Bio

Academic Appointments


Administrative Appointments


  • Director, Comparative Medicine Necropsy Service (2018 - Present)

Honors & Awards


  • Department of Comparative Medicine Distinguished Clinician Award, Stanford University School of Medicine (2018)
  • Dr. Donald R. Cordy Prize in Veterinary Anatomic Pathology, University of California, Davis (2016)
  • Gerald V. Ling Award - Outstanding Small Animal Research Study and Presentation, University of California, Davis (2016)
  • Henry L. Foster DVM Scholar, Tufts Cummings School of Veterinary Medicine (2012-2013)
  • Norman J. MacLeod Endowed Scholar, Tufts Cummings School of Veterinary Medicine (2012)

Boards, Advisory Committees, Professional Organizations


  • Member, Geropathology Research Network (2017 - Present)
  • Member, Digital Pathology Association (2017 - Present)
  • Member, American College of Veterinary Pathologists (2016 - Present)

Professional Education


  • Fellow, Stanford University School of Medicine, Post-Doctoral Research Fellowship (2018)
  • Diplomate, American College of Veterinary Pathologists (ACVP), Anatomic Pathology (2016)
  • Resident, University of California - Davis, Anatomic Pathology (2016)
  • DVM, Tufts University, Veterinary Medicine (2013)
  • BA, Connecticut College, Behavioral Neuroscience (2007)

Publications

All Publications


  • Mitochondrial copper depletion suppresses triple-negative breast cancer in mice. Nature biotechnology Cui, L., Gouw, A. M., LaGory, E. L., Guo, S., Attarwala, N., Tang, Y., Qi, J., Chen, Y., Gao, Z., Casey, K. M., Bazhin, A. A., Chen, M., Hu, L., Xie, J., Fang, M., Zhang, C., Zhu, Q., Wang, Z., Giaccia, A. J., Gambhir, S. S., Zhu, W., Felsher, D. W., Pegram, M. D., Goun, E. A., Le, A., Rao, J. 2020

    Abstract

    Depletion of mitochondrial copper, which shifts metabolism from respiration to glycolysis and reduces energy production, is known to be effective against cancer types that depend on oxidative phosphorylation. However, existing copper chelators are too toxic or ineffective for cancer treatment. Here we develop a safe, mitochondria-targeted, copper-depleting nanoparticle (CDN) and test it against triple-negative breast cancer (TNBC). We show that CDNs decrease oxygen consumption and oxidative phosphorylation, cause a metabolic switch to glycolysis and reduce ATP production in TNBC cells. This energy deficiency, together with compromised mitochondrial membrane potential and elevated oxidative stress, results in apoptosis. CDNs should be less toxic than existing copper chelators because they favorably deprive copper in the mitochondria in cancer cells instead of systemic depletion. Indeed, we demonstrate low toxicity of CDNs in healthy mice. In three mouse models of TNBC, CDN administration inhibits tumor growth and substantially improves survival. The efficacy and safety of CDNs suggest the potential clinical relevance of this approach.

    View details for DOI 10.1038/s41587-020-0707-9

    View details for PubMedID 33077961

  • Novel NanoLuc substrates enable bright two-population bioluminescence imaging in animals. Nature methods Su, Y., Walker, J. R., Park, Y., Smith, T. P., Liu, L. X., Hall, M. P., Labanieh, L., Hurst, R., Wang, D. C., Encell, L. P., Kim, N., Zhang, F., Kay, M. A., Casey, K. M., Majzner, R. G., Cochran, J. R., Mackall, C. L., Kirkland, T. A., Lin, M. Z. 2020

    Abstract

    Sensitive detection of two biological events in vivo has long been a goal in bioluminescence imaging. Antares, a fusion of the luciferase NanoLuc to the orange fluorescent protein CyOFP, has emerged as a bright bioluminescent reporter with orthogonal substrate specificity to firefly luciferase (FLuc) and its derivatives such as AkaLuc. However, the brightness of Antares in mice is limited by the poor solubility and bioavailability of the NanoLuc substrate furimazine. Here, we report a new substrate, hydrofurimazine, whose enhanced aqueous solubility allows delivery of higher doses to mice. In the liver, Antares with hydrofurimazine exhibited similar brightness to AkaLuc with its substrate AkaLumine. Further chemical exploration generated a second substrate, fluorofurimazine, with even higher brightness in vivo. We used Antares with fluorofurimazine to track tumor size and AkaLuc with AkaLumine to visualize CAR-T cells within the same mice, demonstrating the ability to perform two-population imaging with these two luciferase systems.

