Browsing by Subject "SIGNATURES"

Sort by: Order: Results:

Now showing items 21-31 of 31
  • Awad, Shady Adnan; Dufva, Olli; Ianevski, Aleksandr; Ghimire, Bishwa; Koski, Jan; Maliniemi, Pilvi; Thomson, Daniel; Schreiber, Andreas; Heckman, Caroline A.; Koskenvesa, Perttu; Korhonen, Matti; Porkka, Kimmo; Branford, Susan; Aittokallio, Tero; Kankainen, Matti; Mustjoki, Satu (2021)
    Blast-phase chronic myeloid leukemia (BP-CML) is associated with additional chromosomal aberrations,RUNX1mutations being one of the most common. Tyrosine kinase inhibitor therapy has only limited efficacy in BP-CML, and characterization of more defined molecular subtypes is warranted in order to design better treatment modalities for this poor prognosis patient group. Using whole-exome and RNA sequencing we demonstrate thatPHF6andBCORL1mutations,IKZF1deletions, and AID/RAG-mediated rearrangements are enriched inRUNX1(mut)BP-CML leading to typical mutational signature. On transcriptional level interferon and TNF signaling were deregulated in primaryRUNX1(mut)CML cells and stem cell and B-lymphoid factors upregulated giving a rise to distinct phenotype. This was accompanied with the sensitivity ofRUNX1(mut)blasts to CD19-CAR T cells in ex vivo assays. High-throughput drug sensitivity and resistance testing revealed leukemia cells fromRUNX1(mut)patients to be highly responsive for mTOR-, BCL2-, and VEGFR inhibitors and glucocorticoids. These findings were further investigated and confirmed in CRISPR/Cas9-edited homozygousRUNX1(-/-)and heterozygousRUNX1(-/mut)BCR-ABL positive cell lines. Overall, our study provides insights into the pathogenic role ofRUNX1mutations and highlights personalized targeted therapy and CAR T-cell immunotherapy as potentially promising strategies for treatingRUNX1(mut)BP-CML patients.
  • Aaltonen, T.; Amerio, S.; Amidei, D.; Anastassov, A.; Annovi, A.; Antos, J.; Apollinari, G.; Appel, J. A.; Arisawa, T.; Artikov, A.; Asaadi, J.; Ashmanskas, W.; Auerbach, B.; Aurisano, A.; Azfar, F.; Badgett, W.; Bae, T.; Barbaro-Galtieri, A.; Barnes, V. E.; Barnett, B. A.; Barria, P.; Bartos, P.; Bauce, M.; Bedeschi, F.; Behari, S.; Bellettini, G.; Bellinger, J.; Benjamin, D.; Beretvas, A.; Bhatti, A.; Bland, K. R.; Blumenfeld, B.; Bocci, A.; Bodek, A.; Bortoletto, D.; Boudreau, J.; Boveia, A.; Brigliadori, L.; Bromberg, C.; Brucken, E.; Budagov, J.; Budd, H. S.; Burkett, K.; Busetto, G.; Bussey, P.; Butti, P.; Buzatu, A.; Devoto, F.; Mehtala, P.; Orava, R. (2016)
    A search for a Higgs boson with suppressed couplings to fermions, h(f), assumed to be the neutral, lower-mass partner of the Higgs boson discovered at the Large Hadron Collider, is reported. Such a Higgs boson could exist in extensions of the standard model with two Higgs doublets, and could be produced via p (p) over bar -> H(+/-)h(f) -> W*h(f)h(f) -> 4 gamma + X where H (+/-) is a charged Higgs boson. This analysis uses all events withat least three photons in the final state from proton-antiproton collisions at a center-of-mass energy of 1.96 TeV collected by the Collider Detector at Fermilab, corresponding to an integrated luminosity of 9.2 fb(-1). No evidence of a signal is observed in the data. Values of Higgs-boson masses between 10 and 100 GeV/c(2) are excluded at 95% Bayesian credibility.
