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Article ; Online: More than maintenance? A role for IFT genes in planar cell polarity.

Jaffe, Kimberly M / Burdine, Rebecca D

Journal of the American Society of Nephrology : JASN

2010 Volume 21, Issue 8, Page(s) 1240–1241

MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/physiology ; Animals ; Cell Polarity/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/physiology
Chemical Substances	Adaptor Proteins, Signal Transducing ; IFT57 protein, zebrafish ; Zebrafish Proteins
Language	English
Publishing date	2010-08
Publishing country	United States
Document type	Comment ; Editorial
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2010060665
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Article: Imaging cilia in zebrafish.

Jaffe, Kimberly M / Thiberge, Stephan Y / Bisher, Margaret E / Burdine, Rebecca D

Methods in cell biology

2010 Volume 97, Page(s) 415–435

Abstract: Research focused on cilia as extremely important cellular organelles has flourished in recent years. A thorough understanding of cilia regulation and function is critical, as disruptions of cilia structure and/or function have been linked to numerous ... ...

Abstract	Research focused on cilia as extremely important cellular organelles has flourished in recent years. A thorough understanding of cilia regulation and function is critical, as disruptions of cilia structure and/or function have been linked to numerous human diseases and disorders. The tropical freshwater zebrafish is an excellent model organism in which to study cilia structure and function. We can readily image cilia and their motility in embryonic structures including Kupffer's vesicle during somite stages and the pronephros from 1 day postfertilization onward. Here, we describe how to image cilia by whole-mount immunofluorescence, transverse cryosection/immunohistochemistry, and transmission electron microscopy. We also describe how to obtain videos of cilia motility in living embryos.
MeSH term(s)	Animals ; Cilia/chemistry ; Cilia/metabolism ; Cilia/physiology ; Cilia/ultrastructure ; Cryoultramicrotomy/methods ; Embryo, Nonmammalian ; Humans ; Microscopy/methods ; Models, Biological ; Movement/physiology ; Zebrafish/embryology ; Zebrafish/physiology
Language	English
Publishing date	2010-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	0091-679X
ISSN	0091-679X
DOI	10.1016/S0091-679X(10)97022-2
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Article ; Online: Serious Bacterial Infections in Young Febrile Infants With Positive Urinalysis Results.

Mahajan, Prashant / VanBuren, John M / Tzimenatos, Leah / Cruz, Andrea T / Vitale, Melissa / Powell, Elizabeth C / Leetch, Aaron N / Pickett, Michelle L / Brayer, Anne / Nigrovic, Lise E / Dayan, Peter S / Atabaki, Shireen M / Ruddy, Richard M / Rogers, Alexander J / Greenberg, Richard / Alpern, Elizabeth R / Tunik, Michael G / Saunders, Mary / Muenzer, Jared /

Levine, Deborah A / Hoyle, John D / Lillis, Kathleen Grisanti / Gattu, Rajender / Crain, Ellen F / Borgialli, Dominic / Bonsu, Bema / Blumberg, Stephen / Anders, Jennifer / Roosevelt, Genie / Browne, Lorin R / Cohen, Daniel M / Linakis, James G / Jaffe, David M / Bennett, Jonathan E / Schnadower, David / Park, Grace / Mistry, Rakesh D / Glissmeyer, Eric W / Cator, Allison / Bogie, Amanda / Quayle, Kimberly S / Ellison, Angela / Balamuth, Fran / Richards, Rachel / Ramilo, Octavio / Kuppermann, Nathan

Pediatrics

2022 Volume 150, Issue 4

Abstract: It is unknown whether febrile infants 29 to 60 days old with positive urinalysis results require routine lumbar punctures for evaluation of bacterial meningitis.: Objective: To determine the prevalence of bacteremia and/or bacterial meningitis in ... ...