    View details for DOI 10.1038/s41592-020-0889-6

    View details for PubMedID 32661427

  • The Stability and Efficacy of Tricaine Methanesulfonate (MS222) Solution After Long-Term Storage JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE Katz, E. M., Chu, D. K., Casey, K. M., Jampachaisri, K., Felt, S. A., Pacharinsak, C. 2020; 59 (4): 393?400

    Abstract

    Tricaine methanesulfonate (MS222) is widely used for the anesthesia and euthanasia of laboratory zebrafish. Fresh solutions have been recommended for each use; however, researchers often mix and store concentrated stock solutions for convenience and to reduce occupational exposure and environmental waste. While this is common practice, published guidelines are often inconsistent. Thus, the objective of this study was to evaluate the stability and anesthetic efficacy of MS222 after long-term storage and to develop specific storage parameters. Stock solutions (100 mg/mL MS222) were mixed and stored in amber jars at 4 C and -20 C for 2- and 6-mo. Stability of the solutions was analyzed using liquid chromatography-ion trapmass spectrometry and compared with fresh MS222. Fifty adult (30 male, 20 female) wildtype AB zebrafish (Danio rerio) wererandomly anesthetized with 150 mg/L of one of the following MS222 solutions to evaluate anesthetic efficacy: 1) freshly prepared(0m); 2) 2 mo at 4 C (2m4); 3) 2 mo at -20 C (2m-20); 4) 6 mo at 4 C (6m4); 5) 6 mo at -20 C (6m-20). Time to cessation of swimming, loss of equilibrium, lack of response to von Frey (VF) stimulation, return of equilibrium, and resumption of swimming were compared between groups. Two fish from each group were euthanized at 24-h and 2-wk after anesthesia, and histopathology was performed. All solutions were determined to be stable under all storage conditions. No clinically significant differences were observed between the fresh and stored stock groups during anesthetic testing. No evidence ofanesthetic-related histologic changes were noted in the gills, skin, kidneys, muscle, and central nervous system. Hepatic megalocytosis and a reduction in hepatic vacuolation were seen to varying degrees across all groups, but did not follow a treatment-related trend. Therefore, 100 mg/mL solutions of MS222 can be stored in amber jars at 4 C or -20 C for 6 mo and still used to effectively anesthetize zebrafish.

    View details for DOI 10.30802/AALAS-JAALAS-19-000067

    View details for Web of Science ID 000569144100009

    View details for PubMedID 32532365

    View details for PubMedCentralID PMC7338872

  • Tumor shedding and metastatic progression after tumor excision in patient-derived orthotopic xenograft models of triple-negative breast cancer. Clinical & experimental metastasis Razmara, A. M., Sollier, E., Kisirkoi, G. N., Baker, S. W., Bellon, M. B., McMillan, A., Lemaire, C. A., Ramani, V. C., Jeffrey, S. S., Casey, K. M. 2020

    Abstract

    Patient-derived orthotopic xenograft (PDOX) models have been verified as a useful method for studying human cancers in mice. Previous studies on the extent of metastases in these models have been limited by the necessity of welfare euthanasia (primary tumors reaching threshold size), at which point metastases may only be micrometers in diameter, few in number, and solely identified by step-sectioning of formalin-fixed paraffin-embedded tissue. These small micro-metastases are less suitable for many downstream molecular analyses than macro-metastases. Resection of the primary tumor by survival surgery has been proven to allow further time for metastases to grow. Although PDOX models of triple-negative breast cancer (TNBC) shed circulating tumor cells (CTCs) into the bloodstream and metastasize, similar to human TNBC, little data has been collected in these TNBC PDOX models regarding the association between CTC characteristics and distant metastasis following excision of the primary tumor xenograft. This study assembles a timeline of PDOX tumor shedding and metastatic tumor progression before and after tumor excision surgery. We report the ability to use tumorectomies to increase the lifespan of TNBC PDOX models with the potential to obtain larger metastases. CTC clusters and CTCs expressing a mesenchymal marker (vimentin) were associated with metastatic burden in lung and liver. The data collected through these experiments will guide the further use of PDOX models in studying metastatic TNBC.

