29 results on '"Shearer, Debra"'
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2. FLT3L governs the development of partially overlapping hematopoietic lineages in humans and mice
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Momenilandi, Mana, Lévy, Romain, Sobrino, Steicy, Li, Jingwei, Lagresle-Peyrou, Chantal, Esmaeilzadeh, Hossein, Fayand, Antoine, Le Floc’h, Corentin, Guérin, Antoine, Della Mina, Erika, Shearer, Debra, Delmonte, Ottavia M., Yatim, Ahmad, Mulder, Kevin, Mancini, Mathieu, Rinchai, Darawan, Denis, Adeline, Neehus, Anna-Lena, Balogh, Karla, Brendle, Sarah, Rokni-Zadeh, Hassan, Changi-Ashtiani, Majid, Seeleuthner, Yoann, Deswarte, Caroline, Bessot, Boris, Cremades, Cassandre, Materna, Marie, Cederholm, Axel, Ogishi, Masato, Philippot, Quentin, Beganovic, Omer, Ackermann, Mania, Wuyts, Margareta, Khan, Taushif, Fouéré, Sébastien, Herms, Florian, Chanal, Johan, Palterer, Boaz, Bruneau, Julie, Molina, Thierry J., Leclerc-Mercier, Stéphanie, Prétet, Jean-Luc, Youssefian, Leila, Vahidnezhad, Hassan, Parvaneh, Nima, Claeys, Kristl G., Schrijvers, Rik, Luka, Marine, Pérot, Philippe, Fourgeaud, Jacques, Nourrisson, Céline, Poirier, Philippe, Jouanguy, Emmanuelle, Boisson-Dupuis, Stéphanie, Bustamante, Jacinta, Notarangelo, Luigi D., Christensen, Neil, Landegren, Nils, Abel, Laurent, Marr, Nico, Six, Emmanuelle, Langlais, David, Waterboer, Tim, Ginhoux, Florent, Ma, Cindy S., Tangye, Stuart G., Meyts, Isabelle, Lachmann, Nico, Hu, Jiafen, Shahrooei, Mohammad, Bossuyt, Xavier, Casanova, Jean-Laurent, and Béziat, Vivien
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- 2024
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3. The alveolar macrophage toponome of female SP-A knockout mice differs from that of males before and after SP-A1 rescue
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Phelps, David S., Chinchilli, Vernon M., Yang, Lili, Shearer, Debra, Weisz, Judith, Zhang, Xuesheng, and Floros, Joanna
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- 2022
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4. Using toponomics to characterize phenotypic diversity in alveolar macrophages from male mice treated with exogenous SP-A1
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Phelps, David S., Chinchilli, Vernon M., Weisz, Judith, Shearer, Debra, Zhang, Xuesheng, and Floros, Joanna
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- 2020
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5. Out from the Periphery: Engaging Nursing Clinical Adjunct Faculty in Their Professional Development
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Shearer, Debra Connolly
- Abstract
In 2005 the American Association of Colleges of Nursing (AACN) reported that 32,000 qualified nursing candidates were turned away from baccalaureate nursing programs, primarily due to the shortage of nursing faculty. This shortage limited the number of students permitted to enroll in nursing programs when the need for nurses continues to grow. An additional report from the Robert Wood Johnson Foundation (2007) indicated that 92,000 qualified nursing applicants were turned away from undergraduate programs during 2006. The shortage of registered nurses will increase to 340,000 by the year 2020 (Auerbach, Buerhaus, & Staiger 2007). This acute shortage has prompted dramatic growth in undergraduate nursing programs, resulting in an unplanned need for nursing faculty. Clinical nursing faculty is currently challenged by numerous variables: The majority of clinical faculty consists of part-time or contracted employees, many of whom hold full-time positions elsewhere in healthcare settings. Most clinical adjunct faculty has not received formal education as teachers or faculty (AACN, 2003; Diekelmann, 2004; Kelly, 2006). Due to part-time status, important adjunct clinical faculty remains at the periphery of the academic community. As a result, adjunct clinical faculty is disconnected from mentors, academic policies, and academic culture as a whole. Clinical adjunct faculty at Drummer University has not been surveyed formally or informally regarding what would aid them in their development as clinical faculty. As the University cultivated relationships with clinical adjunct faculty, it provided professional development resources necessary for faculty to become nursing educators. As a result of this study, I examined how my actions improved the environment at Drummer University: By enacting my espoused transformational leadership I led the University in articulating and demonstrating the importance of clinical adjunct nursing faculty by building an academic community for clinical adjunct faculty and by increasing faculty engagement related to professional development. By following the professional development initiatives of set forth in this study, and as a result of their participation in it, clinical adjunct faculty reported significantly higher levels of connectivity to the University; their feelings of being strongly connected to the Institution improved from 23% to 32%. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]
- Published
- 2008
6. Depo Medroxyprogesterone (DMPA) Promotes Papillomavirus Infections but Does Not Accelerate Disease Progression in the Anogenital Tract of a Mouse Model.