Abstract	It is unknown whether febrile infants 29 to 60 days old with positive urinalysis results require routine lumbar punctures for evaluation of bacterial meningitis. Objective: To determine the prevalence of bacteremia and/or bacterial meningitis in febrile infants ≤60 days of age with positive urinalysis (UA) results. Methods: Secondary analysis of a prospective observational study of noncritical febrile infants ≤60 days between 2011 and 2019 conducted in the Pediatric Emergency Care Applied Research Network emergency departments. Participants had temperatures ≥38°C and were evaluated with blood cultures and had UAs available for analysis. We report the prevalence of bacteremia and bacterial meningitis in those with and without positive UA results. Results: Among 7180 infants, 1090 (15.2%) had positive UA results. The risk of bacteremia was higher in those with positive versus negative UA results (63/1090 [5.8%] vs 69/6090 [1.1%], difference 4.7% [3.3% to 6.1%]). There was no difference in the prevalence of bacterial meningitis in infants ≤28 days of age with positive versus negative UA results (∼1% in both groups). However, among 697 infants aged 29 to 60 days with positive UA results, there were no cases of bacterial meningitis in comparison to 9 of 4153 with negative UA results (0.2%, difference -0.2% [-0.4% to -0.1%]). In addition, there were no cases of bacteremia and/or bacterial meningitis in the 148 infants ≤60 days of age with positive UA results who had the Pediatric Emergency Care Applied Research Network low-risk blood thresholds of absolute neutrophil count <4 × 103 cells/mm3 and procalcitonin <0.5 ng/mL. Conclusions: Among noncritical febrile infants ≤60 days of age with positive UA results, there were no cases of bacterial meningitis in those aged 29 to 60 days and no cases of bacteremia and/or bacterial meningitis in any low-risk infants based on low-risk blood thresholds in both months of life. These findings can guide lumbar puncture use and other clinical decision making.
MeSH term(s)	Bacteremia/complications ; Bacteremia/diagnosis ; Bacteremia/epidemiology ; Bacterial Infections/complications ; Child ; Fever/complications ; Fever/diagnosis ; Fever/epidemiology ; Humans ; Infant ; Meningitis, Bacterial/complications ; Meningitis, Bacterial/diagnosis ; Meningitis, Bacterial/epidemiology ; Procalcitonin ; Urinalysis ; Urinary Tract Infections/epidemiology
Chemical Substances	Procalcitonin
Language	English
Publishing date	2022-09-09
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	207677-9
ISSN	1098-4275 ; 0031-4005
ISSN (online)	1098-4275
ISSN	0031-4005
DOI	10.1542/peds.2021-055633
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Article ; Online: The Sea Spray Chemistry and Particle Evolution study (SeaSCAPE): overview and experimental methods.

Sauer, Jon S / Mayer, Kathryn J / Lee, Christopher / Alves, Michael R / Amiri, Sarah / Bahaveolos, Cristina J / Franklin, Emily B / Crocker, Daniel R / Dang, Duyen / Dinasquet, Julie / Garofalo, Lauren A / Kaluarachchi, Chathuri P / Kilgour, Delaney B / Mael, Liora E / Mitts, Brock A / Moon, Daniel R / Moore, Alexia N / Morris, Clare K / Mullenmeister, Catherine A /

Ni, Chi-Min / Pendergraft, Matthew A / Petras, Daniel / Simpson, Rebecca M C / Smith, Stephanie / Tumminello, Paul R / Walker, Joseph L / DeMott, Paul J / Farmer, Delphine K / Goldstein, Allen H / Grassian, Vicki H / Jaffe, Jules S / Malfatti, Francesca / Martz, Todd R / Slade, Jonathan H / Tivanski, Alexei V / Bertram, Timothy H / Cappa, Christopher D / Prather, Kimberly A

Environmental science. Processes & impacts

2022 Volume 24, Issue 2, Page(s) 290–315

Abstract: Marine aerosols strongly influence climate through their interactions with solar radiation and clouds. However, significant questions remain regarding the influences of biological activity and seawater chemistry on the flux, chemical composition, and ... ...