    View details for DOI 10.1007/s10585-020-10033-3

    View details for PubMedID 32335861

  • Histologic safety of transcranial focused ultrasound neuromodulation and magnetic resonance acoustic radiation force imaging in rhesus macaques and sheep. Brain stimulation Gaur, P., Casey, K. M., Kubanek, J., Li, N., Mohammadjavadi, M., Saenz, Y., Glover, G. H., Bouley, D. M., Pauly, K. B. 2020; 13 (3): 804?14

    Abstract

    BACKGROUND: Neuromodulation by transcranial focused ultrasound (FUS) offers the potential to non-invasively treat specific brain regions, with treatment location verified by magnetic resonance acoustic radiation force imaging (MR-ARFI).OBJECTIVE: To investigate the safety of these methods prior to widespread clinical use, we report histologic findings in two large animal models following FUS neuromodulation and MR-ARFI.METHODS: Two rhesus macaques and thirteen Dorset sheep were studied. FUS neuromodulation was targeted to the primary visual cortex in rhesus macaques and to subcortical locations, verified by MR-ARFI, in eleven sheep. Both rhesus macaques and five sheep received a single FUS session, whereas six sheep received repeated sessions three to six days apart. The remaining two control sheep did not receive ultrasound but otherwise underwent the same anesthetic and MRI procedures as the eleven experimental sheep. Hematoxylin and eosin-stained sections of brain tissue (harvested zero to eleven days following FUS) were evaluated for tissue damage at FUS and control locations as well as tissue within the path of the FUS beam. TUNEL staining was used to evaluate for the presence of apoptosis in sheep receiving high dose FUS.RESULTS: No FUS-related pre-mortem histologic findings were observed in the rhesus macaques or in any of the examined sheep. Extravascular red blood cells (RBCs) were present within the meninges of all sheep, regardless of treatment group. Similarly, small aggregates of perivascular RBCs were rarely noted in non-target regions of neural parenchyma of FUS-treated (8/11) and untreated (2/2) sheep. However, no concurrent histologic abnormalities were observed, consistent with RBC extravasation occurring as post-mortem artifact following brain extraction. Sheep within the high dose FUS group were TUNEL-negative at the targeted site of FUS.CONCLUSIONS: The absence of FUS-related histologic findings suggests that the neuromodulation and MR-ARFI protocols evaluated do not cause tissue damage.

    View details for DOI 10.1016/j.brs.2020.02.017

    View details for PubMedID 32289711

  • AND-gate contrast agents for enhanced fluorescence-guided surgery. Nature biomedical engineering Widen, J. C., Tholen, M., Yim, J. J., Antaris, A., Casey, K. M., Rogalla, S., Klaassen, A., Sorger, J., Bogyo, M. 2020

    Abstract

    Surgical resection of tumours requires precisely locating and defining the margins between lesions and normal tissue. However, this is made difficult by irregular margin borders. Although molecularly targeted optical contrast agents can be used to define tumour margins during surgery in real time, the selectivity of the contrast agents is often limited by the target being expressed in both healthy and tumour tissues. Here, we show that AND-gate optical imaging probes that require the processing of two substrates by multiple tumour-specific enzymes produce a fluorescent signal with significantly improved specificity and sensitivity to tumour tissue. We evaluated the performance of the probes in mouse models of mammary tumours and of metastatic lung cancer, as well as during fluorescence-guided robotic surgery. Imaging probes that rely on multivariate activation to selectively target complex patterns of enzymatic activity should be useful in disease detection, treatment and monitoring.

    View details for DOI 10.1038/s41551-020-00616-6

    View details for PubMedID 32989286

  • FLASH Irradiation Results in Reduced Severe Skin Toxicity Compared to Conventional-Dose-Rate Irradiation. Radiation research Soto, L. A., Casey, K. M., Wang, J., Blaney, A., Manjappa, R., Breitkreutz, D., Skinner, L., Dutt, S., Ko, R. B., Bush, K., Yu, A. S., Melemenidis, S., Strober, S., Englemann, E., Maxim, P. G., Graves, E. E., Loo, B. W. 2020

    Abstract

    Radiation therapy, along with surgery and chemotherapy, is one of the main treatments for cancer. While radiotherapy is highly effective in the treatment of localized tumors, its main limitation is its toxicity to normal tissue. Previous preclinical studies have reported that ultra-high dose-rate (FLASH) irradiation results in reduced toxicity to normal tissues while controlling tumor growth to a similar extent relative to conventional-dose-rate (CONV) irradiation. To our knowledge this is the first report of a dose-response study in mice comparing the effect of FLASH irradiation vs. CONV irradiation on skin toxicity. We found that FLASH irradiation results in both a lower incidence and lower severity of skin ulceration than CONV irradiation 8 weeks after single-fraction hemithoracic irradiation at high doses (30 and 40 Gy). Survival was also higher after FLASH hemithoracic irradiation (median survival >180 days at doses of 30 and 40 Gy) compared to CONV irradiation (median survival 100 and 52 days at 30 and 40 Gy, respectively). No ulceration was observed at doses 20 Gy or below in either FLASH or CONV. These results suggest a shifting of the dose-response curve for radiation-induced skin ulceration to the right for FLASH, compared to CONV irradiation, suggesting the potential for an enhanced therapeutic index for radiation therapy of cancer.