  • The CMS collaboration; Sirunyan, A. M.; Eerola, P.; Pekkanen, J.; Voutilainen, M.; Härkönen, J.; Järvinen, T.; Karimäki, V.; Kinnunen, R.; Lampén, T.; Lassila-Perini, K.; Lehti, S.; Lindén, T.; Luukka, P.; Tuominen, E.; Tuominiemi, J.; Tuovinen, E.; Talvitie, J.; Tuuva, T. (2018)
    An inclusive search for anomalous Higgs boson production in the diphoton decay channel and in association with at least one jet is presented, using LHC proton-proton collision data collected by the CMS experiment at a center-of-mass energy of 13 TeV and corresponding to an integrated luminosity of 35.9 fb(-1). The razor variables M-R and R-2, as well as the momentum and mass resolution of the diphoton system, are used to categorize events into different search regions. The search result is interpreted in the context of strong and electroweak production of supersymmetric particles. We exclude bottom squark pair-production with masses below 450 GeV for bottom squarks decaying to a bottom quark, a Higgs boson, and the lightest supersymmetric particle (LSP) for LSP masses below 250 GeV. For wino-like chargino-neutralino production, we exclude charginos with mass below 170 GeV for LSP masses below 25 GeV. In the GMSB scenario, we exclude charginos with mass below 205 GeV for neutralinos decaying to a Higgs boson and a goldstino LSP with 100% branching fraction. C) 2018 The Author(s). Published by Elsevier B.V.
  • Aska, Elli-Mari; Dermadi, Denis; Kauppi, Liisa (2020)
    DNA mismatch repair (MMR) corrects replication errors and is recruited by the histone mark H3K36me3, enriched in exons of transcriptionally active genes. To dissect in vivo the mutational landscape shaped by these processes, we employed single-cell exome sequencing on T cells of wild-type andMMR-deficient (Mlh1(-/-)) mice. Within active genes, we uncovered a spatial bias in MMR efficiency: 3' exons, often H3K36me3-enriched, acquire significantly fewer MMR-dependent mutations compared with 5' exons. Huwe1 and Mcm7 genes, both active during lymphocyte development, stood out as mutational hotspots in MMR-deficient cells, demonstrating their intrinsic vulnerability to replication error in this cell type. Both genes are H3K36me3-enriched, which can explain MMR-mediated elimination of replication errors in wild-type cells. Thus, H3K36me3 can boost MMR in transcriptionally active regions, both locally and globally. This offers an attractive concept of thriftyMMR targeting, where critical genes in each cell type enjoy preferential shielding against de novo mutations.
  • Falconi, Marta Tecla; von Lerber, Annakaisa; Ori, Davide; Marzano, Frank Silvio; Moisseev, Dmitri (2018)
    Radar-based snowfall intensity retrieval is investigated at centimeter and millimeter wavelengths using co-located ground-based multi-frequency radar and video-disdrometer observations. Using data from four snowfall events, recorded during the Biogenic Aerosols Effects on Clouds and Climate (BAECC) campaign in Finland, measurements of liquid-water-equivalent snowfall rate S are correlated to radar equivalent reflectivity factors Z(e), measured by the Atmospheric Radiation Measurement (ARM) cloud radars operating at X, Ka and W frequency bands. From these combined observations, power-law Z(e)-S relationships are derived for all three frequencies considering the influence of riming Using microwave radiometer observations of liquid water path, the measured precipitation is divided into lightly, moderately and heavily rimed snow. Interestingly lightly rimed snow events show a spectrally distinct signature of Z(e)-S with respect to moderately or heavily rimed snow cases. In order to understand the connection between snowflake microphysical and multi-frequency backscattering properties, numerical simulations are performed by using the particle size distribution provided by the in situ video disdrometer and retrieved ice particle masses. The latter are carried out by using both the T-matrix method (TMM) applied to soft-spheroid particle models with different aspect ratios and exploiting a pre-computed discrete dipole approximation (DDA) database for rimed aggregates. Based on the presented results, it is concluded that the soft-spheroid approximation can be adopted to explain the observed multifrequency Z(e)-S relations if a proper spheroid aspect ratio is selected. The latter may depend on the degree of riming in snowfall. A further analysis of the backscattering simulations reveals that TMM cross sections are higher than the DDA ones for small ice particles, but lower for larger particles. The differences of computed cross sections for larger and smaller particles are compensating for each other. This may explain why the soft-spheroid approximation is satisfactory for radar reflectivity simulations under study.
