and utilizing these to characterize recombinants in MEN1 families. In addition, we have established a 1200-kb sequence-ready contig consisting of 26 cosmids, eight BACs, and eight PACS that encompass this region. The precise locations for 19 genes and three ESTs within this contig have been determined, and three gene clusters consisting of a centromeric group (VRF, FKBP2, PNG, and PLCB3), a middle group (PYGM, ZFM1, SCG1, SCG2 (which proved to be the MEN1 gene), and PPP2R5B), and a telomeric group (H4B, ANG3, ANG2, ANG1, FON, FAU, NOF, NON, and D11S2196E) were observed. These results represent a valuable transcriptional map of chromosome 11q13 that will help in the search for disease genes in this region.

Transformational leadership has been the center of interest for organizational behavior theorists and management experts due to this leadership style’s significance and appeal with reference to organizational team performance, effectiveness as well as innovativeness. In addition, new product development is considered the core operation of each and every industrial concern. The success of new product development related operations are becoming more challenging in today’s’ turbulent economic conditions. Hence, the current study is an attempt to explore the inter-connection between transformational leadership and new product development team’s effectiveness to support organizational innovation. The empirical study was conducted based on the implementation of especially devised and validated quantitative and qualitative tools. The study sample represented the new product development team’s working at three different global locations of an energy sector company. The data obtained through the mixed mode survey tools was analyzed statistically and qualitatively by implementing statistical methods. The research outcomes revealed that the dimensions of management initiatives (innovation variable), collaboration (NPD team effectiveness variable), communication (NPD team effectiveness variable) and affiliation with leader (transformational leadership variable) have positive association among each other while product innovation (innovation variable), communication (NPD team effectiveness variable) and leader’s competence to empower its team (transformational leadership variable) have shown negative internal association.

To make critical decisions, organizational leaders ensure to collect and analyze information through various sources by employing variety of analytical tools. Consequently, they manage to integrate the results of their analysis to offer diagnostic view by pinpointing the weak areas. Following the above sequence of analytical procedure, the current study presents a diagnostic review of highlighting weak operational areas in a European multinational company. The study findings suggest that the critical gaps are causing communicational breakdown and consequently affecting new product idea mechanism. Such operational areas include; the potential of target company’s internal communication system, data collection and record keeping capability, management’s approach to harness corporate potential of new idea generation and employee empowerment mechanisms. The referred areas are directly linked to the target company’s new product idea generation initiatives, the activities linked to the introduction of innovative products and service styles as well as the overall operational growth.

Anti-EGFR antibodies are used for the treatment of RAS wild type metastatic colorectal cancer. We previously showed that EGFR gene copy number (GCN) predicts response to anti-EGFR therapy in KRAS exon 2 wild type metastatic colorectal cancer. The aim of our study was to analyse the predictive role of EGFR GCN in RAS/BRAF/PIK3CA wild type metastatic colorectal cancer. The material included 102 patients with KRAS exon 2 wild type metastatic colorectal cancer treated with anti-EGFR ± cytotoxic therapy. Next generation sequencing was used for KRAS, NRAS, BRAF and PIK3CA gene mutation analyses. EGFR GCN was analysed by EGFR immunohistochemistry guided automated silver in situ hybridisation. Increased EGFR GCN (≥4.0) predicted a better response and prolonged progression free survival in anti-EGFR treated RAS/BRAF/PIK3CA wild type patients (Log-rank test, p = 0.0004). In contrast, survival of RAS/BRAF/PIK3CA wild type, EGFR GCN below 4.0 patients did not differ from patients with mutant RAS, BRAF or PIK3CA. Our study indicates that EGFR GCN predicts anti-EGFR treatment efficacy in patients with RAS/BRAF/PIK3CA wt metastatic CRC. Tumours with EGFR GCN below 4.0 appear to be as refractory to anti-EGFR treatment as tumours with mutation in any of the RAS/RAF/PIK3CA pathway genes.

Besides histological classification of lung cancers, molecular biological examination of tumors is part of modern diagnostics of lung cancers, and cancer therapies are based on molecular biological diagnosis. Current laboratory technique enables the examination of many mutations as part of standard routine diagnosis, necessitating functional multidisciplinary collaboration, with the pathologist playing a central role in the handling of the specimens. In the future, especially pathologists, pulmonary specialists and oncologists are expected to need a good command of molecular biological data on lung cancer, but basic knowledge will be required also from other physicians working with lung cancer patients.

