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https://www.readbyqxmd.com/read/29743177/hypomorphic-rag1-mutations-alter-the-pre-immune-repertoire-at-early-stages-of-lymphoid-development
#1
Lisa M Ott de Bruin, Marita Bosticardo, Alessandro Barbieri, Sherry G Lin, Jared H Rowe, Pietro L Poliani, Kimberly Ching, Daniel Eriksson, Nils Landegren, Olle Kämpe, John P Manis, Luigi D Notarangelo
Hypomorphic RAG1 mutations allowing residual T and B cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T and B cell repertoire. To examine how hypomorphic Rag1 mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with equivalent mutations found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells, preserved serum immunoglobulin, but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29735981/grainyhead-like-2-grhl2-knockout-abolishes-oral-cancer-development-through-reciprocal-regulation-of-the-map-kinase-and-tgf-%C3%AE-signaling-pathways
#2
Wei Chen, Kyung L Kang, Abdullah Alshaikh, Saaket Varma, Yi-Ling Lin, Ki-Hyuk Shin, Reuben Kim, Cun-Yu Wang, No-Hee Park, Katharina Walentin, Kai M Schmidt-Ott, Mo K Kang
Grainyhead-Like 2 (GRHL2) is an epithelial-specific transcription factor that regulates epithelial morphogenesis and differentiation. Prior studies suggested inverse regulation between GRHL2 and TGF-β in epithelial plasticity and potential carcinogenesis. Here, we report the role of GRHL2 in oral carcinogenesis in vivo using a novel Grhl2 knockout (KO) mouse model and the underlying mechanism involving its functional interaction with TGF-β signaling. We developed epithelial-specific Grhl2 conditional KO mice by crossing Grhl2 floxed mice with those expressing CreER driven by the K14 promoter...
May 8, 2018: Oncogenesis
https://www.readbyqxmd.com/read/29723265/molecular-structures-of-cdc2-like-kinases-in-complex-with-a-new-inhibitor-chemotype
#3
Anne Walter, Apirat Chaikuad, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases...
2018: PloS One
https://www.readbyqxmd.com/read/29713087/molecular-subtypes-of-diffuse-large-b-cell-lymphoma-are-associated-with-distinct-pathogenic-mechanisms-and-outcomes
#4
Bjoern Chapuy, Chip Stewart, Andrew J Dunford, Jaegil Kim, Atanas Kamburov, Robert A Redd, Mike S Lawrence, Margaretha G M Roemer, Amy J Li, Marita Ziepert, Annette M Staiger, Jeremiah A Wala, Matthew D Ducar, Ignaty Leshchiner, Ester Rheinbay, Amaro Taylor-Weiner, Caroline A Coughlin, Julian M Hess, Chandra S Pedamallu, Dimitri Livitz, Daniel Rosebrock, Mara Rosenberg, Adam A Tracy, Heike Horn, Paul van Hummelen, Andrew L Feldman, Brian K Link, Anne J Novak, James R Cerhan, Thomas M Habermann, Reiner Siebert, Andreas Rosenwald, Aaron R Thorner, Matthew L Meyerson, Todd R Golub, Rameen Beroukhim, Gerald G Wulf, German Ott, Scott J Rodig, Stefano Monti, Donna S Neuberg, Markus Loeffler, Michael Pfreundschuh, Lorenz Trümper, Gad Getz, Margaret A Shipp
Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data...
April 30, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29708639/the-distribution-of-active-iron-cycling-bacteria-in-marine-and-freshwater-sediments-is-decoupled-from-geochemical-gradients
#5
Julia M Otte, Johannes Harter, Katja Laufer, Nia Blackwell, Daniel Straub, Andreas Kappler, Sara Kleindienst
Microaerophilic, phototrophic, and nitrate-reducing Fe(II)-oxidizers co-exist in coastal marine and littoral freshwater sediments. However, the in situ abundance, distribution, and diversity of metabolically active Fe(II)-oxidizers remained largely unexplored. Here, we characterized the microbial community composition at the oxic-anoxic interface of littoral freshwater (Lake Constance, Germany) and coastal marine sediments (Kalø Vig and Norsminde Fjord, Denmark) using DNA-/RNA-based next-generation 16S rRNA (gene) amplicon sequencing...
