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  1. Article ; Online: Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction.

    Mar, Florie A / Debnath, Jayanta / Stohr, Bradley A

    Autophagy

    2015  Volume 11, Issue 3, Page(s) 527–537

    Abstract: Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and ... ...

    Abstract Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Recent work has shown that the autophagy pathway regulates both senescence and genome instability in various contexts. Here, we apply models of acute telomere dysfunction to determine whether autophagy modulates the resulting genome instability and senescence responses. While telomere dysfunction rapidly induces autophagic flux in human fibroblast cell lines, inhibition of the autophagy pathway does not have a significant impact upon the transition to senescence, in contrast to what has previously been reported for oncogene-induced senescence. Our results suggest that this difference may be explained by disparities in the development of the senescence-associated secretory phenotype. We also show that chromosome fusions induced by telomere dysfunction are comparable in autophagy-proficient and autophagy-deficient cells. Altogether, our results highlight the complexity of the senescence-autophagy interface and indicate that autophagy induction is unlikely to play a significant role in telomere dysfunction-driven senescence and chromosome fusions.
    MeSH term(s) Animals ; Autophagy ; Autophagy-Related Protein 5 ; Autophagy-Related Protein 7 ; Cell Proliferation ; Cellular Senescence ; Chromosomes/ultrastructure ; DNA Repair ; Enzyme-Linked Immunosorbent Assay ; Fibroblasts/metabolism ; Genomic Instability ; Genomics ; Humans ; In Situ Hybridization, Fluorescence ; Interleukin-6/metabolism ; Interleukin-8/metabolism ; Mice ; Mice, Knockout ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/genetics ; Phenotype ; Shelterin Complex ; Telomere/ultrastructure ; Telomere-Binding Proteins
    Chemical Substances ACD protein, human ; Acd protein, mouse ; Atg5 protein, mouse ; Atg7 protein, mouse ; Autophagy-Related Protein 5 ; Interleukin-6 ; Interleukin-8 ; Microtubule-Associated Proteins ; Shelterin Complex ; Telomere-Binding Proteins ; Autophagy-Related Protein 7 (EC 6.2.1.45)
    Language English
    Publishing date 2015-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2454135-7
    ISSN 1554-8635 ; 1554-8627
    ISSN (online) 1554-8635
    ISSN 1554-8627
    DOI 10.1080/15548627.2015.1017189
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Autophagy in stromal fibroblasts promotes tumor desmoplasia and mammary tumorigenesis.

    Rudnick, Jenny A / Monkkonen, Teresa / Mar, Florie A / Barnes, James M / Starobinets, Hanna / Goldsmith, Juliet / Roy, Srirupa / Bustamante Eguiguren, Sofía / Weaver, Valerie M / Debnath, Jayanta

    Genes & development

    2021  Volume 35, Issue 13-14, Page(s) 963–975

    Abstract: Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how ... ...

    Abstract Autophagy inhibitors are currently being evaluated in clinical trials for the treatment of diverse cancers, largely due to their ability to impede tumor cell survival and metabolic adaptation. More recently, there is growing interest in whether and how modulating autophagy in the host stroma influences tumorigenesis. Fibroblasts play prominent roles in cancer initiation and progression, including depositing type 1 collagen and other extracellular matrix (ECM) components, thereby stiffening the surrounding tissue to enhance tumor cell proliferation and survival, as well as secreting cytokines that modulate angiogenesis and the immune microenvironment. This constellation of phenotypes, pathologically termed desmoplasia, heralds poor prognosis and reduces patient survival. Using mouse mammary cancer models and syngeneic transplantation assays, we demonstrate that genetic ablation of stromal fibroblast autophagy significantly impedes fundamental elements of the stromal desmoplastic response, including collagen and proinflammatory cytokine secretion, extracellular matrix stiffening, and neoangiogenesis. As a result, autophagy in stromal fibroblasts is required for mammary tumor growth in vivo, even when the cancer cells themselves remain autophagy-competent . We propose the efficacy of autophagy inhibition is shaped by this ability of host stromal fibroblast autophagy to support tumor desmoplasia.
    MeSH term(s) Animals ; Autophagy/genetics ; Cell Line, Tumor ; Cell Transformation, Neoplastic/pathology ; Fibroblasts/metabolism ; Humans ; Mice ; Stromal Cells ; Tumor Microenvironment/genetics
    Language English
    Publishing date 2021-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 806684-x
    ISSN 1549-5477 ; 0890-9369
    ISSN (online) 1549-5477
    ISSN 0890-9369
    DOI 10.1101/gad.345629.120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: The Potential Role of Social Media Platforms in Community Awareness of Antibiotic Use in the Gulf Cooperation Council States: Luxury or Necessity?

    Zowawi, Hosam Mamoon / Abedalthagafi, Malak / Mar, Florie A / Almalki, Turki / Kutbi, Abdullah H / Harris-Brown, Tiffany / Harbarth, Stephan / Balkhy, Hanan H / Paterson, David L / Hasanain, Rihab Abdalazez

    Journal of medical Internet research

    2015  Volume 17, Issue 10, Page(s) e233

    Abstract: The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media ... ...

