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  1. Article ; Online: First Case of Invasive Stachybotrys Sinusitis.

    Semis, Margarita / Dadwal, Sanjeet S / Tegtmeier, Bernard R / Wilczynski, Sharon P / Ito, James I / Kalkum, Markus

    Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

    2020  Volume 72, Issue 8, Page(s) 1386–1391

    Abstract: Background: The toxigenic mold Stachybotrys has controversially been linked to idiopathic pulmonary hemorrhage and "sick building syndrome." However, there are no previous clinical records of invasive stachybotryosis.: Methods: Sinus biopsy specimens ...

    Abstract Background: The toxigenic mold Stachybotrys has controversially been linked to idiopathic pulmonary hemorrhage and "sick building syndrome." However, there are no previous clinical records of invasive stachybotryosis.
    Methods: Sinus biopsy specimens from a 23-year-old male with refractory acute lymphocytic leukemia were obtained at 3 different time points during the patient's hospitalization (139 days) and examined by histopathology and immunohistochemistry (IHC). Antifungal susceptibility testing and fungal speciation using multilocus sequence typing were performed.
    Results: Hemorrhage, fungal germination, and hyphal growth were observed in the first sinus biopsy tissues. Areas with fungal growth tested positive for Stachybotrys by IHC. Fungal isolates were genotyped and identified as Stachybotrys chlorohalonata. The patient was cured from Stachybotrys sinusitis following sinus surgery and antifungal treatment. While a subsequent second sinus biopsy and a bronchoscopy showed no signs of fungal infection, a later, third sinus biopsy tested positive for Aspergillus calidoustus, a rare human pathogen.
    Conclusions: Here, we report the first case of invasive S. chlorohalonata sinusitis that was surgically and medically cured but followed by invasive A. calidoustus sinusitis in the setting of refractory leukemia. Our findings emphasize the risk for unusual fungal infections in severely immunocompromised patients.
    MeSH term(s) Adult ; Aspergillus ; Humans ; Male ; Mycoses/diagnosis ; Mycoses/drug therapy ; Sinusitis/diagnosis ; Stachybotrys ; Young Adult
    Language English
    Publishing date 2020-03-09
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1099781-7
    ISSN 1537-6591 ; 1058-4838
    ISSN (online) 1537-6591
    ISSN 1058-4838
    DOI 10.1093/cid/ciaa231
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The Plethora of Angiotensin-Converting Enzyme-Processed Peptides in Mouse Plasma.

    Semis, Margarita / Gugiu, Gabriel B / Bernstein, Ellen A / Bernstein, Kenneth E / Kalkum, Markus

    Analytical chemistry

    2019  Volume 91, Issue 10, Page(s) 6440–6453

    Abstract: Angiotensin-converting enzyme (ACE) converts angiotensin I into the potent vasoconstrictor angiotensin II, which regulates blood pressure. However, ACE activity is also essential for other physiological functions, presumably through processing of ... ...

    Abstract Angiotensin-converting enzyme (ACE) converts angiotensin I into the potent vasoconstrictor angiotensin II, which regulates blood pressure. However, ACE activity is also essential for other physiological functions, presumably through processing of peptides unrelated to angiotensin. The goal of this study was to identify novel natural substrates and products of ACE through a series of mass-spectrometric experiments. This included comparing the ACE-treated and untreated plasma peptidomes of ACE-knockout (KO) mice, validation with select synthetic peptides, and a quantitative in vivo study of ACE substrates in mice with distinct genetic ACE backgrounds. In total, 244 natural peptides were identified ex vivo as possible substrates or products of ACE, demonstrating high promiscuity of the enzyme. ACE prefers to cleave substrates with Phe or Leu at the C-terminal P2' position and Gly in the P6 position. Pro in P1' and Iso in P1 are typical residues in peptides that ACE does not cleave. Several of the novel ACE substrates are known to have biological activities, including a fragment of complement C3, the spasmogenic C3f, which was processed by ACE ex vivo and in vitro. Analyses with N-domain-inactive (NKO) ACE allowed clarification of domain selectivity toward substrates. The in vivo ACE-substrate concentrations in WT, transgenic ACE-KO, NKO, and CKO mice correspond well with the in vitro observations in that higher levels of the ACE substrates were observed when the processing domain was knocked out. This study highlights the vast extent of ACE promiscuity and provides a valuable platform for further investigations of ACE functionality.
    MeSH term(s) Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Gene Expression Regulation, Enzymologic/drug effects ; Mice ; Mice, Knockout ; Peptides/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Plasma/enzymology ; Ramipril/pharmacology ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
    Chemical Substances Angiotensin-Converting Enzyme Inhibitors ; Peptides ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Ramipril (L35JN3I7SJ)
    Language English
    Publishing date 2019-05-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.8b03828
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Macrophage COX2 Mediates Efferocytosis, Resolution Reprogramming, and Intestinal Epithelial Repair.