    View details for DOI 10.1667/RADE-20-00090

    View details for PubMedID 32853385

  • Biodegradable Fluorescent Nanoparticles for Endoscopic Detection of Colorectal Carcinogenesis ADVANCED FUNCTIONAL MATERIALS Rogalla, S., Flisikowski, K., Gorpas, D., Mayer, A. T., Flisikowska, T., Mandella, M. J., Ma, X., Casey, K. M., Felt, S. A., Saur, D., Ntziachristos, V., Schnieke, A., Contag, C. H., Gambhir, S. S., Harmsen, S. 2019; 29 (51)
  • EVALUATION OF DYNAMIN 2 (DNM2) AS A THERAPEUTIC TARGET IN LEPTOMENINGEAL METASTATIC DISEASE Chernikova, S., Polyak, D., Deng, J., Tsau, S., Casey, K., Johnson, E., Bhambhvani, H., Khoeur, L., Stanley, G., Tran, K., Connolly, I., Joyce, A., Li, Y., von Eyben, R., Nagpal, S., Gephart, M. OXFORD UNIV PRESS INC. 2019: 57
  • Investigating circulating tumor cells and distant metastases in patient-derived orthotopic xenograft models of triple-negative breast cancer. Breast cancer research : BCR Ramani, V. C., Lemaire, C. A., Triboulet, M., Casey, K. M., Heirich, K., Renier, C., Vilches-Moure, J. G., Gupta, R., Razmara, A. M., Zhang, H., Sledge, G. W., Sollier, E., Jeffrey, S. S. 2019; 21 (1): 98

    Abstract

    BACKGROUND: Circulating tumor cells (CTCs) represent a temporal "snapshot" of a patient's cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer.METHODS: We used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice.RESULTS: Staining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency.CONCLUSION: PDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.

    View details for DOI 10.1186/s13058-019-1182-4

    View details for PubMedID 31462307

  • Novel NanoLuc substrates enable bright and sustained bioluminescence imaging in animals Walker, J., Park, Y., Smith, T., Wang, D., Hall, M., Liu, L., Hurst, R., Su, Y., Encell, L., Kim, N., Casey, K., Kirkland, T., Lin, M. AMER CHEMICAL SOC. 2019
  • Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses GENOME RESEARCH Benayoun, B. A., Pollina, E. A., Singh, P., Mahmoudi, S., Harel, I., Casey, K. M., Dulken, B. W., Kundaje, A., Brunet, A. 2019; 29 (4): 697?709
  • Western diet regulates immune status and the response to LPS-driven sepsis independent of diet-associated microbiome PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Napier, B. A., Andres-Terre, M., Massis, L. M., Hryckowian, A. J., Higginbottom, S. K., Cumnock, K., Casey, K. M., Haileselassie, B., Lugo, K. A., Schneider, D. S., Sonnenburg, J. L., Monack, D. M. 2019; 116 (9): 3688?94
  • Pravastatin improves fetal survival in mice with a partial deficiency of heme oxygenase-1. Placenta Tsur, A., Kalish, F., Burgess, J., Nayak, N. R., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. 2019; 75: 1?8

    Abstract

    Statins induce heme oxygenase-1 (HO-1) expression in vitro and in vivo. Low HO-1 expression is associated with pregnancy complications, e.g. preeclampsia and recurrent miscarriages. Here, we investigated the effects of pravastatin on HO-1 expression, placental development, and fetal survival in mice with a partial HO-1 deficiency.At E14.5, untreated pregnant wild-type (WT, n=13-18), untreated HO-1+/- (Het, n=6-9), and Het mice treated with pravastatin (Het+Pravastatin, n=12-14) were sacrificed. Numbers of viable fetuses/resorbed concepti were recorded. Maternal livers and placentas were harvested for HO activity. Hematoxylin and eosin (H&E) and CD31 immunohistochemical staining were performed on whole placentas.Compared with WT, HO activity in Het livers (6518%, P<0.001) and placentas (747%, P<0.001) were significantly decreased. Number of viable fetuses per dam was significantly lower in Untreated Het dams (6.02.2) compared with WT (9.11.4, P<0.01), accompanied by a higher relative risk (RR) for concepti resorption (17.1, 95% CI 4.0-73.2). In Hets treated with pravastatin, maternal liver and placental HO activity increased, approaching levels of WT controls (to 837% and 8714%, respectively). The number of viable fetuses per dam increased to 7.72.5 with a decreased RR for concepti resorption (2.7, 95% CI 1.2-5.9). In some surviving Untreated Het placentas, there were focal losses of cellular architecture and changes suggestive of reduced blood flow in the labyrinth. These findings were absent in Het+Pravastatin placentas.Pravastatin induces maternal liver and placental HO activity, may affect placental function and improve fetal survival in the context of a partial deficiency of HO-1.

