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  1. Article ; Online: The antidiabetic SGLT2 inhibitor canagliflozin reduces mitochondrial metabolism in a model of skeletal muscle insulin resistance.

    VanDerStad, Lindsey R / Wyatt, Emily C / Vaughan, Roger A

    Diabetic medicine : a journal of the British Diabetic Association

    2023  Volume 41, Issue 5, Page(s) e15271

    Abstract: Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (CANA) have emerged as an effective adjuvant therapy in the management of diabetes, however, past observations suggest CANA may alter skeletal muscle mass and function. The ... ...

    Abstract Aims: Sodium-glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (CANA) have emerged as an effective adjuvant therapy in the management of diabetes, however, past observations suggest CANA may alter skeletal muscle mass and function. The purpose of this work was to investigate the effects of CANA on skeletal muscle metabolism both with and without insulin resistance.
    Methods: C2C12 myotubes were treated with CANA with or without insulin resistance. Western blot and qRT-PCR were used to assess protein and gene expression, respectively. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Mitochondrial, nuclei and lipid content were measured using fluorescent staining and microscopy.
    Results: CANA decreased mitochondrial function and glycolytic metabolism as did insulin resistance, however, these changes occurred without significant alterations in gene expression associated with each pathway. Additionally, while insulin resistance reduced insulin-stimulated pAkt expression, CANA had no significant effect on insulin sensitivity.
    Conclusions: CANA appears to reduce mitochondrial and glycolytic metabolism without altering gene expression governing these pathways, suggesting a reduction in substrate may be responsible for lower metabolism.
    MeSH term(s) Humans ; Canagliflozin/pharmacology ; Canagliflozin/therapeutic use ; Sodium-Glucose Transporter 2 Inhibitors/pharmacology ; Sodium-Glucose Transporter 2 Inhibitors/therapeutic use ; Insulin Resistance ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Muscle, Skeletal/metabolism ; Mitochondria/metabolism
    Chemical Substances Canagliflozin (0SAC974Z85) ; Sodium-Glucose Transporter 2 Inhibitors ; Hypoglycemic Agents
    Language English
    Publishing date 2023-12-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 605769-x
    ISSN 1464-5491 ; 0742-3071 ; 1466-5468
    ISSN (online) 1464-5491
    ISSN 0742-3071 ; 1466-5468
    DOI 10.1111/dme.15271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1954: Show issues Location:
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  2. Article ; Online: Nanoparticles Containing a Combination of a Drug and an Antibody for the Treatment of Breast Cancer Brain Metastases.

    Wyatt, Emily A / Davis, Mark E

    Molecular pharmaceutics

    2020  Volume 17, Issue 2, Page(s) 717–721

    Abstract: In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic ... ...

    Abstract In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic agents against brain metastases is limited by their inability to permeate the blood-brain and blood-tumor barriers (BBB and BTB) in therapeutic amounts. Here, we investigate the potential of mucic acid-based, targeted nanoparticles designed to transcytose the BBB/BTB to deliver a small molecule drug, camptothecin (CPT), and therapeutic antibody, Herceptin, to brain metastases in mice. Treatment with BBB-targeted combination CPT/Herceptin nanoparticles significantly inhibits tumor growth compared to free CPT/Herceptin and BBB-targeted nanoparticles carrying CPT alone. Though not as efficacious, BBB-targeted nanoparticles carrying only Herceptin also elicit considerable antitumor activity. These results demonstrate the potential of the targeted nanoparticle system for the delivery of an antibody alone or in combination with other drugs across the BBB/BTB to improve the therapeutic outcome.
    MeSH term(s) Animals ; Antineoplastic Agents, Immunological/administration & dosage ; Antineoplastic Agents, Phytogenic/administration & dosage ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain Neoplasms/drug therapy ; Brain Neoplasms/secondary ; Breast Neoplasms/pathology ; Camptothecin/administration & dosage ; Cell Line, Tumor ; Drug Combinations ; Drug Delivery Systems/methods ; Female ; Humans ; Mice ; Nanoparticles/administration & dosage ; Nanoparticles/chemistry ; Sugar Acids/chemistry ; Trastuzumab/administration & dosage ; Treatment Outcome ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents, Immunological ; Antineoplastic Agents, Phytogenic ; Drug Combinations ; Sugar Acids ; galactaric acid (E149J5OTIF) ; Trastuzumab (P188ANX8CK) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2020-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.9b01167
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles.

    Wyatt, Emily A / Davis, Mark E

    Bioengineering & translational medicine

    2018  Volume 4, Issue 1, Page(s) 30–37

    Abstract: HER2-targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood-brain and blood-tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy ... ...

    Abstract HER2-targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood-brain and blood-tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)-targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole-body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC- and ICD-formed brain tumors, while non-targeted nanoparticles show uptake and inhibition only in IC-established metastases. TfR-targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models.
    Language English
    Publishing date 2018-11-05
    Publishing country United States
    Document type Journal Article
    ISSN 2380-6761
    ISSN 2380-6761
    DOI 10.1002/btm2.10108
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Application of a High Throughput and Automated Workflow to Therapeutic Protein Formulation Development.