April 30, 2018: Environmental Microbiology
https://www.readbyqxmd.com/read/29683319/multiply-intercalator-substituted-cu-ii-cyclen-complexes-as-dna-condensers-and-dna-rna-synthesis-inhibitors
#6
Jan Hormann, Jaroslav Malina, Oliver Lemke, Max J Hülsey, Stefanie Wedepohl, Jan Potthoff, Claudia Schmidt, Ingo Ott, Bettina G Keller, Viktor Brabec, Nora Kulak
Many drugs that are applied in anticancer therapy such as the anthracycline doxorubicin contain DNA-intercalating 9,10-anthraquinone (AQ) moieties. When Cu(II) cyclen complexes were functionalized with up to three (2-anthraquinonyl)methyl substituents, they efficiently inhibited DNA and RNA synthesis resulting in high cytotoxicity (selective for cancer cells) accompanied by DNA condensation/aggregation phenomena. Molecular modeling suggests an unusual bisintercalation mode with only one base pair between the two AQ moieties and the metal complex as a linker...
April 23, 2018: Inorganic Chemistry
https://www.readbyqxmd.com/read/29682197/synthesis-and-anticancer-activity-of-the-derivatives-of-marine-compound-rhizochalin-in-castration-resistant-prostate-cancer
#7
Sergey A Dyshlovoy, Katharina Otte, Kseniya M Tabakmakher, Jessica Hauschild, Tatyana N Makarieva, Larisa K Shubina, Sergey N Fedorov, Carsten Bokemeyer, Valentin A Stonik, Gunhild von Amsberg
Development of resistance to standard therapies complicates treatment of advanced prostate cancer. Alternative splicing variants of the androgen receptor (AR), e.g. AR-V7 can mediate resistance to AR-targeting substances abiraterone and enzalutamide. Semi-synthetic marine natural compound rhizochalinin decreases the expression of AR-V7 in human castration-resistant prostate cancer cells and thus resensitizes cells to enzalutamide. In the current study, we modified the structure of rhizochalin in order to determine structure-activity relationships (SAR) and optimize anticancer properties...
March 30, 2018: Oncotarget
https://www.readbyqxmd.com/read/29672531/embryominer-a-new-framework-for-interactive-knowledge-discovery-in-large-scale-cell-tracking-data-of-developing-embryos
#8
Benjamin Schott, Manuel Traub, Cornelia Schlagenhauf, Masanari Takamiya, Thomas Antritter, Andreas Bartschat, Katharina Löffler, Denis Blessing, Jens C Otte, Andrei Y Kobitski, G Ulrich Nienhaus, Uwe Strähle, Ralf Mikut, Johannes Stegmaier
State-of-the-art light-sheet and confocal microscopes allow recording of entire embryos in 3D and over time (3D+t) for many hours. Fluorescently labeled structures can be segmented and tracked automatically in these terabyte-scale 3D+t images, resulting in thousands of cell migration trajectories that provide detailed insights to large-scale tissue reorganization at the cellular level. Here we present EmbryoMiner, a new interactive open-source framework suitable for in-depth analyses and comparisons of entire embryos, including an extensive set of trajectory features...
April 19, 2018: PLoS Computational Biology
https://www.readbyqxmd.com/read/29666909/-aggressive-b%C3%A2-cell-lymphomas-recommendations-from-the-german-panel-of-reference-pathologists-in-the-competence-network-on-malignant-lymphomas-on-diagnostic-procedures-according-to-the-current-who-classification-update-2017
#9
REVIEW
W Klapper, F Fend, A Feller, M L Hansmann, P Möller, H Stein, A Rosenwald, G Ott
The update of the 4th edition of the WHO classification for hematopoietic neoplasms introduces changes in the field of mature aggressive B‑cell lymphomas that are relevant to diagnostic pathologists. In daily practice, the question arises of which analysis should be performed when diagnosing the most common lymphoma entity, diffuse large B‑cell lymphoma. We discuss the importance of the cell of origin, the analysis of MYC translocations, and the delineation of the new WHO entities of high-grade B‑cell lymphomas...
April 17, 2018: Der Pathologe
https://www.readbyqxmd.com/read/29579807/council-of-europe-black-sea-area-project-international-cooperation-for-the-development-of-activities-related-to-donation-and-transplantation-of-organs-in-the-region
#10
E Arredondo, M López-Fraga, E Chatzixiros, B Senemaud, P Brezovsky, C Carella, C Ballesté, A Aydin Mehmet, G Tomadze, I Codreanu, A A Sarkissian, M Simeonova, A Nikonenko, V Zota, M P Gómez, M Manyalich, C Bolotinha, A Franca, A N Costa, M-O Ott, K-H Buchheit
BACKGROUND: In 2011, the European Directorate for the Quality of Medicines & Healthcare of the Council of Europe launched a 3-year collaborative project to address the organ shortage and improve access to transplant health services in Council of Europe member states in the Black Sea area (Armenia, Azerbaijan, Bulgaria, Georgia, Moldova, Romania, Turkey, Ukraine, and the Russian Federation) through the development of safe and ethical donation and transplantation programs. OBJECTIVE: Support the development of donation and transplantation programs through close interstate cooperation between national health organizations and relevant stakeholders...