Hallitus loi vuonna 2013 voimaan tulleen Nuorisotakuu-nimellä kulkevan palkkatukimallin madaltamaan työnantajien kynnystä palkata nuorta työvoimaa yrityksille maksettavan palkkatuen avulla. Nuorisotakuu on suunnattu nuorille, jotka ovat vailla työtä tai koulutusta niin, että jokaiselle alle 25-vuotiaalle nuorelle ja jokaiselle alle 30-vuotiaalle vastavalmistuneelle tarjotaan työ-, opiskelu-, työkokeilu-, työpaja- tai kuntoutuspaikkaa viimeistään kolmen kuukauden sisällä heidän työttömäksi ilmoittautumisensa jälkeen. Tässä tutkimuksessa tarkastellaan työnantajien näkemyksiä heille maksettavan palkkatuen toimivuudesta ja Nuorisotakuun suhteesta yritysten yhteiskuntavastuullisuuteen. Yritysten valta myös niiden harjoittaman varsinaisen liike-elämän ulkopuolella on kasvanut niin paljon, että ei ole yhdentekevää, minkälaiseksi yritykset itse oman roolinsa mieltävät. Yritysten omat perusarvot ovat nousseet pohdintaan myös Suomessa. Yhteiskuntavastuu ja sen ymmärtäminen ovat vahvasti kontekstisidonnaisia eli asiayhteyteen sidottuja asioita. Siten ei ole mielekästä pyrkiä määrittämään yhteiskuntavastuun sisältöjä, vaan ennemmin on ymmärrettävä yhteiskuntavastuu eri konteksteissa. Yritysten valta myös niiden harjoittaman varsinaisen liike-elämän ulkopuolella on kasvanut niin paljon, että ei ole yhdentekevää, minkälaiseksi yritykset itse oman roolinsa näkevät. Ulkopuolelle yrityksen sosiaalinen vastuu näkyy osallistumisena yhteiskunnan ja lähiympäristön kehittämiseen, joka konkretisoituu sen suhtautumisena sidosryhmiinsä. Yhteiskunnan sijoittaessa resursseja nuoriin yrityksille maksettavan palkkatuen muodossa voidaan tällöin myös yrityksiltä odottaa vastavuoroisuutta. Tässä tutkimuksessa teoreettisina viitekehyksinä ovat yritysten yhteiskuntavastuun käsite ja sidosryhmäteoria. Yritysten yhteiskuntavastuu on käsitteenä laaja, kompleksinen ja koko ajan kehittyvä. Nuorisotakuun kautta palkkatuettuja nuoria tarkastellaan yritysten sidosryhmänä. Sidosryhmäteorian mukaan yritysten olemassaolo toteutuu vuorovaikutuksessa ja transaktiossa yrityksen sidosryhmien kanssa. Yrityksen tulee toimia niin, että pidemmällä aikavälillä kaikki sidosryhmät pysyvät tyytyväisenä toteutuneeseen vaihtosuhteeseen. Tutkimusaineisto kerättiin Pirkanmaalaisista mikro- ja pienyrityksistä teemahaastattelumenetelmää hyödyntäen. Vastaukset osoittavat, että työnantajat ovat kokeneet palkkatuen yrityksen kannalta hyödylliseksi ja positiiviseksi erityisesti palkkatuen taloudellisen merkityksen takia. Palkkatukea pidettiin myös rekrytointiprosessia joustavoittavana työkaluna. Hyvän yrityksen yhteiskuntavastuun ei nähty vaativan aktiivista toimijuutta, vaan yhteiskuntavastuun nähtiin sisältyvän verojen ja pakollisten maksujen hoitoon. Tuloksista selviää myös, että nuoria ei nähty täysivaltaisina työyhteisön jäseninä tai sidosryhmänä tukijakson aikana. Sosiaalisen toimijuuden nähtiin kulminoituivan yrityksen sisäisiin henkilöihin ja heidän arvomaailmaansa ja tekoihinsa.