    Ren, Cindy D / Qi, Wei / Wyatt, Emily A / Yeary, Jeffrey / Westland, Kimberly / Berke, Michael / Rathore, Nitin

    Journal of pharmaceutical sciences

    2020  Volume 110, Issue 3, Page(s) 1130–1141

    Abstract: Rapid and efficient formulation development is critical to successfully bringing therapeutic protein drug products into a competitive market under increasingly aggressive timelines. Conventional application of high throughput techniques for formulation ... ...

    Abstract Rapid and efficient formulation development is critical to successfully bringing therapeutic protein drug products into a competitive market under increasingly aggressive timelines. Conventional application of high throughput techniques for formulation development have been limited to lower protein concentrations, which are not applicable to late stage development of high concentration therapeutics. In this work, we present a high throughput (HT) formulation workflow that enables screening at representative concentrations via integration of a micro-buffer exchange system with automated analytical instruments. The operational recommendations associated with the use of such HT systems as well as the efficiencies gained (reduction in hands-on time and run time by over 70% and 30%, respectively), which enable practical characterization of an expanded formulation design space, are discussed. To demonstrate that the workflow is fit for purpose, the formulation properties and stability profiles (SEC and CEX) from samples generated by the HT workflow were compared to those processed by ultrafiltration/diafiltration, and the results were shown to be in good agreement. This approach was further applied to two case studies, one focused on a formulation screen that studied the effects of pH and excipient on viscosity and stability, and the other focused on selection of an appropriate viscosity mimic solution for a protein product.
    MeSH term(s) Antibodies, Monoclonal ; Excipients ; High-Throughput Screening Assays ; Viscosity ; Workflow
    Chemical Substances Antibodies, Monoclonal ; Excipients
    Language English
    Publishing date 2020-10-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3151-3
    ISSN 1520-6017 ; 0022-3549
    ISSN (online) 1520-6017
    ISSN 0022-3549
    DOI 10.1016/j.xphs.2020.10.040
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Regulator of calcineurin-2 is a centriolar protein with a role in cilia length control.

    Stevenson, Nicola L / Bergen, Dylan J M / Xu, Amadeus / Wyatt, Emily / Henry, Freya / McCaughey, Janine / Vuolo, Laura / Hammond, Chrissy L / Stephens, David J

    Journal of cell science

    2018  Volume 131, Issue 9

    Abstract: Almost every cell in the human body extends a primary cilium. Defective cilia function leads to a set of disorders known as ciliopathies, which are characterised by debilitating developmental defects that affect many tissues. Here, we report a new role ... ...

    Abstract Almost every cell in the human body extends a primary cilium. Defective cilia function leads to a set of disorders known as ciliopathies, which are characterised by debilitating developmental defects that affect many tissues. Here, we report a new role for regulator of calcineurin 2 (RCAN2) in primary cilia function. It localises to centrioles and the basal body and is required to maintain normal cilia length. RCAN2 was identified as the most strongly upregulated gene from a comparative RNAseq analysis of cells in which expression of the Golgi matrix protein giantin had been abolished by gene editing. In contrast to previous work where we showed that depletion of giantin by RNAi results in defects in ciliogenesis and in cilia length control, giantin knockout cells generate normal cilia after serum withdrawal. Furthermore, giantin knockout zebrafish show increased expression of RCAN2. Importantly, suppression of RCAN2 expression in giantin knockout cells results in the same defects in the control of cilia length that are seen upon RNAi of giantin itself. Together, these data define RCAN2 as a regulator of cilia function that can compensate for the loss of giantin function.
    MeSH term(s) Animals ; Cell Cycle Proteins/metabolism ; Centrioles/genetics ; Centrioles/metabolism ; Cilia/genetics ; Cilia/metabolism ; Gene Knockout Techniques ; Golgi Matrix Proteins/genetics ; Golgi Matrix Proteins/metabolism ; Humans ; Muscle Proteins/genetics ; Muscle Proteins/metabolism ; Retinal Pigment Epithelium/cytology ; Retinal Pigment Epithelium/metabolism ; Zebrafish
    Chemical Substances Cell Cycle Proteins ; Golgi Matrix Proteins ; Muscle Proteins ; RCAN2 protein, human ; macrogolgin
    Language English
    Publishing date 2018-05-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2993-2
    ISSN 1477-9137 ; 0021-9533
    ISSN (online) 1477-9137
    ISSN 0021-9533
    DOI 10.1242/jcs.212258
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  6. Article ; Online: Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye.