March 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29550943/reliability-of-sonographic-fetal-weight-estimation-in-triplet-pregnancies-a-retrospective-cohort-study
#11
Sophie Pils, Stephanie Springer, Rudolf Seemann, Verena Wehrmann, Christof Worda, Johannes Ott
PURPOSE: To review our experience in ultrasound fetal weight estimation in our large population of triplet pregnancies. METHODS: Ninety-seven triplet pregnancies were retrospectively included between January 2003 and January 2017. Sonographic fetal weight estimation using Hadlock's and Schild's formulas was compared to actual birth weight in a tertiary-care center in Vienna, Austria. Statistical analyses were performed using a stepwise linear regression model and crosstabs...
March 17, 2018: Archives of Gynecology and Obstetrics
https://www.readbyqxmd.com/read/29532202/a-systematic-review-and-meta-analysis-of-outpatient-treatment-for-acute-diverticulitis
#12
REVIEW
S T van Dijk, K Bos, M G J de Boer, W A Draaisma, W A van Enst, R J F Felt, B R Klarenbeek, J A Otte, J B C M Puylaert, A A W van Geloven, M A Boermeester
BACKGROUND: The shift from routine antibiotics towards omitting antibiotics for uncomplicated acute diverticulitis opens up the possibility for outpatient instead of inpatient treatment, potentially reducing the burden of one of the most common gastrointestinal diseases in the Western world. PURPOSE: Assessing the safety and cost savings of outpatient treatment in acute colonic diverticulitis. METHODS: PubMed and EMBASE were searched for studies on outpatient treatment of colonic diverticulitis, confirmed with computed tomography or ultrasound...
May 2018: International Journal of Colorectal Disease
https://www.readbyqxmd.com/read/29523641/cpap-as-treatment-of-sleep-apnea-after-stroke-a-meta-analysis-of-randomized-trials
#13
Anne-Kathrin Brill, Thomas Horvath, Andrea Seiler, Millene Camilo, Alan G Haynes, Sebastian R Ott, Matthias Egger, Claudio L Bassetti
OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the effectiveness of continuous positive airway pressure (CPAP) in stroke patients with sleep disordered breathing (SDB). METHODS: In a systematic literature search of electronic databases (MEDLINE, Embase, and the Cochrane Library) from 1980 to November 2016, we identified RCTs that assessed CPAP compared to standard care or sham CPAP in adult patients with stroke or TIA with SDB...
April 3, 2018: Neurology
https://www.readbyqxmd.com/read/29523314/a-multicentre-verification-study-of-the-quantiferon-%C3%A2-tb-gold-plus-assay
#14
E D Pieterman, F G Liqui Lung, A Verbon, H I Bax, C W Ang, J Berkhout, G Blaauw, A Brandenburg, N D van Burgel, A Claessen, K van Dijk, M Heron, M Hooghiemstra, R Leussenkamp-Hummelink, E van Lochem, I H M van Loo, B Mulder, A Ott, O Pontesilli, A Reuwer, P Rombouts, V Saegeman, M Scholing, S Vainio, J E M de Steenwinkel
OBJECTIVES: The aim of this verification study was to compare the QuantiFERON® -TB Gold Plus (QFT-Plus) to the QuantiFERON® -TB Gold In Tube (QFT-GIT). The new QFT-Plus test contains an extra antigen tube which, according to the manufacturer additionally elicits a CD8+ T-cell response above the CD4+ T-cell response. We assessed the value of this tube in detecting recent latent tuberculosis infections. METHODS: Between May 2015 and December 2016, 1031 subjects underwent QFT-Plus and QFT-GIT test...
January 2018: Tuberculosis
https://www.readbyqxmd.com/read/29507391/functional-trim24-degrader-via-conjugation-of-ineffectual-bromodomain-and-vhl-ligands
#15
Lara N Gechijian, Dennis L Buckley, Matthew A Lawlor, Jaime M Reyes, Joshiawa Paulk, Christopher J Ott, Georg E Winter, Michael A Erb, Thomas G Scott, Mousheng Xu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Nicholas P Kwiatkowski, Jennifer A Perry, Jun Qi, Nathanael S Gray, James E Bradner
The addressable pocket of a protein is often not functionally relevant in disease. This is true for the multidomain, bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders. Recruitment of the VHL E3 ubiquitin ligase by dTRIM24 elicits potent and selective degradation of TRIM24...