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Hu, Jiafen, Brendle, Sarah A., Li, Jingwei J., Walter, Vonn, Cladel, Nancy M., Cooper, Timothy, Shearer, Debra A., Balogh, Karla K., and Christensen, Neil D.
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PAPILLOMAVIRUS diseases ,LABORATORY mice ,MEDROXYPROGESTERONE ,GENITALIA infections ,ANIMAL disease models ,CHLAMYDIA infections - Abstract
Contraceptives such as Depo-medroxyprogesterone (DMPA) are used by an estimated 34 million women worldwide. DMPA has been associated with increased risk of several viral infections including Herpes simplex virus-2 (HSV-2) and Human immunodeficiency virus (HIV). In the current study, we used the mouse papillomavirus (MmuPV1) anogenital infection model to test two hypotheses: (1) contraceptives such as DMPA increase the susceptibility of the anogenital tract to viral infection and (2) long-term contraceptive administration induces more advanced disease at the anogenital tract. DMPA treatments of both athymic nude mice and heterozygous NU/J (Foxn1
nu/+ ) but ovariectomized mice led to a significantly increased viral load at the anogenital tract, suggesting that endogenous sex hormones were involved in increased viral susceptibility by DMPA treatment. Consistent with previous reports, DMPA treatment suppressed host anti-viral activities at the lower genital tract. To test the impact of long-term contraceptive treatment on the MmuPV1-infected lower genital tract, we included two other treatments in addition to DMPA: 17β-estradiol and a non-hormone based contraceptive Cilostazol (CLZ, Pletal). Viral infections were monitored monthly up to nine months post infection by qPCR. The infected vaginal and anal tissues were harvested and further examined by histological, virological, and immunological analyses. Surprisingly, we did not detect a significantly higher grade of histology in animals in the long-term DMPA and 17β-estradiol treated groups when compared to the control groups in the athymic mice we tested. Therefore, although DMPA promotes initial papillomavirus infections in the lower genital tract, the chronic administration of DMPA does not promote cancer development in the infected tissues in our mouse model. [ABSTRACT FROM AUTHOR]- Published
- 2022
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7. Comparison of the Toponomes of Alveolar Macrophages From Wild Type and Surfactant Protein A Knockout Mice and Their Response to Infection.
