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Berlin Brandenburg

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  • 1
    Language: English
    In: Nature, 24 September 2015, Vol.525(7570), pp.543-547
    Description: Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies.
    Keywords: Azepines -- Pharmacology ; Drug Resistance, Neoplasm -- Drug Effects ; Gene Expression Regulation, Neoplastic -- Drug Effects ; Leukemia, Myeloid, Acute -- Genetics ; Nuclear Proteins -- Antagonists & Inhibitors ; Transcription Factors -- Antagonists & Inhibitors ; Transcription, Genetic -- Drug Effects ; Triazoles -- Pharmacology
    ISSN: 00280836
    E-ISSN: 1476-4687
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  • 2
    Language: English
    In: PLoS ONE, 2012, Vol.7(1), p.e29925
    Description: The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring 3 H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC 50 values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1 nu mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC 50 0.5–1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.
    Keywords: Research Article ; Biology ; Immunology ; Molecular Biology ; Cell Biology ; Developmental Biology
    E-ISSN: 1932-6203
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 02 October 2012, Vol.109(40), pp.16041-5
    Description: Gene regulation by DNA binding small molecules could have important therapeutic applications. This study reports the investigation of a DNA-binding pyrrole-imidazole polyamide targeted to bind the DNA sequence 5'-WGGWWW-3' with reference to its potency in a subcutaneous xenograft tumor model. The molecule is capable of trafficking to the tumor site following subcutaneous injection and modulates transcription of select genes in vivo. An FITC-labeled analogue of this polyamide can be detected in tumor-derived cells by confocal microscopy. RNA deep sequencing (RNA-seq) of tumor tissue allowed the identification of further affected genes, a representative panel of which was interrogated by quantitative reverse transcription-PCR and correlated with cell culture expression levels.
    Keywords: Transplantation, Heterologous ; DNA -- Metabolism ; Gene Expression Regulation, Neoplastic -- Drug Effects ; Imidazoles -- Pharmacology ; Nylons -- Pharmacology ; Pyrroles -- Pharmacology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Biophysical Journal, 05 November 2013, Vol.105(9), pp.2016-2023
    Description: Bacterial spores in a metabolically dormant state can survive long periods without nutrients under extreme environmental conditions. The molecular basis of spore dormancy is not well understood, but the distribution and physical state of water within the spore is thought to play an important role. Two scenarios have been proposed for the spore’s core region, containing the DNA and most enzymes. In the gel scenario, the core is a structured macromolecular framework permeated by mobile water. In the glass scenario, the entire core, including the water, is an amorphous solid and the quenched molecular diffusion accounts for the spore’s dormancy and thermal stability. Here, we use H magnetic relaxation dispersion to selectively monitor water mobility in the core of spores in the presence and absence of core Mn ions. We also report and analyze the solid-state H NMR spectrum from these spores. Our NMR data clearly support the gel scenario with highly mobile core water (∼25 ps average rotational correlation time). Furthermore, we find that the large depot of manganese in the core is nearly anhydrous, with merely 1.7% on average of the maximum sixfold water coordination.
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
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  • 5
    Language: English
    In: Journal of bacteriology, September 2012, Vol.194(17), pp.4537-45
    Description: The SleB protein is one of two redundant cortex-lytic enzymes (CLEs) that initiate the degradation of cortex peptidoglycan (PG), a process essential for germination of spores of Bacillus species, including Bacillus anthracis. SleB has been characterized as a soluble lytic transglycosylase that specifically recognizes spore cortex PG and catalyzes the cleavage of glycosidic bonds between N-acetylmuramic acid (NAM) and N-acetylglucosamine residues with concomitant formation of a 1,6-anhydro bond in the NAM residue. We found that like the full-length Bacillus cereus SleB, the catalytic C-terminal domain (SleB(C)) exhibited high degradative activity on cortex PG in vitro, although SleB's N-terminal domain, thought to bind PG, was inactive. The 1.85-Å crystal structure of SleB(C) reveals an ellipsoid molecule with two distinct domains dominated by either α helices or β strands. The overall fold of SleB closely resembles that of the catalytic domain of the family 1 lytic transglycosylases but with a completely different topological arrangement. Structural analysis shows that an invariant Glu157 of SleB is in a position equivalent to that of the catalytic glutamate in other lytic transglycosylases. Indeed, SleB bearing a Glu157-to-Gln mutation lost its cortex degradative activity completely. In addition, the other redundant CLE (called CwlJ) in Bacillus species likely has a three-dimensional structure similar to that of SleB, including the invariant putative catalytic Glu residue. SleB and CwlJ may offer novel targets for the development of anti-spore agents.
    Keywords: Amidohydrolases -- Chemistry ; Bacillus Cereus -- Metabolism ; Bacterial Proteins -- Chemistry ; Peptidoglycan -- Metabolism ; Spores, Bacterial -- Enzymology
    ISSN: 00219193
    E-ISSN: 1098-5530
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  • 6
    Language: English
    In: Women's Studies International Forum, 1996, Vol.19(4), pp.395-407
    Description: The Petze project was set up in Germany in 1992 to train teachers in preventing sexual violence against boys and girls. The project focused on the needs of young students over 12 years and interrogated male and female teachers about their views. The method of proactive prevention was primarily self-reflection work among the teachers. The training benefited the teachers, who are still continuing with violence prevention in schools and professional groups.