April 2018: Nature Chemical Biology
https://www.readbyqxmd.com/read/29499840/discovered-acetylcholinesterase-inhibition-and-antibacterial-activity-of-polyacetylenes-in-tansy-root-extract-via-effect-directed-chromatographic-fingerprints
#16
Ágnes M Móricz, Péter G Ott, Gertrud E Morlock
The knowledge about the activity of polyacetylenes was extended by their new acetylcholinesterase inhibition and antibacterial activity against plant pathogenic bacteria. For this discovery, an utmost streamlined workflow, which we consider to be of high potential in the field of natural product or superfood search was developed. It demonstrates the combined power of biological, biochemical and chemical fingerprints. Bioactive components of tansy (Tanacetum vulgare L.) root extract were profiled and identified by high-performance thin-layer chromatography hyphenated with in situ effect-directed analysis, chemical derivatizations and high-resolution mass spectrometry (HPTLC-UV/Vis/FLD-EDA-HRMS)...
March 30, 2018: Journal of Chromatography. A
https://www.readbyqxmd.com/read/29497953/transplantation-of-frozen-thawed-ovarian-tissue-an-update-on-worldwide-activity-published-in-peer-reviewed-papers-and-on-the-danish-cohort
#17
S E Gellert, S E Pors, S G Kristensen, A M Bay-Bjørn, E Ernst, C Yding Andersen
PURPOSE: The purpose of the study is to review all peer-reviewed published reports of women receiving ovarian tissue transplantation (OTT) with frozen/thawed tissue (OTC) with respect to age, diagnosis, transplantation site, fertility outcome, and potential side effects, including data from all women in the Danish program. METHODS: A systematic review of the literature was performed in PubMed combined with results from all patients who had received OTT in Denmark up to December 2017...
April 2018: Journal of Assisted Reproduction and Genetics
https://www.readbyqxmd.com/read/29484661/hyperthermic-isolated-limb-perfusion-preoperative-radiotherapy-and-surgery-prs-a-new-limb-saving-treatment-strategy-for-locally-advanced-sarcomas
#18
Marc G Stevenson, Jojanneke M Seinen, Elisabeth Pras, Adrienne H Brouwers, Robbert J van Ginkel, Barbara L van Leeuwen, Albert J H Suurmeijer, Lukas B Been, Harald J Hoekstra
BACKGROUND: This feasibility study presents the results of a new intensive treatment regimen for locally advanced extremity soft tissue sarcomas (ESTS), consisting of hyperthermic isolated limb perfusion (HILP), preoperative external beam radiotherapy (EBRT), and surgical resection. METHODS: From 2011 to 2016, 11 high grade locally advanced ESTS patients underwent this treatment regimen. Preoperative EBRT (12 × 3 Gy) started <4 weeks following the HILP (TNF-α and melphalan) and the surgical resection was planned to take place <2 weeks following the end of the EBRT...
February 26, 2018: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/29477386/visualisation-of-intracellular-production-bottlenecks-in-suspension-adapted-cho-cells-producing-complex-biopharmaceuticals-using-fluorescence-microscopy
#19
Sven Mathias, Simon Fischer, René Handrick, Jürgen Fieder, Patrick Schulz, Harald Bradl, Ingo Gorr, Martin Gamer, Kerstin Otte
With the advance of complex biological formats such as bispecific antibodies or fusion proteins, mammalian expression systems often show low performance. Described determining factors may be accumulation or haltering of heterologous proteins within the different cellular compartments disturbing transport or secretion. In case of the investigated bispecific antibody (bsAb)-producing Chinese hamster ovary (CHO) cell line neither impaired transcription nor decreased translation processes were identified and thus satisfactorily explained its low production capacity...
April 10, 2018: Journal of Biotechnology
https://www.readbyqxmd.com/read/29468480/phenotypic-plasticity-of-cuticular-hydrocarbon-profiles-in-insects
#20
REVIEW
Tobias Otte, Monika Hilker, Sven Geiselhardt
The insect integument is covered by cuticular hydrocarbons (CHCs) which provide protection against environmental stresses, but are also used for communication. Here we review current knowledge on environmental and insect-internal factors which shape phenotypic plasticity of solitary living insects, especially herbivorous ones. We address the dynamics of changes which may occur within minutes, but may also last weeks, depending on the species and conditions. Two different modes of changes are suggested, i.e...
March 2018: Journal of Chemical Ecology
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