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Phelps, David S., Chinchilli, Vernon M., Zhang, Xuesheng, Shearer, Debra, Weisz, Judith, and Floros, Joanna
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ALVEOLAR macrophages ,KNOCKOUT mice ,SURFACE active agents ,INFLAMMATORY mediators ,NATURAL immunity - Abstract
Background: Surfactant protein-A (SP-A) plays a critical role in lung innate immunity by regulating alveolar macrophages (AM), expression of inflammatory mediators, and other host defense proteins. The toponome imaging system (TIS), a serial immunostainer, was used to study the AM toponome because it characterizes the localization of multiple markers and identifies marker combinations in each pixel as combinatorial molecular phenotypes (CMPs). We used TIS to study the AM toponome from wild type (WT) and SP-A knockout (KO) mice and changes following Klebsiella pneumoniae exposure. Methods: WT or KO mice received intratracheal K. pneumoniae or vehicle and AM were obtained by bronchoalveolar lavage after one hour. AM were attached to slides and underwent TIS analysis. Images were analyzed to characterize all pixels. AM CMPs from WT vehicle (n=3) and infected (n=3) mice were compared to each other and to AM from KO (n=3 vehicle; n=3 infected). Histograms provided us with a tool to summarize the representation of each marker in a set of CMPs. Results: Using the histograms and other tools we identified markers of interest and observed that: 1) Both comparisons had conserved (present in all group members) CMPs, only in vehicle AM and only in infected AM, or common to both vehicle and infected AM, (i.e., unaffected by the condition). 2) the CMP number decreased with infection in WT and KO versus vehicle controls. 3) More infection-specific CMPs in WT vs KO AM. 4) When AM from WT and KO vehicle or infected were compared, there were more unique CMPs exclusive to the KO AM. 5) All comparisons showed CMPs shared by both groups. Conclusions: The decrease of CMPs exclusive to infected AM in KO mice may underlie the observed susceptibility of KO mice to infection. However, both KO groups had more exclusive CMPs than the corresponding WT groups, perhaps indicating a vigorous effort by KO to overcome deficits in certain proteins and CMPs that are dysregulated by the absence of SP-A. Moreover, the presence of shared CMPs in the compared groups indicates that regulation of these CMPs is not dependent on either infection or the presence or absence of SP-A. [ABSTRACT FROM AUTHOR]
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- 2022
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8. A Pilot Proteomic Study of Vestibular Fluid From Patients With Vulvodynia.
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MacNeill, Colin, Umstead, Todd, Shearer, Debra, Weisz, Judith BChir, Phelps, David S., Floros, Joanna, and Weisz, Judith
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- 2022
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9. Altered gene expression in breast cancer liver metastases
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Erin, Nuray, Wang, Ning, Xin, Ping, Bui, Voung, Weisz, Judith, Barkan, Guliz A., Zhao, Wei, Shearer, Debra, and Clawson, Gary A.
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- 2009
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10. Surfactant protein A, an innate immune factor, is expressed in the vaginal mucosa and is present in vaginal lavage fluid
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MACNEILL, COLIN, UMSTEAD, TODD M., PHELPS, DAVID S., LIN, ZHENWU, FLOROS, JOANNA, SHEARER, DEBRA A., and WEISZ, JUDITH
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- 2004
11. Expression of a retinol dehydrogenase (hRoDH-4), a member of the retinol/steroid dehydrogenase family implicated in retinoic acid biosynthesis, in normal and neoplastic endometria
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Cain, Joanna M., Zaino, Richard, Shearer, Debra, Bennett, R. Alan, Olt, George, and Weisz, Judith
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- 2002
12. Embracing the convenient care concept
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Ferris, Allison H., McAndrew, Thomas M., Shearer, Debra, Donnelly, Gloria F., and Miller, Howard A.
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Ambulatory medical care -- Models ,Health - Published
- 2010
13. Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models.
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Cladel, Nancy M., Jiang, Pengfei, Li, Jingwei J., Peng, Xuwen, Cooper, Timothy K., Majerciak, Vladimir, Balogh, Karla K., Meyer, Thomas J., Brendle, Sarah A., Budgeon, Lynn R., Shearer, Debra A., Munden, Regina, Cam, Maggie, Vallur, Raghavan, Christensen, Neil D., Zheng, Zhi-Ming, and Hu, Jiafen
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- 2019
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14. An essential clinical resource for the diagnosis and management of pediatric skin conditions
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Shearer, Debra Connolly
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Curbside Consultation in Pediatric Dermatology (Nonfiction work) -- Treat, J. -- Book reviews ,Books -- Book reviews ,Health - Abstract
Review of: Treat, J. (Ed.). (2012). Curbside consultation in pediatric dermatology. Thorofare, NJ: Slack, Inc. Skin conditions in infants, children, and adolescents are frequently, seen in primary care offices Diagnosing [...]