Abstract	Marine aerosols strongly influence climate through their interactions with solar radiation and clouds. However, significant questions remain regarding the influences of biological activity and seawater chemistry on the flux, chemical composition, and climate-relevant properties of marine aerosols and gases. Wave channels, a traditional tool of physical oceanography, have been adapted for large-scale ocean-atmosphere mesocosm experiments in the laboratory. These experiments enable the study of aerosols under controlled conditions which isolate the marine system from atmospheric anthropogenic and terrestrial influences. Here, we present an overview of the 2019 Sea Spray Chemistry and Particle Evolution (SeaSCAPE) study, which was conducted in an 11 800 L wave channel which was modified to facilitate atmospheric measurements. The SeaSCAPE campaign sought to determine the influence of biological activity in seawater on the production of primary sea spray aerosols, volatile organic compounds (VOCs), and secondary marine aerosols. Notably, the SeaSCAPE experiment also focused on understanding how photooxidative aging processes transform the composition of marine aerosols. In addition to a broad range of aerosol, gas, and seawater measurements, we present key results which highlight the experimental capabilities during the campaign, including the phytoplankton bloom dynamics, VOC production, and the effects of photochemical aging on aerosol production, morphology, and chemical composition. Additionally, we discuss the modifications made to the wave channel to improve aerosol production and reduce background contamination, as well as subsequent characterization experiments. The SeaSCAPE experiment provides unique insight into the connections between marine biology, atmospheric chemistry, and climate-relevant aerosol properties, and demonstrates how an ocean-atmosphere-interaction facility can be used to isolate and study reactions in the marine atmosphere in the laboratory under more controlled conditions.
MeSH term(s)	Aerosols/chemistry ; Atmosphere/chemistry ; Oceans and Seas ; Phytoplankton ; Seawater/chemistry
Chemical Substances	Aerosols
Language	English
Publishing date	2022-02-23
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2703814-2
ISSN	2050-7895 ; 2050-7887
ISSN (online)	2050-7895
ISSN	2050-7887
DOI	10.1039/d1em00260k
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Article ; Online: c21orf59/kurly Controls Both Cilia Motility and Polarization.

Jaffe, Kimberly M / Grimes, Daniel T / Schottenfeld-Roames, Jodi / Werner, Michael E / Ku, Tse-Shuen J / Kim, Sun K / Pelliccia, Jose L / Morante, Nicholas F C / Mitchell, Brian J / Burdine, Rebecca D

Cell reports

2016 Volume 14, Issue 8, Page(s) 1841–1849

Abstract: Cilia are microtubule-based projections that function in the movement of extracellular fluid. This requires cilia to be: (1) motile and driven by dynein complexes and (2) correctly polarized on the surface of cells, which requires planar cell polarity ( ... ...

Abstract	Cilia are microtubule-based projections that function in the movement of extracellular fluid. This requires cilia to be: (1) motile and driven by dynein complexes and (2) correctly polarized on the surface of cells, which requires planar cell polarity (PCP). Few factors that regulate both processes have been discovered. We reveal that C21orf59/Kurly (Kur), a cytoplasmic protein with some enrichment at the base of cilia, is needed for motility; zebrafish mutants exhibit characteristic developmental abnormalities and dynein arm defects. kur was also required for proper cilia polarization in the zebrafish kidney and the larval skin of Xenopus laevis. CRISPR/Cas9 coupled with homologous recombination to disrupt the endogenous kur locus in Xenopus resulted in the asymmetric localization of the PCP protein Prickle2 being lost in mutant multiciliated cells. Kur also makes interactions with other PCP components, including Disheveled. This supports a model wherein Kur plays a dual role in cilia motility and polarization.
MeSH term(s)	Animals ; Binding Sites ; CRISPR-Cas Systems ; Cell Movement ; Cell Polarity ; Cilia/metabolism ; Dishevelled Proteins/genetics ; Dishevelled Proteins/metabolism ; Embryo, Nonmammalian ; Gene Expression ; Genetic Loci ; Homologous Recombination ; Kidney/cytology ; Kidney/growth & development ; Kidney/metabolism ; LIM Domain Proteins/genetics ; LIM Domain Proteins/metabolism ; Larva/genetics ; Larva/growth & development ; Larva/metabolism ; Microtubules/metabolism ; Microtubules/ultrastructure ; Mutation ; Protein Binding ; Signal Transduction ; Skin/cytology ; Skin/growth & development ; Skin/metabolism ; Xenopus Proteins/genetics ; Xenopus Proteins/metabolism ; Xenopus laevis/embryology ; Xenopus laevis/genetics ; Xenopus laevis/metabolism ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/metabolism ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	DVL1 protein, Xenopus ; Dishevelled Proteins ; Dvl2 protein, zebrafish ; LIM Domain Proteins ; Xenopus Proteins ; Zebrafish Proteins
Language	English
Publishing date	2016-02-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2016.01.069
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Article: The Sea Spray Chemistry and Particle Evolution study (SeaSCAPE): overview and experimental methods

Sauer, Jon S. / Mayer, Kathryn J. / Lee, Christopher / Alves, Michael R. / Amiri, Sarah / Bahaveolos, Cristina J. / Franklin, Emily B. / Crocker, Daniel R. / Dang, Duyen / Dinasquet, Julie / Garofalo, Lauren A. / Kaluarachchi, Chathuri P. / Kilgour, Delaney B. / Mael, Liora E. / Mitts, Brock A. / Moon, Daniel R. / Moore, Alexia N. / Morris, Clare K. / Mullenmeister, Catherine A. /

Ni, Chi-Min / Pendergraft, Matthew A. / Petras, Daniel / Simpson, Rebecca M. C. / Smith, Stephanie / Tumminello, Paul R. / Walker, Joseph L. / DeMott, Paul J. / Farmer, Delphine K. / Goldstein, Allen H. / Grassian, Vicki H. / Jaffe, Jules S. / Malfatti, Francesca / Martz, Todd R. / Slade, Jonathan H. / Tivanski, Alexei V. / Bertram, Timothy H. / Cappa, Christopher D. / Prather, Kimberly A.

