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  • 1
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    Totowa, N.J. : Humana Press
    Associated volumes
    Call number: QH506:60/322 ; A050:87
    Keywords: Xenopus Laevis ; Eggs ; Cytology ; Signal Transduction
    Pages: xv, 489 p. : ill.
    ISBN: 9781588293626
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    QH506:60/322 available
    A050:87 departmental collection or stack – please contact the library
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  • 2
    Publication Date: 2018-07-20
    Description: Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
    Keywords: Cell Biology, Medicine, Diseases
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2018-05-18
    Description: Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) comprises ~10% to 15% of childhood ALL cases, many of which respond exquisitely to tyrosine kinase inhibitors (TKIs), for example, imatinib in PDGFRB -rearranged ALL. However, some cases developed drug resistance to TKIs and the mechanisms are poorly understood. In this study, we identified a novel PDGFRB fusion gene, namely AGGF1 - PDGFRB , and functionally characterized its oncogenic potential in vitro. Further genomic profiling of longitudinally collected samples during treatment revealed the emergence of a mutation, PDGFRB C843G , which directly conferred resistance to all generations of ABL TKIs, including imatinib, dasatinib, nilotinib, and ponatinib. PDGFRB -mutant leukemia cells are highly sensitive to multitarget kinase inhibitor CHZ868, suggesting potential therapeutic options for some patients resistant to ABL TKIs. In summary, we describe a complex clonal evolution pattern in Ph-like ALL and identified a novel PDGFRB point mutation that drives leukemia relapse after ABL TKI treatment.
    Keywords: Free Research Articles, Lymphoid Neoplasia, CME article, Brief Reports
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 4
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  132. Kongress der Deutschen Gesellschaft für Chirurgie; 20150428-20150501; München; DOC15dgch139 /20150424/
    Publication Date: 2015-04-25
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 5
    Keywords: CANCER ; BLOOD ; DISEASE ; RISK ; GENE ; PROTEIN ; SAMPLES ; PATIENT ; DNA ; FAMILY ; FREQUENCY ; BREAST ; BREAST-CANCER ; family history ; OVARIAN-CANCER ; WOMEN ; MUTATION ; MUTATIONS ; PREVALENCE ; BRCA1/2 ; BRCA2 MUTATIONS ; early-onset breast cancer ; German population ; germline mutations ; POPULATION-BASED SAMPLE
    Abstract: This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high- risk populations
    Type of Publication: Journal article published
    PubMed ID: 12774040
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  • 6
    Keywords: BOVINE, CELL, CELLS, endocytosis, endothelial cell, endothelial cells, ENDOTHELIAL-CELLS, PRODUCTS
    Abstract: Objectives: Age-related changes in Bruch's membrane (BM), situated between the retina and the choroid, include the accumulation of advanced glycation end-products (AGEs) and other modified macromolecules. An important clearance mechanism for such molecules is endocytosis via macrophages and specialized endothelial cells. This study examined the endocytic clearance of AGEs in choriocapillaris endothelial (CCE) cells, which are strategically located beneath the BM. Materials and Methods: Bovine CCE cultures were incubated with radiolabeled or fluorescently labeled AGE-modified bovine serum albumin (AGE-BSA). Cells and tissues were examined for the expression of two AGE-binding scavenger receptors, stabilin-1 and -2, by immunohistochemistry and Western blotting, and with antibody inhibition studies. Results: CCE cells effectively endocytosed AGE-BSA via a scavenger receptor-mediated pathway. A polyclonal antibody against stabilin-2 significantly inhibited endocytosis (40%). Tissue sections stained positive for stabilin-2 and -1 in the choriocapillaris layer, which was confirmed by immunoblots of cell extracts. Colocalization of stabilin-1 and -2 and internalized AGE-BSA was seen in early endosomes. Conclusions: CCEs actively endocytose AGE-BSA and express the scavenger receptors, stabilin-1 and -2, of which at least stabilin-2 is involved in AGE-BSA uptake. Impairment of this stabilin-mediated clearance function may contribute to depositions of waste macromolecules in BM and subsequent retinopathy.
    Type of Publication: Journal article published
    PubMed ID: 19657967
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  • 7
    Abstract: Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5 flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5 flanking regions suggests that this locus is involved in 1% of individuals with ASD and intellectual disability.