    View details for PubMedID 30712660

  • Validation of a geropathology grading system for aging mouse studies. GeroScience Snyder, J. M., Snider, T. A., Ciol, M. A., Wilkinson, J. E., Imai, D. M., Casey, K. M., Vilches-Moure, J. G., Pettan-Brewer, C., Pillai, S. P., Carrasco, S. E., Salimi, S., Ladiges, W. 2019

    Abstract

    An understanding of early-onset mechanisms underlying age-related changes can be obtained by evaluating changes that precede frailty and end of life using histological characterization of age-related lesions. Histopathology-based information as a component of aging studies in mice can complement and add context to molecular, cellular, and physiologic data, but there is a lack of information regarding scoring criteria and lesion grading guidelines. This report describes the validation of a grading system, designated as the geropathology grading platform (GGP), which generated a composite lesion score (CLS) for comparison of histological lesion scores in tissues from aging mice. To assess reproducibility of the scoring system, multiple veterinary pathologists independently scored the same slides from the heart, lung, liver, and kidney from two different strains (C57BL/6 and CB6F1) of male mice at 8, 16, 24, and 32months of age. There was moderate to high agreement between pathologists, particularly when agreement within a 1-point range was considered. CLS for all organs was significantly higher in older versus younger mice, suggesting that the GGP was reliable for detecting age-related pathology in mice. The overall results suggest that the GGP guidelines reliably distinguish between younger and older mice and may therefore be accurate in distinguishing between experimental groups of mice with more, or less, age-related pathology.

    View details for DOI 10.1007/s11357-019-00088-w

    View details for PubMedID 31468322

  • Biodegradable fluorescent nanoparticles for endoscopic detection of colorectal carcinogenesis. Advanced functional materials Rogalla, S., Flisikowski, K., Gorpas, D., Mayer, A. T., Flisikowska, T., Mandella, M. J., Ma, X., Casey, K. M., Felt, S. A., Saur, D., Ntziachristos, V., Schnieke, A., Contag, C. H., Gambhir, S. S., Harmsen, S. 2019; 29 (51)

    Abstract

    Early and comprehensive endoscopic detection of colonic dysplasia - the most clinically significant precursor lesion to colorectal adenocarcinoma - provides an opportunity for timely, minimally-invasive intervention to prevent malignant transformation. Here, the development and evaluation of biodegradable near-infrared fluorescent silica nanoparticles (FSN) is described that have the potential to improve adenoma detection during fluorescence-assisted white-light colonoscopic surveillance in rodent and human-scale models of colorectal carcinogenesis. FSNs are biodegradable (t1/2 of 2.7 weeks), well-tolerated, and enable detection and delineation of adenomas as small as 0.5 mm2 with high tumor-to-background ratios. Furthermore, in the human-scale, APC 1311/+ porcine model, the clinical feasibility and benefit of using FSN-guided detection of colorectal adenomas using video-rate fluorescence-assisted white-light endoscopy is demonstrated. Since nanoparticles of similar size (e.g., 100-150-nm) or composition (i.e., silica, silica/gold hybrid) have already been successfully translated to the clinic, and, clinical fluorescent/white light endoscopy systems are becoming more readily available, there is a viable path towards clinical translation of the proposed strategy for early colorectal cancer detection and prevention in high-risk patients.

    View details for DOI 10.1002/adfm.201904992

    View details for PubMedID 33041743

    View details for PubMedCentralID PMC7546531

  • Proliferative Typhlocolitis With Multinucleated Giant Cells: A Nonspecific Enteropathy in Immunodeficient Sentinel Mice VETERINARY PATHOLOGY Casey, K. M., Johnson, A. L., Hunrath, M. N., Fraser, J. K., McCowan, N. C., Wasson, K., Doty, R. A., Griffey, S. M., Imai, D. M. 2019; 56 (1): 157?68
  • Evaluation of 3 Alcohol-based Agents for Presurgical Skin Preparation in Mice. Journal of the American Association for Laboratory Animal Science : JAALAS Huss, M. K., Casey, K. M., Hu, J., Moorhead, R. C., Chum, H. H. 2019