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- 2013
15. Infrared microspectroscopy identifies biomolecular changes associated with chronic oxidative stress in mammary epithelium and stroma of breast tissues from healthy young women.
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Patel, Imran I., Shearer, Debra A., Fogarty, Simon W., Fullwood, Nigel J., Quaroni, Luca, Martin, Francis L., and Weisz, Judith
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- 2014
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16. Keeping it together
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Shearer, Debra
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Suturing -- Management -- Methods ,Wounds and injuries -- Care and treatment ,Company business management ,Health - Abstract
Before suturing friable skin, apply half-inch strips of sterile adhesive along the wound edge. Then, stitch the wound through the strips. Debra Shearer, MSN, CS, FNP-C Mantua, [...]
- Published
- 2009
17. Keeping it together
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Shearer, Debra
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Adhesives in surgery -- Usage ,Suturing -- Methods -- Usage ,Wounds and injuries -- Care and treatment ,Health - Abstract
Before suturing friable skin, apply half-inch strips of sterile adhesive along the wound edge. Then, stitch the wound through the strips. Debra Shearer, MSN, CS, FNP-C Mantua, [...]
- Published
- 2007
18. Down-Regulation of HtrA1 Activates the Epithelial- Mesenchymal Transition and ATM DNA Damage Response Pathways.
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Ning Wang, Eckert, Kristin A., Zomorrodi, Ali R., Ping Xin, Weihua Pan, Shearer, Debra A., Weisz, Judith, Maranus, Costas D., and Clawson, Gary A.
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SERINE proteinases ,GENE expression ,EPITHELIAL cells ,MESENCHYMAL stem cells ,DNA damage ,CANCER chemotherapy ,CELL lines - Abstract
Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-tomesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-tomesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways. [ABSTRACT FROM AUTHOR]
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- 2012
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19. Identification of mammary epithelial cells subject to chronic oxidative stress in mammary epithelium of young women and teenagers living in USA.
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Weisz, Judith, Shearer, Debra A., Murata, Erin, Patrick, Susan D., Han, Bing, Berg, Arthur, and Clawson, Gary A.
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- 2012
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20. Mouse Papillomavirus L1 and L2 Are Dispensable for Viral Infection and Persistence at Both Cutaneous and Mucosal Tissues.
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Brendle, Sarah, Li, Jingwei J., Cladel, Nancy M., Shearer, Debra A., Budgeon, Lynn R., Balogh, Karla K., Atkins, Hannah, Costa-Fujishima, Marina, Lopez, Paul, Christensen, Neil D., Doorbar, John, Murooka, Thomas T., and Hu, Jiafen
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MUCOUS membranes ,VIRUS diseases ,PAPILLOMAVIRUSES ,VIRAL DNA ,DNA replication ,CAPSIDS - Abstract
Papillomavirus L1 and L2, the major and minor capsid proteins, play significant roles in viral assembly, entry, and propagation. In the current study, we investigate the impact of L1 and L2 on viral life cycle and tumor growth with a newly established mouse papillomavirus (MmuPV1) infection model. MmuPV1 L1 knockout, L2 knockout, and L1 plus L2 knockout mutant genomes (designated as L1ATGko-4m, L2ATGko, and L1-L2ATGko respectively) were generated. The mutants were examined for their ability to generate lesions in athymic nude mice. Viral activities were examined by qPCR, immunohistochemistry (IHC), in situ hybridization (ISH), and transmission electron microscopy (TEM) analyses. We demonstrated that viral DNA replication and tumor growth occurred at both cutaneous and mucosal sites infected with each of the mutants. Infections involving L1ATGko-4m, L2ATGko, and L1-L2ATGko mutant genomes generally resulted in smaller tumor sizes compared to infection with the wild type. The L1 protein was absent in L1ATGko-4m and L1-L2ATGko mutant-treated tissues, even though viral transcripts and E4 protein expression were robust. Therefore, L1 is not essential for MmuPV1-induced tumor growth, and this finding parallels our previous observations in the rabbit papillomavirus model. Very few viral particles were detected in L2ATGko mutant-infected tissues. Interestingly, the localization of L1 in lesions induced by L2ATGko was primarily cytoplasmic rather than nuclear. The findings support the hypothesis that the L2 gene influences the expression, location, transport, and assembly of the L1 protein in vivo. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Passive Immunization with a Single Monoclonal Neutralizing Antibody Protects against Cutaneous and Mucosal Mouse Papillomavirus Infections.