Environmental science. 2022 Feb. 23, v. 24, no. 2

2022

Abstract	Marine aerosols strongly influence climate through their interactions with solar radiation and clouds. However, significant questions remain regarding the influences of biological activity and seawater chemistry on the flux, chemical composition, and climate-relevant properties of marine aerosols and gases. Wave channels, a traditional tool of physical oceanography, have been adapted for large-scale ocean-atmosphere mesocosm experiments in the laboratory. These experiments enable the study of aerosols under controlled conditions which isolate the marine system from atmospheric anthropogenic and terrestrial influences. Here, we present an overview of the 2019 Sea Spray Chemistry and Particle Evolution (SeaSCAPE) study, which was conducted in an 11 800 L wave channel which was modified to facilitate atmospheric measurements. The SeaSCAPE campaign sought to determine the influence of biological activity in seawater on the production of primary sea spray aerosols, volatile organic compounds (VOCs), and secondary marine aerosols. Notably, the SeaSCAPE experiment also focused on understanding how photooxidative aging processes transform the composition of marine aerosols. In addition to a broad range of aerosol, gas, and seawater measurements, we present key results which highlight the experimental capabilities during the campaign, including the phytoplankton bloom dynamics, VOC production, and the effects of photochemical aging on aerosol production, morphology, and chemical composition. Additionally, we discuss the modifications made to the wave channel to improve aerosol production and reduce background contamination, as well as subsequent characterization experiments. The SeaSCAPE experiment provides unique insight into the connections between marine biology, atmospheric chemistry, and climate-relevant aerosol properties, and demonstrates how an ocean-atmosphere-interaction facility can be used to isolate and study reactions in the marine atmosphere in the laboratory under more controlled conditions.
Keywords	aerosols ; algal blooms ; atmospheric chemistry ; bioactive properties ; chemical composition ; climate ; oceanography ; photooxidation ; seawater ; solar radiation
Language	English
Dates of publication	2022-0223
Size	p. 290-315.
Publishing place	The Royal Society of Chemistry
Document type	Article
ZDB-ID	2703814-2
ISSN	2050-7895 ; 2050-7887
ISSN (online)	2050-7895
ISSN	2050-7887
DOI	10.1039/d1em00260k
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: SUMOylated SoxE factors recruit Grg4 and function as transcriptional repressors in the neural crest.

Lee, Pei-Chih / Taylor-Jaffe, Kimberly M / Nordin, Kara M / Prasad, Maneeshi S / Lander, Rachel M / LaBonne, Carole

The Journal of cell biology

2012 Volume 198, Issue 5, Page(s) 799–813

Abstract: A growing number of transcriptional regulatory proteins are known to be modified by the small ubiquitin-like protein, SUMO. Posttranslational modification by SUMO may be one means by which transcriptional regulatory factors that play context-dependent ... ...