The emergence of the Internet of Things has accelerated the development of smart cities. Currently, an increasing number of smart city applications comprising various scenarios and use cases is being deployed and tested. However, to realize a smart city, it is necessary to have converging solutions as opposed to niche, detached solutions. Smart city platforms need to take into account existing services and infrastructures. Furthermore, in the context of a smart city it is important to account for various kinds of stakeholders with a variety of requirements with regard to data ownership, legal and organizational frameworks as well as commercial interests. We present the ALMANAC Smart City Platform as a solution which handles the described heterogeneity. Firstly, the platform allows the development of smart city applications by creating interoperability among devices and services. Secondly, the platform is deployed in a de-centralized, federated way that allows to map the organizational requirements to the deployed city systems. We introduce the concept of federation for smart cities and describe its implementation in the ALMANAC Platform through a case study which simulates a scenario in the waste management domain. This scenario models realworld requirements of a waste management company and the municipality of Turin. Keywords-internet of things; smart city; federation

peerReviewed

Tässä tutkimuksessa tutkitaan 1.- ja 6. -luokkalaisten kokemuksia välituntiliikunnasta psyykkisen jaksamisen näkökulmasta. Lisäksi tarkastellaan oppilaiden välituntiliikunta- aktiivisuutta sekä sitä, millaiset välituntitoiminnot ovat oppilaiden suosiossa. Tutkimus koostui kahdesta vaiheesta. Ensimmäisessä vaiheessa kerättiin aineisto 6.- luokkalaisilta kyselylomakkeita ja havainnointia aineistonkeruumenetelminä käyttäen. Toi- sessa vaiheessa kerättiin aineisto 1.-luokkalaisilta käyttäen aineistonkeruumenetelminä säh- köisiä kyselylomakkeita sekä oppilaiden itse toteuttamia äänikirjoja. Tutkimukseen osallis- tui yhteensä 23 kuudesluokkalaista ja 19 ykkösluokkalaista. Tulokset analysoitiin kysely- lomakkeiden ja havainnoinnin osalta määrällisesti laskemalla ja taulukoimalla frekvenssi- ja prosenttijakaumia sekä laskemalla keskiarvoja. Äänikirjat analysoitiin sisällön analyysin mukaisesti. Kuudesluokkalaisista suurin osa eri aineistonkeruukerroilla liikkui välitunnilla. Eri- tyisesti kuvataiteen tunneilla välitunnilla liikkuneet oppilaat kokivat välituntiliikunnan vai- kuttavan heidän psyykkiseen jaksamiseensa. Ykkösluokkalaiset arvioivat itsensä pääosin liikunnallisesti aktiivisiksi välituntisin sekä kokivat välitunnilla liikkumisen mielekkääksi. Tuloksista voidaan päätellä, että välituntiliikunta saattaa parantaa oppilaiden psyykkistä jaksamista. Välituntiliikunnalla voi myös olla pirteyden pysyvyyttä sekä keskittymiskyvyn tasaisuutta lisäävä vaikutus. Välituntisin oppilaille tärkeää on pääasiassa liikkuminen ja sosiaalinen kanssakäyminen kavereiden kanssa. Välitunti näyttäisi myös tuovan oppilaille vapauden tunnetta, mikä tutkitusti parantaa psyykkistä hyvinvointia. Oppilaat haluavat myös pitää tästä vapaudesta kiinni. Yhtenä jatkotutkimushaasteena voidaan pitää sitä, mitä erilaisia toimintoja ja ele- menttejä oppilaat kaipaisivat välitunneille ja tutkia, lisäisikö oppilaiden välituntitoimintoi- hin liittyvien toiveiden ja tarpeiden kartoittaminen ja toteuttaminen oppilaiden liikunnallista aktiivisuutta välitunneilla.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with rather poor prognosis. Apart from surgery, no evidence-based treatments exist. A 48-year-old woman presented with weight loss, nausea, constipation, hypercalcemic crisis, and a recurrent neck tumor 5 years after primary surgery of a parathyroid tumor that primarily was classified as an adenoma. Histopathological reevaluation of the original tumor revealed the correct diagnosis to be parathyroid carcinoma (PC). The patient underwent surgery of the recurrent tumor, which was locally invasive with metastatic spread to the mediastinum and neck lymph nodes. Computed tomography demonstrated large lytic bone lesions in both iliac bones including, on the right, a soft tissue mass compatible with bone metastasis. The patient was treated with cinacalcet, repeated zoledronic acid infusions, and temozolomide cycles for 1 year. She underwent two additional neck surgeries for PC and sternotomy for resection of mediastinal metastases. Massive osteolytic lesions in both femoral necks caused imminent fracture risk and therefore both femurs were prophylactically stabilized by intramedullary nail. Serum calcium normalized after the third neck surgery, cinacalcet was discontinued, and parathyroid hormone gradually normalized during continued treatments with temozolomide, adjuvant radiotherapy, and zoledronic acid, with no signs of active disease on imaging and normal biochemistry. The patient remains in remission 17 years after successful combined treatments for recurrent, metastasized PC. The parathyroid tumor tissue demonstrated high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive temozolomide treatment response in other tumors. In addition, synergistic effects of multiple treatments may have accounted for the favorable response. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