    Type of Publication: Journal article published
    PubMed ID: 20844286
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  • 8
    Keywords: CANCER ; COHORT ; RISK ; SWEDEN ; adenocarcinoma ; CARCINOID-TUMORS ; PSORIASIS ; DISORDERS ; MYASTHENIA-GRAVIS ; autoimmune disease ; FAMILIAL RISKS ; PERNICIOUS-ANEMIA ; HOSPITALIZATIONS ; digestive tract
    Abstract: BACKGROUND: Dysregulation of the immune function in autoimmune diseases could potentially lead to cancer development and there is definite evidence linking some autoimmune mechanisms with cancer. We analyzed systematically the occurrence of histology-specific digestive tract cancers in patients diagnosed with 33 different autoimmune diseases in order to address the question of shared susceptibility. PATIENTS AND METHODS: Standardized incidence ratios (SIRs) were calculated for subsequent digestive tract cancers up to the year 2008 and in patients hospitalized for autoimmune disease after the year 1964. RESULTS: Myasthenia gravis associated with five different cancers with SIRs ranging from 1.35 to 2.78. Pernicious anemia, Crohn disease, ulcerative colitis, systemic lupus erythematosis and psoriasis were also associated with cancers at multiple sites. Rheumatoid arthritis associated with no cancer and the standardized incidence ratio was decreased for colon adenocarcinoma, also in ankylosing spondylitis patients. CONCLUSIONS: Increased risks of cancer were observed in patients with several autoimmune diseases. Myasthenia gravis and pernicious anemia were associated with many cancers; this is possibly related to immunosuppressant medication in myasthenia gravis. The decreased risks in colon and rectal adenocarcinomas in rheumatoid arthritis and ankylosing spondylitis suggest underlying inflammatory mechanisms as the risks may have been suppressed by the use of anti-inflammatory medication.
    Type of Publication: Journal article published
    PubMed ID: 21810731
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  • 9
    Keywords: EXPRESSION ; TUMORS ; ABERRATIONS ; METHYLATION ; EMBRYONIC STEM-CELLS ; MULTIFORME ; HIGH-GRADE GLIOMAS ; TELOMERES ; INTEGRATED GENOMIC ANALYSIS ; ATRX
    Abstract: Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis
    Type of Publication: Journal article published
    PubMed ID: 22286061
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  • 10
    Keywords: FOLLOW-UP ; BREAST-CANCER ; SWEDEN ; aspirin ; MALIGNANCY ; RHEUMATOID-ARTHRITIS PATIENTS ; METAANALYSIS ; FAMILIAL RISKS ; HOSPITALIZATIONS ; HYPOTHYROIDISM
    Abstract: OBJECTIVES: Patients with autoimmune (AI) diseases are diagnosed with increased frequencies of some cancers, which may depend on the underlying dysregulation of the immune system or treatment. Data on female cancers are limited. METHODS: We analyzed systematically risk and survival of female cancers of the breast, uterus, ovary and other genital organs in close to 200,000 patients diagnosed with any of 33 different AI diseases. Standardized incidence ratios (SIRs) for risk and hazard ratios (HRs) for survival were calculated for subsequent incident cancers or cancer deaths up to year 2008. RESULTS: For all breast cancer after any AI diseases, the SIR was 0.94; SIRs were modestly increased after two AI diseases and decreased after nine AI diseases, including Sjogren syndrome (0.46). For cervical cancer, the risk was increased after discoid lupus erythematosus (3.34) and systemic sclerosis (2.43). The HR was 2.12 in chronic rheumatic heart disease patients. The overall SIR for endometrial cancer was 0.85, with low SIR in ankylosing spondylitis (0.37); the HR was 4.05 for Sjogren syndrome. The SIR for ovarian cancer was increased for polymyositis/dermatomyositis (3.26) while the HR was increased for multiple sclerosis (2.43). The overall SIR for other genital cancers was increased to 1.54 and a very high risk of 35.88 was observed in localized scleroderma. CONCLUSIONS: Breast, endometrial and ovarian cancers were decreased after all AI diseases and most significant changes after individual AI diseases were towards lower risks. Probably treatment related factors explain the findings. For cervical and other genital cancers all significant changes were increased risks.
    Type of Publication: Journal article published
    PubMed ID: 22819787
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