    Abstract

    Appropriate aseptic technique is a crucial component of rodent survival surgery. Ease of technique, surgical space constraint,batch surgery, and cost are factors that may affect researcher compliance with appropriate aseptic technique. The first part of this study compared 3 antiseptic preparation agents with the standard triplicate application of povidone-iodine and alcohol. Euthanized mice (n = 40) were shaved on the dorsum, and culture swabs were taken for RODAC plating and bacterial identification. Shaved sites were prepared by using one of the 4 antiseptic preparation agents. Culture samples were obtained immediately and at 20 min after antiseptic preparation. In the 2nd part of the study, 8 mice (n = 2 per group)were prepared for a survival surgical procedure by using one of the 4 antiseptic preparation agents to evaluate whether the antiseptic preparation agents caused skin irritation or impaired healing. Results from this study indicated that all 3 of the antiseptic agents evaluated were equally effective at reducing bacterial populations immediately and at 20 min after preparation. Histopathologic examination of the incision sites revealed signs of normal healing without lesions adjacent to the incision site. We conclude that all 3 of the products evaluated are comparable to traditional povidone-iodine and alcohol as agents for aseptic preparation of surgical sites.

    View details for DOI 10.30802/AALAS-JAALAS-19-000053

    View details for PubMedID 31753064

  • What is your diagnosis? Conjunctival smear in a dog. Veterinary clinical pathology Gonzales-Viera, O., Casey, K., Keel, M. K. 2018

    View details for PubMedID 29989194

  • Pravastatin Induces Heme Oxygenase Activity and Enhances Placental Development in a Murine Model. Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K. M., Druzin, M. L., Wong, R. J., Stevenson, D. K. SAGE PUBLICATIONS INC. 2018: 155A?156A
  • Pravastatin improves pregnancy outcome and placental development in heme oxygenase-1 deficient mice Tsur, A., Kalish, F., Burgess, J., Zhao, H., Casey, K., Druzin, M. L., Wong, R. J., Stevenson, D. K. MOSBY-ELSEVIER. 2018: S202
  • SETD3 is an actin histidine methyltransferase that prevents primary dystocia. Nature Wilkinson, A. W., Diep, J., Dai, S., Liu, S., Ooi, Y. S., Song, D., Li, T. M., Horton, J. R., Zhang, X., Liu, C., Trivedi, D. V., Ruppel, K. M., Vilches-Moure, J. G., Casey, K. M., Mak, J., Cowan, T., Elias, J. E., Nagamine, C. M., Spudich, J. A., Cheng, X., Carette, J. E., Gozani, O. 2018

    Abstract

    For more than 50years, the methylation of mammalian actin at histidine 73 has been known to occur1. Despite the pervasiveness of His73 methylation, which we find is conserved in several model animals and plants, its function remains unclear and the enzyme that generates this modification is unknown. Here we identify SET domain protein 3 (SETD3) as the physiological actin His73 methyltransferase. Structural studies reveal that an extensive network of interactions clamps the actin peptide onto the surface of SETD3 to orient His73 correctly within the catalytic pocket and to facilitate methyl transfer. His73 methylation reduces the nucleotide-exchange rate on actin monomers and modestly accelerates the assembly of actin filaments. Mice that lack SETD3 show complete loss of actin His73 methylation in several tissues, and quantitative proteomics analysis shows that actin His73 methylation is the only detectable physiological substrate of SETD3. SETD3-deficient female mice have severely decreased litter sizes owing to primary maternal dystocia that is refractory to ecbolic induction agents. Furthermore, depletion of SETD3 impairs signal-induced contraction in primary human uterine smooth muscle cells. Together, our results identify a mammalian histidine methyltransferase and uncover a pivotal role for SETD3 and actin His73 methylation in the regulation of smooth muscle contractility. Our data also support the broader hypothesis that protein histidine methylation acts as a common regulatory mechanism.

    View details for PubMedID 30626964

  • Identification of occult micrometastases and isolated tumour cells within regional lymph nodes of previously diagnosed non-metastatic (stage 0) canine carcinomas VETERINARY AND COMPARATIVE ONCOLOGY Casey, K. M., Steffey, M. A., Affolter, V. K. 2017; 15 (3): 785?92

    Abstract

    Metastatic dissemination of carcinomas to lymph nodes impacts prognosis and treatment recommendations in human and veterinary medicine. Routine histopathologic evaluation of regional lymph nodes involves haematoxylin and eosin (H&E) staining to identify intra-nodal neoplastic cells; however, identification of small volume metastases (micrometastases and individual tumour cells) may be missed without the aid of immunohistochemistry or additional step-sections. The aim of this study was to identify occult carcinoma metastases in previously diagnosed non-metastatic lymph nodes using step-sections and pancytokeratin (panCK) immunohistochemistry. Samples from 20 regional lymph nodes diagnosed as non-metastatic were serially sectioned and evaluated with panCK. Of these, 25% (n?=?5) contained micrometastases (n?=?1) or isolated tumour cells (n?=?4). This study demonstrates the increased efficacy of serial step-sections combined with panCK immunohistochemistry to identify small volume metastases in regional lymph nodes. The prognostic significance of micrometastases and isolated tumour cells in regional lymph nodes warrants further investigation in veterinary medicine.