Abstract	A growing number of transcriptional regulatory proteins are known to be modified by the small ubiquitin-like protein, SUMO. Posttranslational modification by SUMO may be one means by which transcriptional regulatory factors that play context-dependent roles in multiple processes can be regulated such that they direct the appropriate cellular and developmental outcomes. In early vertebrate embryos, SUMOylation of SoxE transcription factors profoundly affects their function, inhibiting their neural crest-inducing activity and promoting ear formation. In this paper, we provide mechanistic insight into how SUMO modification modulates SoxE function. We show that SUMOylation dramatically altered recruitment of transcriptional coregulator factors by SoxE proteins, displacing coactivators CREB-binding protein/p300 while promoting the recruitment of a corepressor, Grg4. These data demonstrate that SoxE proteins can function as transcriptional repressors in a SUMO-dependent manner. They further suggest a novel multivalent mechanism for SUMO-mediated recruitment of transcriptional coregulatory factors.
MeSH term(s)	CREB-Binding Protein/genetics ; CREB-Binding Protein/metabolism ; Cell Line, Tumor ; Histone Deacetylases/genetics ; Histone Deacetylases/metabolism ; Humans ; Intramolecular Oxidoreductases/genetics ; Intramolecular Oxidoreductases/metabolism ; Microphthalmia-Associated Transcription Factor/genetics ; Microphthalmia-Associated Transcription Factor/metabolism ; Neural Crest/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic/genetics ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; SOX9 Transcription Factor/genetics ; SOX9 Transcription Factor/metabolism ; SOXE Transcription Factors/genetics ; SOXE Transcription Factors/metabolism ; SUMO-1 Protein/genetics ; SUMO-1 Protein/metabolism ; Sumoylation/genetics ; Transcription, Genetic ; Transcriptional Activation/genetics
Chemical Substances	MITF protein, human ; Microphthalmia-Associated Transcription Factor ; Nuclear Proteins ; Repressor Proteins ; SOX9 Transcription Factor ; SOX9 protein, human ; SOXE Transcription Factors ; SUMO-1 Protein ; TLE4 protein, human ; CREB-Binding Protein (EC 2.3.1.48) ; CREBBP protein, human (EC 2.3.1.48) ; Histone Deacetylases (EC 3.5.1.98) ; Intramolecular Oxidoreductases (EC 5.3.-) ; dopachrome isomerase (EC 5.3.3.12)
Language	English
Publishing date	2012-08-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201204161
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Article ; Online: c21orf59/kurly Controls Both Cilia Motility and Polarization

Kimberly M. Jaffe / Daniel T. Grimes / Jodi Schottenfeld-Roames / Michael E. Werner / Tse-Shuen J. Ku / Sun K. Kim / Jose L. Pelliccia / Nicholas F.C. Morante / Brian J. Mitchell / Rebecca D. Burdine

Cell Reports, Vol 14, Iss 8, Pp 1841-

2016 Volume 1849

Abstract	Cilia are microtubule-based projections that function in the movement of extracellular fluid. This requires cilia to be: (1) motile and driven by dynein complexes and (2) correctly polarized on the surface of cells, which requires planar cell polarity (PCP). Few factors that regulate both processes have been discovered. We reveal that C21orf59/Kurly (Kur), a cytoplasmic protein with some enrichment at the base of cilia, is needed for motility; zebrafish mutants exhibit characteristic developmental abnormalities and dynein arm defects. kur was also required for proper cilia polarization in the zebrafish kidney and the larval skin of Xenopus laevis. CRISPR/Cas9 coupled with homologous recombination to disrupt the endogenous kur locus in Xenopus resulted in the asymmetric localization of the PCP protein Prickle2 being lost in mutant multiciliated cells. Kur also makes interactions with other PCP components, including Disheveled. This supports a model wherein Kur plays a dual role in cilia motility and polarization.
Keywords	Kurly (Kur) ; c21orf59 ; cilia ; planar cell polarity ; disheveled ; ciliopathy ; primary ciliary dyskinesia ; multiciliated cell ; Biology (General) ; QH301-705.5
Subject code	571
Language	English
Publishing date	2016-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Increased incidence of sterile endophthalmitis after intravitreal triamcinolone acetonide in spring 2006.

Stepien, Kimberly E / Eaton, Alexander M / Jaffe, Glenn J / Davis, Janet L / Raja, Junaid / Feuer, William

Retina (Philadelphia, Pa.)

2009 Volume 29, Issue 2, Page(s) 207–213

Abstract: Purpose: To compare the incidence of sterile endophthalmitis after intravitreal triamcinolone acetonide injections during a 6 month period in 2006 to the same period in 2005 and determine the incidence after switching to intravitreal preservative-free ... ...