    Abstract The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media campaigns worldwide have been launched; however, such campaigns can be costly and the outcomes are variable and difficult to assess. Social media platforms, including Twitter, Facebook, and YouTube, are now frequently utilized to address health-related issues. In many geographical locations, such as the countries of the Gulf Cooperation Council (GCC) States (Saudi Arabia, United Arab Emirates, Kuwait, Oman, Qatar, and Bahrain), these platforms are becoming increasingly popular. The socioeconomic status of the GCC states and their reliable communication and networking infrastructure has allowed the penetration and scalability of these platforms in the region. This might explain why the Saudi Ministry of Health is using social media platforms alongside various other media platforms in a large-scale public awareness campaign to educate at-risk communities about the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper discusses the potential for using social media tools as cost-efficient and mass education platforms to raise awareness of appropriate antibiotic use in the general public and in the medical communities of the Arabian Peninsula.
    MeSH term(s) Anti-Bacterial Agents/therapeutic use ; Health Promotion/statistics & numerical data ; Humans ; Middle East ; Social Media/statistics & numerical data
    Chemical Substances Anti-Bacterial Agents
    Keywords covid19
    Language English
    Publishing date 2015-10-15
    Publishing country Canada
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2028830-X
    ISSN 1438-8871 ; 1439-4456
    ISSN (online) 1438-8871
    ISSN 1439-4456
    DOI 10.2196/jmir.3891
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity.

    Siegal, Deborah M / Curnutte, John T / Connolly, Stuart J / Lu, Genmin / Conley, Pamela B / Wiens, Brian L / Mathur, Vandana S / Castillo, Janice / Bronson, Michele D / Leeds, Janet M / Mar, Florie A / Gold, Alex / Crowther, Mark A

    The New England journal of medicine

    2015  Volume 373, Issue 25, Page(s) 2413–2424

    Abstract: Background: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.: ... ...

    Abstract Background: Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors.
    Methods: Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant.
    Results: Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported.
    Conclusions: Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).
    MeSH term(s) Administration, Oral ; Aged ; Antidotes/pharmacology ; Antidotes/therapeutic use ; Blood Coagulation/drug effects ; Double-Blind Method ; Factor Xa/metabolism ; Factor Xa/pharmacology ; Factor Xa/therapeutic use ; Factor Xa Inhibitors/adverse effects ; Factor Xa Inhibitors/therapeutic use ; Female ; Hemorrhage/chemically induced ; Hemorrhage/drug therapy ; Humans ; Male ; Middle Aged ; Peptide Fragments/metabolism ; Protein Precursors/metabolism ; Prothrombin/metabolism ; Pyrazoles/adverse effects ; Pyrazoles/therapeutic use ; Pyridones/adverse effects ; Pyridones/therapeutic use ; Recombinant Proteins/pharmacology ; Recombinant Proteins/therapeutic use ; Rivaroxaban/adverse effects ; Rivaroxaban/therapeutic use
    Chemical Substances Antidotes ; Factor Xa Inhibitors ; PRT064445 ; Peptide Fragments ; Protein Precursors ; Pyrazoles ; Pyridones ; Recombinant Proteins ; apixaban (3Z9Y7UWC1J) ; prothrombin fragment 1 (72270-84-9) ; prothrombin fragment 2 (78768-79-3) ; Prothrombin (9001-26-7) ; Rivaroxaban (9NDF7JZ4M3) ; Factor Xa (EC 3.4.21.6)
    Language English
    Publishing date 2015-12-17
    Publishing country United States
    Document type Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMoa1510991
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.34: Show issues Location:
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  5. Article ; Online: The Potential Role of Social Media Platforms in Community Awareness of Antibiotic Use in the Gulf Cooperation Council States

    Zowawi, Hosam Mamoon / Abedalthagafi, Malak / Mar, Florie A / Almalki, Turki / Kutbi, Abdullah H / Harris-Brown, Tiffany / Harbarth, Stephan / Balkhy, Hanan H / Paterson, David L / Hasanain, Rihab Abdalazez

    Journal of Medical Internet Research, Vol 17, Iss 10, p e

    Luxury or Necessity?

    2015  Volume 233

    Abstract: The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media ... ...

    Abstract The increasing emergence and spread of antimicrobial resistance (AMR) is a serious public health issue. Increasing the awareness of the general public about appropriate antibiotic use is a key factor for combating this issue. Several public media campaigns worldwide have been launched; however, such campaigns can be costly and the outcomes are variable and difficult to assess. Social media platforms, including Twitter, Facebook, and YouTube, are now frequently utilized to address health-related issues. In many geographical locations, such as the countries of the Gulf Cooperation Council (GCC) States (Saudi Arabia, United Arab Emirates, Kuwait, Oman, Qatar, and Bahrain), these platforms are becoming increasingly popular. The socioeconomic status of the GCC states and their reliable communication and networking infrastructure has allowed the penetration and scalability of these platforms in the region. This might explain why the Saudi Ministry of Health is using social media platforms alongside various other media platforms in a large-scale public awareness campaign to educate at-risk communities about the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV). This paper discusses the potential for using social media tools as cost-efficient and mass education platforms to raise awareness of appropriate antibiotic use in the general public and in the medical communities of the Arabian Peninsula.
    Keywords Computer applications to medicine. Medical informatics ; R858-859.7 ; Public aspects of medicine ; RA1-1270
    Subject code 070
    Language English
    Publishing date 2015-10-01T00:00:00Z
    Publisher JMIR Publications
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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