    Meriwether, David / Jones, Anthony E / Ashby, Julianne W / Solorzano-Vargas, R Sergio / Dorreh, Nasrin / Noori, Shoreh / Grijalva, Victor / Ball, Andréa B / Semis, Margarita / Divakaruni, Ajit S / Mack, Julia J / Herschman, Harvey R / Martin, Martin G / Fogelman, Alan M / Reddy, Srinivasa T

    Cellular and molecular gastroenterology and hepatology

    2022  Volume 13, Issue 4, Page(s) 1095–1120

    Abstract: Background and aims: Phagocytosis (efferocytosis) of apoptotic neutrophils by macrophages anchors the resolution of intestinal inflammation. Efferocytosis prevents secondary necrosis and inhibits further inflammation, and also reprograms macrophages to ... ...

    Abstract Background and aims: Phagocytosis (efferocytosis) of apoptotic neutrophils by macrophages anchors the resolution of intestinal inflammation. Efferocytosis prevents secondary necrosis and inhibits further inflammation, and also reprograms macrophages to facilitate tissue repair and promote resolution function. Macrophage efferocytosis and efferocytosis-dependent reprogramming are implicated in the pathogenesis of inflammatory bowel disease. We previously reported that absence of macrophage cyclooxygenase 2 (COX2) exacerbates inflammatory bowel disease-like intestinal inflammation. To elucidate the underlying pathogenic mechanism, we investigated here whether COX2 mediates macrophage efferocytosis and efferocytosis-dependent reprogramming, including intestinal epithelial repair capacity.
    Methods: Using apoptotic neutrophils and synthetic apoptotic targets, we determined the effects of macrophage specific Cox2 knockout and pharmacological COX2 inhibition on the efferocytosis capacity of mouse primary macrophages. COX2-mediated efferocytosis-dependent eicosanoid lipidomics was determined by liquid chromatography tandem mass spectrometry. Small intestinal epithelial organoids were employed to assay the effects of COX2 on efferocytosis-dependent intestinal epithelial repair.
    Results: Loss of COX2 impaired efferocytosis in mouse primary macrophages, in part, by affecting the binding capacity of macrophages for apoptotic cells. This effect was comparable to that of high-dose lipopolysaccharide and was accompanied by both dysregulation of macrophage polarization and the inhibited expression of genes involved in apoptotic cell binding. COX2 modulated the production of efferocytosis-dependent lipid inflammatory mediators that include the eicosanoids prostaglandin I2, prostaglandin E2, lipoxin A4, and 15d-PGJ2; and further affected secondary efferocytosis. Finally, macrophage efferocytosis induced, in a macrophage COX2-dependent manner, a tissue restitution and repair phenotype in intestinal epithelial organoids.
    Conclusions: Macrophage COX2 potentiates efferocytosis capacity and efferocytosis-dependent reprogramming, facilitating macrophage intestinal epithelial repair capacity.
    MeSH term(s) Animals ; Cyclooxygenase 2/genetics ; Cyclooxygenase 2/metabolism ; Cyclooxygenase 2/pharmacology ; Inflammation/pathology ; Inflammatory Bowel Diseases/pathology ; Macrophages/metabolism ; Mice ; Phagocytosis/genetics
    Chemical Substances Ptgs2 protein, mouse (EC 1.14.99.-) ; Cyclooxygenase 2 (EC 1.14.99.1)
    Language English
    Publishing date 2022-01-10
    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, P.H.S.
    ZDB-ID 2819778-1
    ISSN 2352-345X ; 2352-345X
    ISSN (online) 2352-345X
    ISSN 2352-345X
    DOI 10.1016/j.jcmgh.2022.01.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Galleria mellonella as a model system to study virulence potential of mucormycetes and evaluation of antifungal treatment.

