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  • 1
    Online-Ressource
    Online-Ressource
    Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 13 ( 2019-03-26), p. 6308-6312
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 13 ( 2019-03-26), p. 6308-6312
    Kurzfassung: Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6–8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage ( 〈 3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1819799116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2019
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
    Open Access Wunsch
    Verfügbarkeit (elektronisch / print)
    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 2
    Online-Ressource
    Online-Ressource
    Arsenic trioxide replacing or reducing chemotherapy in consolidation therapy for acute promyelocytic leukemia (APL2012 trial)
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 6 ( 2021-02-09)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 6 ( 2021-02-09)
    Kurzfassung: As all- trans retinoic acid (ATRA) and arsenic trioxide (ATO) are widely accepted in treating acute promyelocytic leukemia (APL), deescalating toxicity becomes a research hotspot. Here, we evaluated whether chemotherapy could be replaced or reduced by ATO in APL patients at different risks. After achieving complete remission with ATRA-ATO–based induction therapy, patients were randomized (1:1) into ATO and non-ATO groups for consolidation: ATRA-ATO versus ATRA–anthracycline for low-/intermediate-risk patients, or ATRA-ATO–anthracycline versus ATRA–anthracycline–cytarabine for high-risk patients. The primary end point was to assess disease-free survival (DFS) at 3 y by a noninferiority margin of –5%; 855 patients were enrolled with a median follow-up of 54.9 mo, and 658 of 755 patients could be evaluated at 3 y. In the ATO group, 96.1% (319/332) achieved 3-y DFS, compared to 92.6% (302/326) in the non-ATO group. The difference was 3.45% (95% CI –0.07 to 6.97), confirming noninferiority ( P 〈 0.001). Using the Kaplan–Meier method, the estimated 7-y DFS was 95.7% (95% CI 93.6 to 97.9) in ATO and 92.6% (95% CI 89.8 to 95.4) in non-ATO groups ( P = 0.066). Concerning secondary end points, the 7-y cumulative incidence of relapse (CIR) was significantly lower in ATO (2.2% [95% CI 1.1 to 4.2]) than in non-ATO group (6.1% [95% CI 3.9 to 9.5] , P = 0.011). In addition, grade 3 to 4 hematological toxicities were significantly reduced in the ATO group during consolidation. Hence, ATRA-ATO in both chemotherapy-replacing and -reducing settings in consolidation is not inferior to ATRA–chemotherapy ( https://www.clinicaltrials.gov/ , NCT01987297).
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2020382118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2021
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
    Open Access Wunsch
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 3
    Online-Ressource
    Online-Ressource
    Cysteine carboxyethylation generates neoantigens to induce HLA-restricted autoimmunity
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 379, No. 6637 ( 2023-03-17)
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6637 ( 2023-03-17)
    Kurzfassung: Autoimmune diseases such as ankylosing spondylitis (AS) can be caused by emerging neoantigens that break immune tolerance in humans. Posttranslational modifications (PTMs) have been shown to be a critical mechanism that alters protein structure and function to generate neoantigens and induce subsequent autoimmune responses. Previous studies have confirmed that citrulline-modified peptides are a critical source of neoantigens in rheumatoid arthritis. However, the molecular mechanisms underlying neoantigen formation and pathogenic autoreactive responses for AS are largely unknown. There is an urgent need to develop a systematic approach to profiling the possible PTMs in patients with AS and identifying AS-associated PTMs responsible for autoreactive neoantigen production to better understand the etiology of autoimmune diseases. RATIONALE AS has been suggested to be an autoimmune disease because of its clear correlation with certain major histocompatibility complex (MHC) alleles, including HLA-B27. Neoantigens have been hypothesized to induce an aberrant immune response, leading to pathogenic autoreactive T cell responses and autoantibody generation in AS. Here, we developed a systematic open search approach to identify any possible amino acid residues and derivatives in the proteins that are different from the genomic coding sequences. We then applied this information to identify AS-related neoantigens with PTMs within a possible pool of PTM autoantigens and elucidate the pathogenesis of AS. RESULTS An open search approach was applied to identify any possible amino acid derivatives across the proteome of patients with AS. This approach generated a large set of noncoded amino acids representing the mass differences between the coded amino acids and actual residues. Among these, an amino acid derivative with a delta mass of 72.021 showed the greatest increase in patients with AS and resulted from a PTM called cysteine carboxyethylation. In vitro and in vivo experiments