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Brendle, Sarah A., Jingwei Li, Cladel, Nancy M., Balogh, Karla K., Booth, Jennifer, Shearer, Debra A., Walter, Vonn, Song Lu, Christensen, Neil D., Covington, Danielle, DeBroff, Jake, Milici, Janice, Yusheng Zhu, Viscidi, Raphael, and Jiafen Hua
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PAPILLOMAVIRUS diseases , *IMMUNOGLOBULINS , *MUCOUS membranes , *IMMUNIZATION , *GENITALIA , *MICE , *VIRAL antibodies - Abstract
We have established a mouse papillomavirus (MmuPV1) model that induces both cutaneous and mucosal infections and cancers. In the current study, we use this model to test our hypothesis that passive immunization using a single neutralizing monoclonal antibody can protect both cutaneous and mucosal sites at different time points after viral inoculation. We conducted a series of experiments involving the administration of either a neutralizing monoclonal antibody, MPV.A4, or control monoclonal antibodies to both outbred and inbred athymic mice. Three clinically relevant mucosal sites (lower genital tract for females and anus and tongue for both males and females) and two cutaneous sites (muzzle and tail) were tested. At the termination of the experiments, all tested tissues were harvested for virological analyses. Significantly lower levels of viral signals were detected in the MPV.A4-treated female mice up to 6 h post-viral inoculation compared to those in the isotype control. Interestingly, males displayed partial protection when they received MPV.A4 at the time of viral inoculation, even though they were completely protected when receiving MPV.A4 at 24 h before viral inoculation. We detected MPV.A4 in the blood starting at 1 h and up to 8 weeks postadministration in some mice. Parallel to these in vivo studies, we conducted in vitro neutralization using a mouse keratinocyte cell line and observed complete neutralization up to 8 h post-viral inoculation. Thus, passive immunization with a monoclonal neutralizing antibody can protect against papillomavirus infection at both cutaneous and mucosal sites and is time dependent. [ABSTRACT FROM AUTHOR]
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- 2022
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22. Differentiation of xenografted human fetal lung parenchyma
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Pavlovic, Jelena, Floros, Joanna, Phelps, David S., Wigdahl, Brian, Welsh, Patricia, Weisz, Judith, Shearer, Debra A., Leure du Pree, Alphonse, Myers, Roland, and Howett, Mary K.
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XENOGRAFTS , *TRANSPLANTATION of organs, tissues, etc. , *LUNGS , *EPITHELIUM - Abstract
Abstract: The goal of this study was to characterize xenografted human fetal lung tissue with respect to developmental stage-specific cytodifferentiation. Human fetal lung tissue (pseudoglandular stage) was grafted either beneath the renal capsule or the skin of athymic mice (NCr-nu). Tissues were analyzed from 3 to 42 days post-engraftment for morphological alterations by light and electron microscopy (EM), and for surfactant protein mRNA and protein by reverse transcription-polymerase chain reaction (RT-PCR) and immunocytochemistry (ICC), respectively. The changes observed resemble those seen in human lung development in utero in many respects, including the differentiation of epithelium to the saccular stage. Each stage occurred over approximately one week in the graft in contrast to the eight weeks of normal in utero development. At all time points examined, all four surfactant proteins (SP-A, SP-B, SP-C, and SP-D) were detected in the epithelium by ICC. Lamellar bodies were first identified by EM in 14 day xenografts. By day 21, a significant increase in lamellar body expression was observed. Cellular proliferation, as marked by PCNA ICC and elastic fiber deposition resembled those of canalicular and saccular in utero development. This model in which xenografted lung tissue in different stages of development is available may facilitate the study of human fetal lung development and the impact of various pharmacological agents on this process. [Copyright &y& Elsevier]
- Published
- 2008
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23. The environmental pollutant and tobacco smoke constituent dibenzo[def,p]chrysene is a co-factor for malignant progression of mouse oral papillomavirus infections.