    View details for DOI 10.1111/vco.12219

    View details for Web of Science ID 000408772500013

    View details for PubMedID 27135991

  • Partial gastrectomy for resection of a gastric leiomyoma in a guinea pig (Cavia porcellus) JAVMA-JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION Gardhouse, S. M., Guzman, D., Sadar, M. J., DeRouen, A. J., Bucy, D. S., Adedeji, A. O., Vernau, W., Casey, K. M., Mohr, F., Steffey, M. A. 2016; 249 (12): 1415?20

    Abstract

    CASE DESCRIPTION A 4-year-old sexually intact male pet guinea pig (Cavia porcellus) was evaluated for a routine wellness examination. CLINICAL FINDINGS During physical examination, a small mass was palpated in the cranial aspect of the abdomen. Abdominal radiographic and ultrasonographic findings were suggestive of a gastric mass. Cytologic evaluation of a fine-needle aspirate of the mass was indicative of spindle cell proliferation most consistent with a sarcoma. TREATMENT AND OUTCOME The patient was anesthetized, and an exploratory laparotomy and partial gastrectomy were performed to resect the gastric mass. Histologic and immunohistochemical examinations of the mass revealed that it was a gastric leiomyoma. The patient recovered from surgery without complications. No evidence of mass recurrence was observed during an abdominal ultrasonographic examination performed approximately 19 months after surgery. CLINICAL RELEVANCE To our knowledge, this was the first report of the clinical diagnosis and successful surgical treatment of a gastric neoplasm in a guinea pig. Gastric leiomyomas are not uncommon in guinea pigs, and although benign, they can cause clinical signs if they become large enough to impair gastric function. Gastrointestinal surgery should be considered as a treatment option for guinea pigs with similar gastric neoplasms.

    View details for DOI 10.2460/javma.249.12.1415

    View details for Web of Science ID 000388906500016

    View details for PubMedID 27901456

  • Bilateral Aural Adenocarcinoma in a Congo African Grey Parrot (Psittacus erithacus erithacus) JOURNAL OF AVIAN MEDICINE AND SURGERY Houck, E. L., Keller, K. A., Hawkins, M. G., Burton, A. G., Casey, K. M., Keel, K., Tong, N., Guzman, D. 2016; 30 (3): 257?62

    Abstract

    A 28-year-old female Congo African grey parrot ( Psittacus erithacus erithacus) was evaluated because of a mass in the left external auditory meatus. Results of a computed tomography scan revealed an osteolytic left hemimandibular mass with irregular bone production and a soft tissue mass in the left external auditory meatus. Results of cytologic examination of fine needle aspirates of the hemimandible were interpreted as adenocarcinoma with reactive osteoblasts. The owner chose palliative treatment, and a debulking procedure was performed on the left external auditory meatus mass 52 days after initial presentation to control self-trauma. Euthanasia was elected 67 days after initial presentation because of poor prognosis associated with the development of bilateral masses of the external auditory meatus and lateral deviation of the mandible, findings that were confirmed by postmortem examination. Histopathologic results confirmed the diagnosis of bilateral aural adenocarcinoma with invasion of both temporal bones and hemimandibles.

    View details for Web of Science ID 000385596600006

    View details for PubMedID 27736232

  • Bilaterally Symmetric Focal Cortical Dysplasia in a Golden Retriever Dog JOURNAL OF COMPARATIVE PATHOLOGY Casey, K. M., Bollen, A. W., Winger, K. M., Vernau, K. M., Dickinson, P. J., Higgins, R. J., Siso, S. 2014; 151 (4): 375?79

    Abstract

    A 10-year-old golden retriever dog was referred with a 24-h history of generalized seizures. Magnetic resonance imaging of the brain found no abnormalities on 3 mm transverse sections and the dog was subsequently humanely destroyed. Microscopically there was bilaterally symmetrical focal disorganization of cortical grey matter within the tips of the right and left suprasylvian gyri of the temporal cortex. The focal abnormal cortical lamination was characterized by loss of pyramidal neurons with abnormal, irregular, angular, remaining neurons occasionally forming clusters, surrounded by fibrillary astrogliosis and microgliosis and vascular proliferation. These histological findings are consistent with focal cortical dysplasia, a cerebral cortical malformation that causes seizures in people, but not reported previously in the dog.