  • Andersson, Emma I.; Brück, Oscar; Braun, Till; Mannisto, Susanna; Saikko, Leena; Lagström, Sonja; Ellonen, Pekka; Leppä, Sirpa; Herling, Marco; Kovanen, Panu E.; Mustjoki, Satu (2020)
    Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK(+) ALCL, 38% of ALK ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK(-) ALCL (15%). Concurrent mutations were found in all subgroups except ALK(+) ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30(+) phenotype representing primarily ALK ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.
  • Mason, Shannon L.; Hogan, Robin J.; Westbrook, Christopher D.; Kneifel, Stefan; Moisseev, Dmitri; von Terzi, Leonie (2019)
    The accurate representation of ice particles is essential for both remotely sensed estimates of clouds and precipitation and numerical models of the atmosphere. As it is typical in radar retrievals to assume that all snow is composed of aggregate snowflakes, both denser rimed snow and the mixed-phase cloud in which riming occurs may be under-diagnosed in retrievals and therefore difficult to evaluate in weather and climate models. Recent experimental and numerical studies have yielded methods for using triple-frequency radar measurements to interrogate the internal structure of aggregate snowflakes and to distinguish more dense and homogeneous rimed particles from aggregates. In this study we investigate which parameters of the morphology and size distribution of ice particles most affect the triple-frequency radar signature and must therefore be accounted for in order to carry out triple-frequency radar retrievals of snow. A range of ice particle morphologies are represented, using a fractal representation for the internal structure of aggregate snowflakes and homogeneous spheroids to represent graupel-like particles; the mass-size and area-size relations are modulated by a density factor. We find that the particle size distribution (PSD) shape parameter and the parameters controlling the internal structure of aggregate snowflakes both have significant influences on triple-frequency radar signature and are at least as important as that of the density factor. We explore how these parameters may be allowed to vary in order to prevent triple-frequency radar retrievals of snow from being over-constrained, using two case studies from the Biogenic Aerosols - Effects of Clouds and Climate (BAECC) 2014 field campaign at Hyytiala, Finland. In a case including heavily rimed snow followed by large aggregate snowflakes, we show that triple-frequency radar measurements provide a strong constraint on the PSD shape parameter, which can be estimated from an ensemble of retrievals; however, resolving variations in the PSD shape parameter has a limited impact on estimates of snowfall rate from radar. Particle density is more effectively constrained by the Doppler velocity than triple-frequency radar measurements, due to the strong dependence of particle fall speed on density. Due to the characteristic signatures of aggregate snowflakes, a third radar frequency is essential for effectively constraining the size of large aggregates. In a case featuring rime splintering, differences in the internal structures of aggregate snowflakes are revealed in the triple-frequency radar measurements. We compare retrievals assuming different aggregate snowflake models against in situ measurements at the surface and show significant uncertainties in radar retrievals of snow rate due to changes in the internal structure of aggregates. The importance of the PSD shape parameter and snowflake internal structure to triple-frequency radar retrievals of snow highlights that the processes by which ice particles interact may need to be better understood and parameterized before triple-frequency radar measurements can be used to constrain retrievals of ice particle morphology.
  • Ballhausen, Alexej; Przybilla, Moritz Jakob; Jendrusch, Michael; Haupt, Saskia; Pfaffendorf, Elisabeth; Seidler, Florian; Witt, Johannes; Hernandez Sanchez, Alejandro; Urban, Katharina; Draxlbauer, Markus; Krausert, Sonja; Ahadova, Aysel; Kalteis, Martin Simon; Pfuderer, Pauline L.; Heid, Daniel; Stichel, Damian; Gebert, Johannes; Bonsack, Maria; Schott, Sarah; Blaeker, Hendrik; Seppälä, Toni; Mecklin, Jukka-Pekka; Ten Broeke, Sanne; Nielsen, Maartje; Heuveline, Vincent; Krzykalla, Julia; Benner, Axel; Riemer, Angelika Beate; von Knebel Doeberitz, Magnus; Kloor, Matthias (2020)
    The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers. DNA mismatch repair (MMR)-deficient cancers with microsatellite-instability are characterized by a high load of frameshift mutation-derived neoantigens. Here, by mapping the frameshift mutation landscape and predicting the immunogenicity of the resulting peptides, the authors show evidence of immunoediting in MMR-deficient colorectal and endometrial cancers.