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Christensen, Neil D., Chen, Kun-Ming, Hu, Jiafen, Stairs, Douglas B., Sun, Yuan-Wan, Aliaga, Cesar, Balogh, Karla K., Atkins, Hannah, Shearer, Debra, Li, Jingwei, Brendle, Sarah A., Gowda, Krishne, Amin, Shantu, Walter, Vonn, Viscidi, Raphael, and El-Bayoumy, Karam
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TOBACCO smoke pollution , *TOBACCO smoke , *PAPILLOMAVIRUS diseases , *CHRYSENE , *MOUTH , *SQUAMOUS cell carcinoma , *POLYCHLORINATED dibenzodioxins - Abstract
HPV infections in the oral cavity that progress to cancer are on the increase in the USA. Model systems to study co-factors for progression of these infections are lacking as HPVs are species-restricted and cannot grow in preclinical animal models. We have recently developed a mouse papillomavirus (MmuPV1) oral mucosal infection model that provides opportunities to test, for the first time, the hypothesis that tobacco carcinogens are co-factors that can impact the progression of oral papillomas to squamous cell carcinoma (SCC). Four cohorts of mice per sex were included: (1) infected with MmuPV1 and treated orally with DMSO-saline; (2) infected with MmuPV1 and treated orally with the tobacco carcinogen, dibenzo[ def,p ]chrysene (DBP); (3) uninfected and treated orally with DMSO-saline, and (4) uninfected and treated orally with DBP. Oral swabs were collected monthly for subsequent assessment of viral load. Oral tissues were collected for in situ viral DNA/RNA detection, viral protein staining, and pathological assessment for hyperplasia, papillomas and SCC at study termination. We observed increased rates of SCC in oral tissue infected with MmuPV1 and treated with DBP when compared to mice treated with DBP or virus individually, each of which showed minimal disease. Virally-infected epithelium showed strong levels of viral DNA/RNA and viral protein E4/L1 staining. In contrast, areas of SCC showed reduced viral DNA staining indicative of lower viral copy per nucleus but strong RNA signals. Several host markers (p120 ctn, p53, S100A9) were also examined in the mouse oral tissues; of particular significance, p120 ctn discriminated normal un-infected epithelium from SCC or papilloma epithelium. In summary, we have confirmed that our infection model is an excellent platform to assess the impact of co-factors including tobacco carcinogens for oral PV cancerous progression. Our findings can assist in the design of novel prevention/treatment strategies for HPV positive vs. HPV negative disease. Image 1 • Increased rates of oral cancer in mice infected with MmuPV1 and treated topically with DBP into the oral cavity. • Mice treated with DBP alone or virus alone showed lower to no incidence of squamous cell carcinoma, respectively. • Virally infected epithelium showed strong levels of viral DNA staining; squamous cell carcinoma showed reduced levels. • p120 ctn expression discriminated normal uninfected epithelium from squamous cell carcinoma or papilloma. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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24. Monitoring mouse papillomavirus-associated cancer development using longitudinal Pap smear screening.