    Keywords: Women'S Studies
    ISSN: 0277-5395
    E-ISSN: 1879-243X
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  • 7
    Language: English
    In: American Journal of Surgery, July, 2012, Vol.204(1), p.23(5)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.amjsurg.2011.07.023 Byline: Brionna Hair (a), Peter Hussey (b), Barbara Wynn (b) Keywords: Ambulatory surgery; Ambulatory surgery center; Hospital outpatient department; Anesthesia use; Surgical time Abstract: The volume of surgical procedures performed in ambulatory surgical centers has increased rapidly. Author Affiliation: (a) Department of Epidemiology, University of North Carolina at Chapel Hill, CB #7435, 2101 McGavran-Greenberg Hall, Chapel Hill, NC 27599-7435, USA (b) RAND Corporation, Arlington, VA, USA Article History: Received 29 April 2011; Revised 29 July 2011 Article Note: (footnote) Work originated from the RAND Corporation., Peter Hussey and Barbara Wynn are employees of RAND Corporation; Brionna Hair reports no conflicts of interest.
    Keywords: Surgical Clinics -- Comparative Analysis ; Surgical Clinics -- Analysis
    ISSN: 0002-9610
    E-ISSN: 18791883
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  • 8
    Language: English
    In: Neuropsychologia, August 2013, Vol.51(10), pp.1802-1813
    Description: Grapheme-color synesthetes perceive color when reading letters or digits. We investigated oscillatory brain signals of synesthetes vs. controls using magnetoencephalography. Brain oscillations specifically in the alpha band (∼10 Hz) have two interesting features: alpha has been linked to inhibitory processes and can act as a marker for attention. The possible role of reduced inhibition as an underlying cause of synesthesia, as well as the precise role of attention in synesthesia is widely discussed. To assess alpha power effects due to synesthesia, synesthetes as well as matched controls viewed synesthesia-inducing graphemes, colored control graphemes, and non-colored control graphemes while brain activity was recorded. Subjects had to report a color change at the end of each trial which allowed us to assess the strength of synesthesia in each synesthete. Since color (synesthetic or real) might allocate attention we also included an attentional cue in our paradigm which could direct covert attention. In controls the attentional cue always caused a lateralization of alpha power with a contralateral decrease and ipsilateral alpha increase over occipital sensors. In synesthetes, however, the influence of the cue was overruled by color: independent of the attentional cue, alpha power decreased contralateral to the color (synesthetic or real). This indicates that in synesthetes color guides attention. This was confirmed by reaction time effects due to color, i.e. faster RTs for the color side independent of the cue. Finally, the stronger the observed color dependent alpha lateralization, the stronger was the manifestation of synesthesia as measured by congruency effects of synesthetic colors on RTs. Behavioral and imaging results indicate that color induces a location-specific, automatic shift of attention towards color in synesthetes but not in controls. We hypothesize that this mechanism can facilitate coupling of grapheme and color during the development of synesthesia.
    Keywords: Synaesthesia ; Attention ; Colour ; Alpha Oscillations ; Magnetoencephalography ; Medicine
    ISSN: 0028-3932
    E-ISSN: 1873-3514
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  • 9
    In: Circulation, 2016, Vol.133(14), pp.e592-e593
    Description: We thank Dr Belge and colleagues for their interest in our study reporting mitomycin-C–induced pulmonary veno-occlusive disease (PVOD) in patients displaying anal cancer and our preclinical model of PVOD in rats.1 Interestingly, they report 2 additional cases of PVOD in patients with anal cancer treated with mitomycin-C and 5-fluorouracil, initially masquerading as drug-induced pulmonary arterial hypertension according to the precapillary pulmonary hypertension pattern on right-sided heart catheterization and the absence of radiological abnormalities detected on high-resolution computed tomography (HRCT) of the chest. These 2 cases highlight the difficulty in accurately diagnosing PVOD in clinical practice. The crucial issue is that a definite diagnosis of PVOD is based on pathological assessment, but lung biopsies are contraindicated in these frail patients.2 Thus, diagnosis of PVOD requires a multiple noninvasive approach.2,3 Even if PVOD is characterized by anatomic obstruction of pulmonary venules, right-sided heart catheterization typically shows a precapillary pulmonary hypertension pattern.2,3 The explanation is that pulmonary artery wedge pressure merely reflects the pressure in a pulmonary vein of the same size as the wedged pulmonary artery.2 At …
    Keywords: Medicine ; Anatomy & Physiology;
    ISSN: 0009-7322
    E-ISSN: 15244539
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  • 10
    Language: English
    In: Journal of bacteriology, September 2011, Vol.193(17), pp.4523-30
    Description: We identified two additional genes of Helicobacter pylori encoding Ccrp proteins. All four Ccrps have different multimerization and filamentation properties and different types of smallest subunits and do not copurify, suggesting a system of individual Ccrp filaments. Despite the presence of morphologically unaltered flagella, all ccrp mutants displayed significantly reduced motility.
    Keywords: Genes, Bacterial ; Bacterial Proteins -- Metabolism ; Helicobacter Pylori -- Genetics
    ISSN: 00219193
    E-ISSN: 1098-5530
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