The pathogenesis of common variable immunodeficiency (CVID) and many other immunodeficiencies is elusive, and no cure for these diseases exists. The characteristic features of CVID are immunoglobulin deficiency and recurrent infections, but autoimmunity co-manifests in 30% and lymphoproliferation in 50% of CVID cases. The failure to produce sufficient quantities of immunoglobulins is attributed to B cells, but as T cells are critical players in adaptive immune response and autoimmune disease, they have also suggested to play a role in CVID. As monogenic germline mutations account only for 2-10% of CVID cases, the etiology of CVID remains unknown in most cases. To study if somatic mutations in T cells contribute to immunodeficiencies, we recruited patients with broad immune dysregulation: 8 patients with late-onset CVID, and 9 patients with other type of immunodeficiency and/or severe autoimmunity. All patients signed informed consent and the declaration of Helsinki principles were followed. Study design and key patient characteristics are depicted in the Figure. To discover somatic mutations in T cells, we sequenced both CD4+ and CD8+ cells with a custom gene panel comprising of 2500 immune-related genes with an average coverage of 500x. Somatic variants were identified using the GATK MuTect2 toolset by using a panel of 21 healthy controls' CD4+ and CD8+ cells as a background. Variants were called using paired samples (CD4+ vs CD8+ and vice versa). This approach identifies variants that have occurred in mature T cells. To complement this approach, we performed variant calling also in single-sample mode to identify variants originating from hematopoietic progenitors. Paired-sample analyses revealed 44 somatic mutations in mature T cells in 10/17 (59%) patients: 30 (68%) in CD8+ and 14 (32%) in CD4+ cells. The mutations included 2 frameshift-, 37 missense-, and 5 nonsense variants. In silico tools (both Polyphen-2 and SIFT) predicted 19 (51%) of the missense mutations to be damaging. The Catalogue Of Somatic mutations In Cancer (COSMIC) database included 9/44 (20%) of all mutations. Also, pathway analysis annotated 20% of the mutated genes to be involved in inflammatory response regulation, 27.5% in protein phosphorylation regulation, and 22.5% in positive regulation of cell proliferation. Interesting mutation findings included two patients with STAT5B mutations (N418K and T628S) with a low variant-allele (VAF) frequencies (3.2-3.6% in CD4+ cells), one patient with a KRAS T58I mutation (VAF 7.9% in CD8+), and two patients with distinct C5AR1 mutations (R197W and T62M). Complementing the paired-sample variant calling strategy, single-sample analyses revealed mutations associated with clonal hematopoiesis with low VAFs (2.2-5.5%) in T cells in 4 (23.5%) patients. Three patients had DNMT3A mutations and one patient 4 distinct TET2 mutations (2 nonsense-, 1 frameshift-, and 1 missense mutations). CD4+ and CD8+ T-cell receptor (TCR) repertoires were profiled with deep TCR beta chain (TCRB) sequencing. Healthy controls' CD4+ and CD8+ cells (n=27) were used as comparators. Although some CVID patients harbor major (17-20% of CD8+) T-cell clones, overall CD4+ or CD8+ clonality did not significantly differ from age-matched healthy controls. As a marker of selective pressure, CVID patients' CD4+ and CD8+ cells harbored more clones that shared a CDR3 amino-acid but had distinct nucleotide CDR3 sequences than healthy controls (7.0% vs 3.3% of all amino-acid rearrangements, p=0.021 for CD8+; 4.3% vs 3.5% p=0.013 for CD4+). These TCRs were not enriched with pathogen-specific (such as cytomegalovirus or Epstein-Barr virus) TCRs. Moreover, high CD4+ clonality was associated with a lower frequency of switched-memory-B cells. In conclusion, somatic mutations in T cells occurred in 59% of patients with immunodeficiency in this study, and some of the mutated genes (such as STAT5B) have previously been implicated for the pathogenesis of autoimmunity and lymphoproliferation. Also, clonal hematopoiesis in T cells was discovered in 23.5% of patients. The overall T-cell clonality was not increased, but CVID patients showed slight selective pressure in the TCR repertoire. Our results demonstrate that further research on somatic mutations in immunodeficiencies is needed, as they may contribute to disease pathogenesis in a subset of immunodeficiency patients. Disclosures Martelius: Gilead: Other: lecture fee; Octapharma: Other: travel grant; CSL Behring: Other: lecture fee and travel grant; MSD: Other: lecture fee and travel grant; Sanguin: Other: travel grant and grants. Kankainen:Medix Biochemica: Consultancy. Seppänen:CSL Behring: Other: Chairing and speaker fees. Mustjoki:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding.