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Atkins HM, Uslu AA, Li JJ, Shearer DA, Brendle SA, Han C, Kozak M, Lopez P, Nayar D, Balogh KK, Abendroth C, Copper J, Cheng KC, Christensen ND, Zhu Y, Avril S, Burgener AD, Murooka TT, and Hu J
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- Animals, Female, Mice, Early Detection of Cancer methods, Papillomaviridae genetics, Papillomaviridae isolation & purification, DNA, Viral genetics, Vaginal Smears, Humans, Longitudinal Studies, Papanicolaou Test, Papillomavirus Infections virology, Papillomavirus Infections diagnosis, Disease Models, Animal, Uterine Cervical Neoplasms virology, Uterine Cervical Neoplasms pathology
- Abstract
A substantial percentage of the population remains at risk for cervical cancer due to pre-existing human papillomavirus (HPV) infections, despite prophylactic vaccines. Early diagnosis and treatment are crucial for better disease outcomes. The development of new treatments heavily relies on suitable preclinical model systems. Recently, we established a mouse papillomavirus (MmuPV1) model that is relevant to HPV genital pathogenesis. In the current study, we validated the use of Papanicolaou (Pap) smears, a valuable early diagnostic tool for detecting HPV cervical cancer, to monitor disease progression in the MmuPV1 mouse model. Biweekly cervicovaginal swabs were collected from the MmuPV1-infected mice for viral DNA quantitation and cytology assessment. The Pap smear slides were evaluated for signs of epithelial cell abnormalities using the 2014 Bethesda system criteria. Tissues from the infected mice were harvested at various times post-viral infection for additional histological and virological assays. Over time, increased viral replication was consistent with higher levels of viral DNA, and it coincided with an uptick in epithelial cell abnormalities with higher severity scores noted as early as 10 weeks after viral infection. The cytological results also correlated with the histological evaluation of tissues harvested simultaneously. Both immunocompromised and immunocompetent mice with squamous cell carcinoma (SCC) cytology also developed vaginal SCCs. Notably, samples from the MmuPV1-infected mice exhibited similar cellular abnormalities compared to the corresponding human samples at similar disease stages. Hence, Pap smear screening proves to be an effective tool for the longitudinal monitoring of disease progression in the MmuPV1 mouse model., Importance: Papanicolaou (Pap) smear has saved millions of women's lives as a valuable early screening tool for detecting human papillomavirus (HPV) cervical precancers and cancer. However, more than 200,000 women in the United States alone remain at risk for cervical cancer due to pre-existing HPV infection-induced precancers, as there are currently no effective treatments for HPV-associated precancers and cancers other than invasive procedures including a loop electrosurgical excision procedure (LEEP) to remove abnormal tissues. In the current study, we validated the use of Pap smears to monitor disease progression in our recently established mouse papillomavirus model. To the best of our knowledge, this is the first study that provides compelling evidence of applying Pap smears from cervicovaginal swabs to monitor disease progression in mice. This HPV-relevant cytology assay will enable us to develop and test novel antiviral and anti-tumor therapies using this model to eliminate HPV-associated diseases and cancers., Competing Interests: The authors declare no conflict of interest.
- Published
- 2024
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25. Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy.