Abstract	Purpose: To compare the incidence of sterile endophthalmitis after intravitreal triamcinolone acetonide injections during a 6 month period in 2006 to the same period in 2005 and determine the incidence after switching to intravitreal preservative-free triamcinolone acetonide. Methods: Retrospective multicenter interventional case series in which patients receiving intravitreal triamcinolone acetonide at three institutions from March 2005 to August 2005 and from March 2006 to August 2006 and intravitreal preservative-free triamcinolone acetonide from late summer 2006 through February 2007 were reviewed for the development of sterile endophthalmitis. Results: From March 2005 to August 2005, the rate of sterile endophthalmitis was 0% at all institutions. From March 2006 to August 2006, a statistically significant increase in sterile endophthalmitis was seen at all institutions with frequencies of 3.5% to 6.3% (P < 0.001). With transition to preservative-free triamcinolone acetonide, sterile endophthalmitis over the next 6 months decreased to 0% at two sites and to 2.5% (from 5.5%) at the third institution (P < 0.009). Conclusions: A statistically significant increase in the rate of sterile endophthalmitis after intravitreal triamcinolone acetonide was seen in a 6 month period in 2006 when compared with the same period in 2005. Transition to preservative-free triamcinolone acetonide produced a frequency of sterile endophthalmitis similar to 2005.
MeSH term(s)	Aged ; Aged, 80 and over ; Endophthalmitis/chemically induced ; Endophthalmitis/diagnosis ; Female ; Glucocorticoids/adverse effects ; Humans ; Incidence ; Injections ; Male ; Middle Aged ; Preservatives, Pharmaceutical ; Retrospective Studies ; Risk Factors ; Seasons ; Time Factors ; Triamcinolone Acetonide/adverse effects ; Vitreous Body
Chemical Substances	Glucocorticoids ; Preservatives, Pharmaceutical ; Triamcinolone Acetonide (F446C597KA)
Language	English
Publishing date	2009-02
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603192-4
ISSN	1539-2864 ; 0275-004X
ISSN (online)	1539-2864
ISSN	0275-004X
DOI	10.1097/IAE.0b013e31818eccb3
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Article ; Online: Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

Bandopadhayay, Pratiti / Piccioni, Federica / O'Rourke, Ryan / Ho, Patricia / Gonzalez, Elizabeth M / Buchan, Graham / Qian, Kenin / Gionet, Gabrielle / Girard, Emily / Coxon, Margo / Rees, Matthew G / Brenan, Lisa / Dubois, Frank / Shapira, Ofer / Greenwald, Noah F / Pages, Melanie / Balboni Iniguez, Amanda / Paolella, Brenton R / Meng, Alice /

Sinai, Claire / Roti, Giovanni / Dharia, Neekesh V / Creech, Amanda / Tanenbaum, Benjamin / Khadka, Prasidda / Tracy, Adam / Tiv, Hong L / Hong, Andrew L / Coy, Shannon / Rashid, Rumana / Lin, Jia-Ren / Cowley, Glenn S / Lam, Fred C / Goodale, Amy / Lee, Yenarae / Schoolcraft, Kathleen / Vazquez, Francisca / Hahn, William C / Tsherniak, Aviad / Bradner, James E / Yaffe, Michael B / Milde, Till / Pfister, Stefan M / Qi, Jun / Schenone, Monica / Carr, Steven A / Ligon, Keith L / Kieran, Mark W / Santagata, Sandro / Olson, James M / Gokhale, Prafulla C / Jaffe, Jacob D / Root, David E / Stegmaier, Kimberly / Johannessen, Cory M / Beroukhim, Rameen

Nature communications

2019 Volume 10, Issue 1, Page(s) 2400

Abstract: BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, ... ...

Abstract	BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
MeSH term(s)	Animals ; Azepines/pharmacology ; Basic Helix-Loop-Helix Transcription Factors/drug effects ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; CRISPR-Cas Systems ; Cell Cycle/drug effects ; Cell Cycle Proteins/drug effects ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Lineage ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/genetics ; Cyclin D2/drug effects ; Cyclin D2/metabolism ; Cyclin-Dependent Kinase 4/antagonists & inhibitors ; Cyclin-Dependent Kinase 6/antagonists & inhibitors ; Drug Resistance, Neoplasm ; Gene Expression Profiling ; Humans ; Medulloblastoma/drug therapy ; Medulloblastoma/genetics ; Mice ; Neural Stem Cells/drug effects ; Neural Stem Cells/metabolism ; Neurogenesis/drug effects ; Proteins/antagonists & inhibitors ; Proto-Oncogene Proteins c-myc/genetics ; S Phase/drug effects ; Triazoles/pharmacology
Chemical Substances	(+)-JQ1 compound ; Azepines ; Basic Helix-Loop-Helix Transcription Factors ; Cell Cycle Proteins ; Cyclin D2 ; MYC protein, human ; Proteins ; Proto-Oncogene Proteins c-myc ; Triazoles ; bromodomain and extra-terminal domain protein, human ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 6 (EC 2.7.11.22)
Language	English
Publishing date	2019-06-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10307-9
Database	MEDical Literature Analysis and Retrieval System OnLINE

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