demonstrated that carboxyethylation at a cysteine residue of integrin αIIb [ITGA2B (CD41)] was catalyzed by cystathionine beta synthase (CBS) in a process that required 3-hydroxypropionic acid (3-HPA), a metabolite commonly released from gut microbes. Cysteine carboxyethylation induced the lysosomal degradation of ITGA2B and produced neoantigens that triggered MHC-II–dependent CD4 + T cell responses. Fluorescence polarization and enzyme-linked immunosorbent assay (ELISA) demonstrated that the identified carboxyethylated peptide (ITGA2B-ceC96) specifically interacted with HLA-DRA*01/HLA-DRB1*04 and was associated with autoantibody production and T cell responses in HLA-DRB1*04 patients. Additional in vitro assays showed that the neoantigen ITGA2B-ceC96 correlated with 3-HPA levels but was independent of CBS expression. HLA-DRB1 haplotype, the carboxyethylated peptide, specific autoantibodies, and 3-HPA levels in patients with AS all correlated with one another. 3-HPA–treated and ITGA2B-ceC96–immunized HLA-DR4 transgenic mice developed colitis and vertebral bone erosion. Thus, cysteine carboxyethylation induced by the metabolite 3-HPA generates a neoantigen that appears to be critical for autoimmune responses in patients with AS. CONCLUSION Cysteine carboxyethylation is an in vivo protein modification induced by the metabolite 3-HPA, which is commonly released from gut microbes. Carboxyethylated ITGA2B then induces autoantibody production and autoimmune response in AS. Our work provides a systematic workflow to identify differentially modified proteins that are important for neoantigen production in immune disorders. This approach furthers our understanding of AS pathogenesis and may aid in the development of neoantigen-based diagnosis and treatment for AS and other autoimmune diseases. Metabolite-induced cysteine carboxyethylation provokes HLA-restricted autoimmune responses in ankylosing spondylitis. 3-HPA, which is commonly obtained from food and gut microbes, induces carboxyethylation of cysteine residues in integrin αIIb (ITGA2B). Cysteine carboxyethylation requires CBS, and carboxyethylated ITGA2B (ITGA2B-ceC96) peptides are recruited to the HLA-DR4 complex and thereby stimulate CD4 + T cell responses closely related to AS.
    Materialart: Online-Ressource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.abg2482
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: American Association for the Advancement of Science (AAAS)
    Publikationsdatum: 2023
    ZDB Id: 128410-1
    ZDB Id: 2066996-3
    ZDB Id: 2060783-0
    SSG: 11
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Wissenschaftspark Albert Einstein
    TH Wildau
  • 4
    Online-Ressource
    Online-Ressource
    Structural selection of graphene supramolecular assembly oriented by molecular conformation and alkyl chain
    Proceedings of the National Academy of Sciences ; 2008
    In:  Proceedings of the National Academy of Sciences Vol. 105, No. 44 ( 2008-11-04), p. 16849-16854
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 44 ( 2008-11-04), p. 16849-16854
    Kurzfassung: Graphene molecules, hexafluorotribenzo[a,g,m]coronene with n -carbon alkyl chains (FTBC-Cn, n = 4, 6, 8, 12) and Janus-type “double-concave” conformation, are used to fabricate self-assembly on highly oriented pyrolytic graphite surface. The structural dependence of the self-assemblies with molecular conformation and alkyl chain is investigated by scanning tunneling microscopy and density functional theory calculation. An interesting reverse face “up–down” way is observed in FTBC-C4 assembly due to the existence of hydrogen bonds. With the increase of the alkyl chain length and consequently stronger van der Waals interaction, the molecules no longer take alternating “up–down” orientation in their self-assembly and organize into various adlayers with lamellar, hexagonal honeycomb, and pseudohoneycomb structures based on the balance between intermolecular and molecule-substrate interactions. The results demonstrate that the featured “double-concave” molecules are available block for designing graphene nanopattern. From the results of scanning tunneling spectroscopy measurement, it is found that the electronic property of the featured graphene molecules is preserved when they are adsorbed on solid surface.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0809427105
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2008
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 5
    Online-Ressource
    Online-Ressource
    Reply to Ma and Zuo: Ecological restoration on the Tibetan Plateau would benefit terrestrial CO 2 uptake
    Proceedings of the National Academy of Sciences ; 2022
    In:  Proceedings of the National Academy of Sciences Vol. 119, No. 5 ( 2022-02)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 119, No. 5 ( 2022-02)
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2121009119
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2022
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 6
    Online-Ressource
    Online-Ressource
    Genomic landscape of CD34 + hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 23 ( 2014-06-10), p. 8589-8594