    Tesar, Devin / Luoma, Jacob / Wyatt, Emily A / Shi, Catherine / Shatz, Whitney / Hass, Philip E / Mathieu, Mary / Yi, Li / Corn, Jacob E / Maass, Katie F / Wang, Kathryn / Dion, Michelle Z / Andersen, Nisana / Loyet, Kelly M / van Lookeren Campagne, Menno / Rajagopal, Karthikan / Dickmann, Leslie / Scheer, Justin M / Kelley, Robert F

    mAbs

    2017  Volume 9, Issue 8, Page(s) 1297–1305

    Abstract: To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long-acting ... ...

    Abstract To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long-acting delivery (LAD) technologies is highly desirable. These technologies usually require a highly concentrated formulation and the antibody must be stable against extended exposure to physiological conditions. Here we have increased the potential of a therapeutic antibody antigen-binding fragment (Fab) for LAD by using protein engineering to enhance the chemical and physical stability of the molecule. Structure-guided amino acid substitutions in a negatively charged complementarity determining region (CDR-L1) of an anti-factor D (AFD) Fab resulted in increased chemical stability and solubility. A variant of AFD (AFD.v8), which combines light chain substitutions (VL-D28S:D30E:D31S) with a substitution (VH-D61E) to stabilize a heavy chain isomerization site, retained complement factor D binding and inhibition potency and has properties suitable for LAD. This variant was amenable to high protein concentration (>250 mg/mL), low ionic strength formulation suitable for intravitreal injection. AFD.v8 had acceptable pharmacokinetic (PK) properties upon intravitreal injection in rabbits, and improved stability under both formulation and physiological conditions. Simulations of expected human PK behavior indicated greater exposure with a 25-mg dose enabled by the increased solubility of AFD.v8.
    MeSH term(s) Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/immunology ; Antibodies, Monoclonal/pharmacokinetics ; Antibody Affinity/immunology ; Complement Factor D/immunology ; Complementarity Determining Regions/genetics ; Complementarity Determining Regions/immunology ; Drug Delivery Systems ; Drug Stability ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fab Fragments/genetics ; Immunoglobulin Fab Fragments/immunology ; Models, Molecular ; Protein Conformation ; Protein Engineering/methods ; Rabbits ; Retinal Diseases/drug therapy ; Retinal Diseases/immunology ; Retinal Diseases/metabolism
    Chemical Substances Antibodies, Monoclonal ; Complementarity Determining Regions ; Immunoglobulin Fab Fragments ; CFD protein, human (EC 3.4.21.46) ; Complement Factor D (EC 3.4.21.46)
    Language English
    Publishing date 2017-08-30
    Publishing country United States
    Document type Journal Article
    ISSN 1942-0870
    ISSN (online) 1942-0870
    DOI 10.1080/19420862.2017.1372078
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Development and characterization of a Yucatan miniature biomedical pig permanent middle cerebral artery occlusion stroke model.

    Platt, Simon R / Holmes, Shannon P / Howerth, Elizabeth W / Duberstein, Kylee Jo J / Dove, C Robert / Kinder, Holly A / Wyatt, Emily L / Linville, Amie V / Lau, Vivian W / Stice, Steven L / Hill, William D / Hess, David C / West, Franklin D

    Experimental & translational stroke medicine

    2014  Volume 6, Issue 1, Page(s) 5

    Abstract: Background: Efforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic ... ...

    Abstract Background: Efforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic development process. One of the major factors believed to be limiting effective screening of these treatments is the absence of an animal model more predictive of human responses to treatments. The pig may potentially fill this gap with a gyrencephalic brain that is larger in size with a more similar gray-white matter composition to humans than traditional stroke animal models. In this study we develop and characterize a novel pig middle cerebral artery occlusion (MCAO) ischemic stroke model.
    Methods: Eleven male pigs underwent MCAO surgery with the first 4 landrace pigs utilized to optimize stroke procedure and 7 additional Yucatan stroked pigs studied over a 90 day period. MRI analysis was done at 24 hrs and 90 days and included T2w, T2w FLAIR, T1w FLAIR and DWI sequences and associated ADC maps. Pigs were sacrificed at 90 days and underwent gross and microscopic histological evaluation. Significance in quantitative changes was determined by two-way analysis of variance and post-hoc Tukey's Pair-Wise comparisons.
    Results: MRI analysis of animals that underwent MCAO surgery at 24 hrs had hyperintense regions in T2w and DWI images with corresponding ADC maps having hypointense regions indicating cytotoxic edema consistent with an ischemic stroke. At 90 days, region of interest analysis of T1 FLAIR and ADC maps had an average lesion size of 59.17 cc, a loss of 8% brain matter. Histological examination of pig brains showed atrophy and loss of tissue, consistent with MRI, as well as glial scar formation and macrophage infiltration.
    Conclusions: The MCAO procedure led to significant and consistent strokes with high survivability. These results suggest that the pig model is potentially a robust system for the study of stroke pathophysiology and potential diagnostics and therapeutics.
    Language English
    Publishing date 2014-03-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 2520967-X
    ISSN 2040-7378
    ISSN 2040-7378
    DOI 10.1186/2040-7378-6-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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