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by multiple molecular subtypes and lack of effective targeted therapies. Here, we performed extensive molecular profiling and ex vivo drug testing with 515 approved and emerging cancer drugs on 164 AML patient samples. The aim was to i) assign individualized treatment options to advanced AML patients in real time, ii) explore drug response patterns across the molecular subtypes of AML and iii) identify opportunities to repurpose existing and emerging cancer drugs. Bone marrow samples (n=164) from 129 consecutive AML patients and 17 healthy donors were studied from the Helsinki University Hospital and the Haukeland University Hospital, Bergen. Mononuclear cells were resuspended either in mononuclear cell medium (MCM) or stroma conditioned medium (CM) and tested for drug sensitivity and resistance as previously described (PMID: 24056683) and studied by exome and transcriptome sequencing. The study protocol allowed us to return data to the clinician for consideration of novel treatment options. For the meta-analysis of associations between drug responses and molecular and clinical parameters, Wilcoxon signed ranked test and logistic regression were applied. Clustering of all patient samples based on ex vivo drug response patterns in both media types identified 7 distinct functional groups of AML. For example, a subgroup of samples was highly resistant to chemotherapeutics and all targeted drugs except BCL-2 inhibitors. The differences in drug responses in the two media types highlighted the importance of assay conditions for ex vivo drug testing. Strong clustering of several drugs in the same drug classes was often observed as well as clustering across different classes, for example between BET (JQ1, I-BET151, birabresib) and MEK (trametinib, cobimetinib) inhibitors. About 24 percent of the FLT3 negative AML patients manifested strong ex vivo sensitivity to glucocorticoids, highlighting a potential drug repositioning opportunity in this subset of AML patients. Overall, we identified 320 significant associations between drugs and mutated driver genes including association between NPM1 mutation and sensitivity to JAK inhibitors. Altogether, targeted treatment opportunities were clinically tested in 25 occasions in chemorefractory AML patients. The tailored clinical therapy led to transient complete remission or leukemia free state in 36% (9/25) of these cases. In conclusion, we discovered and clinically implemented individualized therapeutic options for AML patients, which resulted in a 36% clinical responses in a non-randomized proof-of-concept study. The associations identified between ex-vivo drug response and driver mutations provided novel drug repositioning opportunities in specific molecular subtypes. Citation Format: Disha Malani, Ashwini Kumar, Bhagwan Yadav, Mika Kontro, Swapnil Potdar, Oscar Brück, Sari Kytölä, Jani Saarela, Samuli Eldfors, Poojitha Ojamies, Karjalainen Riikka, Muntasir Mamun Majumder, Imre Västrik, Pekka Ellonen, Matti Kankainen, Minna Suvela, Siv Knappila, Alun Parson, Aino Palva, Pirkko Mattila, Evgeny Kulesskiy1, Laura Turunen, Karoliina Laamanen, Elina Lehtinen, Piia Mikkonen, Maria Nurmi, Sanna Timonen, Astrid Murumägi, Bjorn Tore Gjersten, Satu Mustjoki, Tero Aittokallio, Krister Wennerberg, Simon Anders, Maija Wolf, Caroline Heckman, Kimmo Porkka, Olli Kallioniemi. Discovery and clinical implementation of individualized therapies in acute myeloid leukemia based on ex vivo drug sensitivity testing and multi-omics profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3899.

A space of local martingales of SLE type growth processes forms a representation of Virasoro algebra, but apart from a few simplest cases not much is known about this representation. The purpose of this article is to exhibit examples of representations where L_0 is not diagonalizable - a phenomenon characteristic of logarithmic conformal field theory. Furthermore, we observe that the local martingales bear a close relation with the fusion product of the boundary changing fields. Our examples reproduce first of all many familiar logarithmic representations at certain rational values of the central charge. In particular we discuss the case of SLE(kappa=6) describing the exploration path in critical percolation, and its relation with the question of operator content of the appropriate conformal field theory of zero central charge. In this case one encounters logarithms in a probabilistically transparent way, through conditioning on a crossing event. But we also observe that some quite natural SLE variants exhibit logarithmic behavior at all values of kappa, thus at all central charges and not only at specific rational values., Comment: 40 pages, 7 figures. v3: completely rewritten, new title, new results