  • Li, Haoran; Moisseev, Dmitri (2020)
    Dual-frequency dual-polarization radar observations of the melting of two ice populations in a stratiform rainfall event are presented. The observed phenomenon occurs as a two-layer linear depolarization ratio (LDR) signature in a single radar bright band. Doppler spectra observations show that the upper LDR layer is caused by the melting of ice needles, potentially generated by the rime-splintering process, while the lower one is mainly due to the melting of background ice particles formed at the cloud top. The melting signal of small needles acts as a unique benchmark for detecting the onset of melting and is used to verify the current methods for the identification of melting layer boundaries. The radar-derived characteristics of the melting layer are found to be dependent on the radar variable and frequency used. The implications of the presented findings for radar-based studies of precipitation properties in and above the melting layer are also discussed.
  • Mäkitie, Riikka E.; Hackl, Matthias; Weigl, Moritz; Frischer, Amelie; Kämpe, Anders; Costantini, Alice; Grillari, Johannes; Mäkitie, Outi (2020)
    Plastin 3 (PLS3), encoded byPLS3, is a newly recognized regulator of bone metabolism, and mutations in the encoding gene result in severe childhood-onset osteoporosis. Because it is an X chromosomal gene,PLS3mutation-positive males are typically more severely affected whereas females portray normal to increased skeletal fragility. Despite the severe skeletal pathology, conventional metabolic bone markers tend to be normal and are thus insufficient for diagnosing or monitoring patients. Our study aimed to explore serum microRNA (miRNA) concentrations in subjects with defective PLS3 function to identify novel markers that could differentiate subjects according to mutation status and give insight into the molecular mechanisms by which PLS3 regulates skeletal health. We analyzed fasting serum samples for a custom-designed panel comprising 192 miRNAs in 15 mutation-positive (five males, age range 8-76 years, median 41 years) and 14 mutation-negative (six males, age range 8-69 years, median 40 years) subjects from four Finnish families with differentPLS3mutations. We identified a unique miRNA expression profile in the mutation-positive subjects with seven significantly upregulated or downregulated miRNAs (miR-93-3p, miR-532-3p, miR-133a-3p, miR-301b-3p, miR-181c-5p, miR-203a-3p, and miR-590-3p;pvalues, range .004-.044). Surprisingly, gender subgroup analysis revealed the difference to be even more distinct in female mutation-positive subjects (congruentpvalues, range .007-.086) than in males (pvalues, range .127-.843) in comparison to corresponding mutation-negative subjects. Although the seven identified miRNAs have all been linked to bone metabolism and two of them (miR-181c-5p and miR-203a-3p) have bioinformatically predicted targets in thePLS33 ' untranslated region (3 '-UTR), none have previously been reported to associate with PLS3. Our results indicate thatPLS3mutations are reflected in altered serum miRNA levels and suggest there is crosstalk between PLS3 and these miRNAs in bone metabolism. These provide new understanding of the pathomechanisms by which mutations inPLS3lead to skeletal disease and may provide novel avenues for exploring miRNAs as biomarkers in PLS3 osteoporosis or as target molecules in future therapeutic applications. (c) 2020 The Authors.Journal of Bone and Mineral Researchpublished by American Society for Bone and Mineral Research.
  • Tiira, Jussi; Moisseev, Dmitri (2020)
    Vertical profiles of polarimetric radar variables can be used to identify fingerprints of snow growth processes. In order to systematically study such manifestations of precipitation processes, we have developed an unsupervised classification method. The method is based on k-means clustering of vertical profiles of polarimetric radar variables, namely reflectivity, differential reflectivity and specific differential phase. For rain events, the classification is applied to radar profiles truncated at the melting layer top. For the snowfall cases, the surface air temperature is used as an additional input parameter. The proposed unsupervised classification was applied to 3.5 years of data collected by the Finnish Meteorological Institute Ikaalinen radar. The vertical profiles of radar variables were computed above the University of Helsinki Hyytiala station, located 64 km east of the radar. Using these data, we show that the profiles of radar variables can be grouped into 10 and 16 classes for rainfall and snowfall events, respectively. These classes seem to capture most important snow growth and ice cloud processes. Using this classification, the main features of the precipitation formation processes, as observed in Finland, are presented.