    View details for DOI 10.1016/j.jcpa.2014.08.002

    View details for Web of Science ID 000347662200011

    View details for PubMedID 25246180

  • Reproductive Experience Alters Neural and Behavioural Responses to Acute Oestrogen Receptor alpha Activation JOURNAL OF NEUROENDOCRINOLOGY Byrnes, E. M., Casey, K., Carini, L. M., Bridges, R. S. 2013; 25 (12): 1280?89

    Abstract

    Reproductive experience (i.e. parturition and lactation) leads to persistent alterations in anxiety-like behaviour that are influenced by the oestrous cycle. We recently found that repeated administration of the selective oestrogen receptors (ER)? agonist propyl-pyrazole triol (PPT) results in anxiolytic-like behaviours on the elevated plus maze (EPM) in primiparous (but not nulliparous) female rats. The present study examined the effects of the acute administration of PPT on EPM behaviour in primiparous and aged-matched, nulliparous female rats. In addition, corticosterone secretion, corticotrophin-releasing hormone (CRH) gene expression and expression of the immediate early gene product Fos in the paraventricular nucleus (PVN) and amygdala were measured either after EPM testing or in home cage controls. Acute PPT administration significantly modified EPM behaviour as a function of reproductive experience, with nulliparous females tending toward increased anxiety-like behaviours and primiparous females tending toward decreased anxiety-like behaviours. In home cage controls, PPT increased corticosterone secretion in all females; however, both vehicle- and PPT-treated, primiparous females had reduced corticosterone levels compared to their nulliparous counterparts. Significant effects of PPT on CRH mRNA within the PVN were observed after the administration of PPT but only in primiparous females tested on the EPM. PPT also increased Fos expression within the PVN of EPM-exposed females; however, both vehicle- and PPT-treated primiparous females had reduced Fos expression compared to nulliparous females. In the amygdala, PPT increased Fos immunoreactivity in the central but not the medial or basolateral amygdala, although these effects were only observed in home cage females. Additionally, both vehicle- and PPT-treated home cage, primiparous females had increased Fos in the central nucleus of the amygdala compared to nulliparous controls. Overall, these data demonstrate that reproductive experience alters the behavioural response to acute ER? activation. Moreover, the findings suggest that central regulation of the hypothalamic-adrenal-pituitary axis is modified as a consequence of reproductive experience.

    View details for DOI 10.1111/jne.12113

    View details for Web of Science ID 000327295200006

    View details for PubMedID 24118285

    View details for PubMedCentralID PMC4269101

  • Reproductive experience modifies the effects of estrogen receptor alpha activity on anxiety-like behavior and corticotropin releasing hormone mRNA expression HORMONES AND BEHAVIOR Byrnes, E. M., Casey, K., Bridges, R. S. 2012; 61 (1): 44?49

    Abstract

    Previous studies have demonstrated that prior reproductive experience can influence anxiety-like behaviors, although neural mechanisms underlying this shift remain unknown. Studies in virgin females suggest that activation of the two estrogen receptor subtypes, ER? and ER?, have differing effects on anxiety. Specifically, ER? activation has been shown to reduce anxiety-like behaviors, while ER? activation has no significant effect. The purpose of the present study was to examine the possible roles of ER? and ER? subtypes in parity-induced alterations in anxiety-like behavior, as tested on the elevated plus maze (EPM). Groups of ovariectomized, age-matched, nulliparous and primiparous females were tested on the EPM following administration of the ER? agonist 4,4',4''-(4-Propyl-{1H}-pyrazole-1,3,5-tryl)trisphenol (PPT; 1 mg/kg), the ER? agonist Diarylpropionitrile (DPN; 1 mg/kg) or vehicle (DMSO). All drugs were administered once daily for 4 days prior to testing as this dosing paradigm has previously been used to demonstrate anxiolytic effects of DPN in virgin rats. In addition, as exposure to the EPM is a psychological stressor, physiological markers of the stress response were measured in both plasma (corticosterone) and brain (corticotropin releasing hormone; CRH) post-EPM testing. Unexpectedly, the ER? agonist PPT selectively increased the time spent exploring the open arms of the EPM in non-lactating, primiparous females, with no significant effects of DPN observed in either nulliparous or primiparous subjects. All females administered PPT and tested on the EPM demonstrated significantly reduced corticosterone secretion when compared to vehicle-treated controls. In addition, significant effects of both reproductive experience and PPT administration on CRH mRNA expression were observed in both the paraventricular nucleus and amygdala using qPCR. These findings indicate that reproductive experience modulates the effects of ER? activation on both EPM behavior related to anxiety and CRH gene expression.

    View details for DOI 10.1016/j.yhbeh.2011.10.001

    View details for Web of Science ID 000300120000008

    View details for PubMedID 22033279

    View details for PubMedCentralID PMC3264805

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