Data from 207 production trials (998 treatment means) were used to study the effects of animal and dietary characteristics on the efficiency of N utilization for milk protein production, and on fecal N, urinary N, and total manure N output. The average efficiency of transferring dietary N to milk N (MNE; milk N/N intake) was 277 (SD = 36.0) g/kg. Nitrogen efficiency was poorly related to milk yield. Dietary concentrations of crude protein (CP) and protein balance in the rumen (PBV) were the best single predictors of MNE. Dietary CP concentration explained variation in MNE better than did N intake. Bivariate models with PBV or metabolizable protein (MP) explained the variation better than CP alone. The effects of protein feeding parameters on MNE were consistent among data subsets from studies investigating the effects of the amount and protein concentration of concentrate supplement, silage digestibility, silage fermentation quality, or substitution of grass silage with legume silage. The model with total dry matter and N intakes as independent variables explained fecal, urinary, and total manure N output more precisely than N intake alone. The model of fecal N output suggested that the true digestibility of dietary N was 0.91, and that metabolic and endogenous N was the major component in fecal N. The proportion of urine N in manure N was strongly related to dietary CP concentration. Including the concentration of dietary carbohydrates only slightly improved the models, indicating that the most effective strategy to improve MNE and to decrease N losses in manure, especially in urine, is to avoid feeding diets with excessively high CP concentration and especially excess ruminally degradable CP.

Colorectal cancer (CRC) accounts for high mortality. So far, there is lack of markers capable of predicting which patients are at risk of aggressive course of the disease. Protein phosphatase‐2A (PP2A) inhibitor proteins have recently gained interest as markers of more aggressive disease in certain cancers. Here, we report the role of PP2A inhibitor PME‐1 in CRC. PME‐1 expression was assessed from a rectal cancer patient cohort by immunohistochemistry, and correlations were performed for various clinicopathological variables and patient survival. Rectal cancer patients with higher cytoplasmic PME‐1 protein expression (above median) had less recurrences (P = 0.003, n = 195) and better disease‐free survival (DFS) than the patients with low cytoplasmic PME‐1 protein expression (below median). Analysis of PPME‐1 mRNA expression from TCGA dataset of colon and rectal adenocarcinoma (COADREAD) patient cohort confirmed high PPME1 expression as an independent protective factor predicting favorable overall survival (OS) (P = 0.005, n = 396) compared to patients with low PPME1 expression. CRC cell lines were used to study the effect of PME‐1 knockdown by siRNA on cell survival. Contrary to other cancer types, PME‐1 inhibition in CRC cell lines did not reduce the viability of cells or the expression of active phosphorylated AKT and ERK proteins. In conclusion, PME‐1 expression predicts for a favorable outcome of CRC patients. The unexpected role of PME‐1 in CRC in contrast with the oncogenic role of PP2A inhibitor proteins in other malignancies warrants further studies of cancer‐specific function for each of these proteins.

SLE(kappa; rho), a generalization of chordal Schramm-Lowner evolution (SLE), is discussed from the point of view of statistical mechanics and conformal field theory (CFT). Certain ratios of CFT correlation functions are shown to be martingales. The interpretation is that SLE(kappa; rho) describes an interface in a statistical mechanics model whose boundary conditions are created in the Coulomb gas formalism by vertex operators with charges alpha = rho/(2 sqrt(kappa)). The total charge vanishes and therefore the partition function has a simple product form. We also suggest a generalization of SLE(kappa; rho).

We have characterized the cytogenetic alterations of the human embyronal cell line 293 by spectral karyotyping and G-banding analysis. To investigate its genomic stability, we compared the karyotypes of 293 and its daughter line EcR-293. Genotype profiling through short tandem repeats complemented the analysis. While displaying almost identical STR profiles and thus verifying their origin and their close relation, the two lines were remarkably different in their number of chromosomes and setup of aberrant chromosomes. However, the cell lines retained a stable karyotype in long term culture. The establishment of subclones from EcR-293, expressing inducible lacZ or MEN1 transgenes, only added minor changes to the karyotype. Our study shows that the cytogenetic constitution of a clonal cell line of the 293 origin appears to be sufficiently stable. However, care should be taken when comparing the properties of independent 293 lineages, since clonal variations might be substantial.