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 23 ( 2014-06-10), p. 8589-8594
    Kurzfassung: Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34 + hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34 + versus CD34 − cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB ( n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) ( n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1407688111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2014
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 7
    Online-Ressource
    Online-Ressource
    DNMT3A Arg882 mutation drives chronic myelomonocytic leukemia through disturbing gene expression/DNA methylation in hematopoietic cells
    Proceedings of the National Academy of Sciences ; 2014
    In:  Proceedings of the National Academy of Sciences Vol. 111, No. 7 ( 2014-02-18), p. 2620-2625
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 111, No. 7 ( 2014-02-18), p. 2620-2625
    Kurzfassung: The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in ∼20% of acute myeloid leukemia cases, with Arg882 (R882) as the hotspot. Here, we addressed the transformation ability of the DNMT3A-Arg882His (R882H) mutant by using a retroviral transduction and bone marrow transplantation (BMT) approach and found that the mutant gene can induce aberrant proliferation of hematopoietic stem/progenitor cells. At 12 mo post-BMT, all mice developed chronic myelomonocytic leukemia with thrombocytosis. RNA microarray analysis revealed abnormal expressions of some hematopoiesis-related genes, and the DNA methylation assay identified corresponding changes in methylation patterns in gene body regions. Moreover, DNMT3A-R882H increased the CDK1 protein level and enhanced cell-cycle activity, thereby contributing to leukemogenesis.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1400150111
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2014
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 8
    Online-Ressource
    Online-Ressource
    Plant uptake of CO 2 outpaces losses from permafrost and plant respiration on the Tibetan Plateau
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 33 ( 2021-08-17)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 33 ( 2021-08-17)
    Kurzfassung: High-latitude and high-altitude regions contain vast stores of permafrost carbon. Climate warming may result in the release of CO 2 from both the thawing of permafrost and accelerated autotrophic respiration, but it may also increase the fixation of CO 2 by plants, which could relieve or even offset the CO 2 losses. The Tibetan Plateau contains the largest area of alpine permafrost on Earth. However, the current status of the net CO 2 balance and feedbacks to warming remain unclear, given that the region has recently experienced an atmospheric warming rate of over 0.3 °C decade −1 . We examined 32 eddy covariance sites and found an unexpected net CO 2 sink during 2002 to 2020 (26 of the sites yielded a net CO 2 sink) that was four times the amount previously estimated. The CO 2 sink peaked at an altitude of roughly 4,000 m, with the sink at lower and higher altitudes limited by a low carbon use efficiency and a cold, dry climate, respectively. The fixation of CO 2 in summer is more dependent on temperature than the loss of CO 2 than it is in the winter months, especially at higher altitudes. Consistently, 16 manipulative experiments and 18 model simulations showed that the fixation of CO 2 by plants will outpace the loss of CO 2 under a wetting–warming climate until the 2090s (178 to 318 Tg C y −1 ). We therefore suggest that there is a plant-dominated negative feedback to climate warming on the Tibetan Plateau.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2015283118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2021
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 9
    Online-Ressource
    Online-Ressource
    A fault prediction method that uses improved case-based reasoning to continuously predict the status of a shaft furnace
    Elsevier BV ; 2014
    In:  Information Sciences Vol. 259 ( 2014-02), p. 269-281
    Details
    In: Information Sciences, Elsevier BV, Vol. 259 ( 2014-02), p. 269-281
    Materialart: Online-Ressource
    ISSN: 0020-0255
    URL: Article
    DOI: 10.1016/j.ins.2013.04.025
    RVK:
    SA 5420
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2014
    ZDB Id: 218760-7
    ZDB Id: 1478990-5
    SSG: 24,1
    SSG: 7,11
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    TH Wildau
  • 10
    Online-Ressource
    Online-Ressource
    HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 28 ( 2021-07-13)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 28 ( 2021-07-13)
    Kurzfassung: Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB–mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2 +/− bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2 −/− BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2021798118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2021
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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    Online-Ressource
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
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