    Maurer, Elisabeth / Hörtnagl, Caroline / Lackner, Michaela / Grässle, Denise / Naschberger, Verena / Moser, Patrizia / Segal, Esther / Semis, Margarita / Lass-Flörl, Cornelia / Binder, Ulrike

    Medical mycology

    2018  Volume 57, Issue 3, Page(s) 351–362

    Abstract: Mucorales can cause cutaneous to deep-seated infections, mainly in the immunocompromised host, resulting in high mortality rates due to late and inefficient treatment. In this study, Galleria mellonella larvae were evaluated as a heterologous ... ...

    Abstract Mucorales can cause cutaneous to deep-seated infections, mainly in the immunocompromised host, resulting in high mortality rates due to late and inefficient treatment. In this study, Galleria mellonella larvae were evaluated as a heterologous invertebrate host to study pathogenicity of clinically relevant mucormycetes (Rhizopus spp., Rhizomucor spp., Lichtheimia spp., Mucor spp.). All tested species were able to infect G. mellonella larvae. Virulence potential was species-specific and correlated to clinical relevance. Survival of infected larvae was dependent on (a) the species (growth speed and spore size), (b) the infection dose, (c) the incubation temperature, (d) oxidative stress tolerance, and (e) iron availability in the growth medium. Moreover, we exploited the G. mellonella system to determine antifungal efficacy of liposomal amphotericin B, posaconazole, isavuconazole, and nystatin-intralipid. Outcome of in vivo treatment was strongly dependent upon the drug applied and the species tested. Nystatin-intralipid exhibited best activity against Mucorales, followed by posaconazole, while limited efficacy was seen for liposomal amphotericin B and isavuconazole. Pharmacokinetic properties of the tested antifungals within this alternative host system partly explain the limited treatment efficacy. In conclusion, G. mellonella represents a useful invertebrate infection model for studying virulence of mucormycetes, while evaluation of treatment response was limited.
    MeSH term(s) Amphotericin B/pharmacokinetics ; Amphotericin B/therapeutic use ; Animals ; Antifungal Agents/pharmacokinetics ; Antifungal Agents/therapeutic use ; Disease Models, Animal ; Drug Resistance, Fungal ; Larva/microbiology ; Lepidoptera/microbiology ; Microbial Sensitivity Tests ; Mucor/drug effects ; Mucor/pathogenicity ; Mucorales/drug effects ; Mucorales/pathogenicity ; Mucormycosis/drug therapy ; Mucormycosis/microbiology ; Nitriles/pharmacokinetics ; Nitriles/therapeutic use ; Pyridines/pharmacokinetics ; Pyridines/therapeutic use ; Rhizopus/drug effects ; Rhizopus/pathogenicity ; Triazoles/pharmacokinetics ; Triazoles/therapeutic use ; Virulence
    Chemical Substances Antifungal Agents ; Nitriles ; Pyridines ; Triazoles ; liposomal amphotericin B ; isavuconazole (60UTO373KE) ; posaconazole (6TK1G07BHZ) ; Amphotericin B (7XU7A7DROE)
    Language English
    Publishing date 2018-06-19
    Publishing country England
    Document type Journal Article
    ZDB-ID 1421796-x
    ISSN 1460-2709 ; 1369-3786
    ISSN (online) 1460-2709
    ISSN 1369-3786
    DOI 10.1093/mmy/myy042
    Database MEDical Literature Analysis and Retrieval System OnLINE

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