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Béziat V, Rapaport F, Hu J, Titeux M, Bonnet des Claustres M, Bourgey M, Griffin H, Bandet É, Ma CS, Sherkat R, Rokni-Zadeh H, Louis DM, Changi-Ashtiani M, Delmonte OM, Fukushima T, Habib T, Guennoun A, Khan T, Bender N, Rahman M, About F, Yang R, Rao G, Rouzaud C, Li J, Shearer D, Balogh K, Al Ali F, Ata M, Dabiri S, Momenilandi M, Nammour J, Alyanakian MA, Leruez-Ville M, Guenat D, Materna M, Marcot L, Vladikine N, Soret C, Vahidnezhad H, Youssefian L, Saeidian AH, Uitto J, Catherinot É, Navabi SS, Zarhrate M, Woodley DT, Jeljeli M, Abraham T, Belkaya S, Lorenzo L, Rosain J, Bayat M, Lanternier F, Lortholary O, Zakavi F, Gros P, Orth G, Abel L, Prétet JL, Fraitag S, Jouanguy E, Davis MM, Tangye SG, Notarangelo LD, Marr N, Waterboer T, Langlais D, Doorbar J, Hovnanian A, Christensen N, Bossuyt X, Shahrooei M, and Casanova JL
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- Adult, Amino Acid Sequence, Animals, Base Sequence, CD28 Antigens genetics, CD28 Antigens metabolism, CD4-Positive T-Lymphocytes immunology, Child, Endopeptidases metabolism, Female, Genes, Recessive, HEK293 Cells, Homozygote, Humans, Immunity, Humoral, Immunologic Memory, Jurkat Cells, Keratinocytes pathology, Male, Mice, Inbred C57BL, Oncogenes, Papilloma pathology, Papilloma virology, Pedigree, Protein Sorting Signals, RNA, Messenger genetics, RNA, Messenger metabolism, Mice, CD28 Antigens deficiency, Inheritance Patterns genetics, Papillomaviridae physiology, Skin virology, T-Lymphocytes immunology
- Abstract
We study a patient with the human papilloma virus (HPV)-2-driven "tree-man" phenotype and two relatives with unusually severe HPV4-driven warts. The giant horns form an HPV-2-driven multifocal benign epithelial tumor overexpressing viral oncogenes in the epidermis basal layer. The patients are unexpectedly homozygous for a private CD28 variant. They have no detectable CD28 on their T cells, with the exception of a small contingent of revertant memory CD4
+ T cells. T cell development is barely affected, and T cells respond to CD3 and CD2, but not CD28, costimulation. Although the patients do not display HPV-2- and HPV-4-reactive CD4+ T cells in vitro, they make antibodies specific for both viruses in vivo. CD28-deficient mice are susceptible to cutaneous infections with the mouse papillomavirus MmuPV1. The control of HPV-2 and HPV-4 in keratinocytes is dependent on the T cell CD28 co-activation pathway. Surprisingly, human CD28-dependent T cell responses are largely redundant for protective immunity., Competing Interests: Declaration of interests L.D.N. receives compensation as Chief Editor of Frontiers in Immunology. T.W. serves on advisory boards for MSD (Merck Sharp and Dohme). J.-L.C. serves on the scientific advisory boards of ADMA Biologics Inc., Kymera Therapeutics, and Elixiron Immunotherapeutics. All other authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
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26. Differences in the alveolar macrophage toponome in humanized SP-A1 and SP-A2 transgenic mice.
- Author
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Phelps DS, Chinchilli VM, Weisz J, Yang L, Shearer D, Zhang X, and Floros J
- Subjects
- Animals, Humans, Immunity, Innate physiology, Macrophages, Alveolar physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence methods, Proteome metabolism, Pulmonary Surfactant-Associated Protein A genetics, Pulmonary Surfactant-Associated Protein A physiology, Pulmonary Surfactants metabolism, Macrophages, Alveolar metabolism, Pulmonary Surfactant-Associated Protein A metabolism
- Abstract
Alveolar macrophages (AMs) are differentially regulated by human surfactant protein-A1 (SP-A1) or SP-A2. However, AMs are very heterogeneous and differences are difficult to characterize in intact cells. Using the Toponome Imaging System (TIS), an imaging technique that uses sequential immunostaining to identify patterns of biomarker expression or combinatorial molecular phenotypes (CMPs), we studied individual single cells and identified subgroups of AMs (n = 168) from SP-A-KO mice and mice expressing either SP-A1 or SP-A2. The effects, as shown by CMPs, of SP-A1 and SP-A2 on AMs were significant and differed. SP-A1 AMs were the most diverse and shared the fewest CMPs with KO and SP-A2. Clustering analysis of each group showed 3 clusters where the CMP-based phenotype was distinct in each cluster. Moreover, a clustering analysis of all 168 AMs revealed 10 clusters, many dominated by 1 group. Some CMP overlap among groups was observed with SP-A2 AMs sharing the most CMPs and SP-A1 AMs the fewest. The CMP-based patterns identified here provide a basis for understanding not only AMs' diversity, but also most importantly, the molecular basis for the diversity of functional differences in mouse models where the impact of genetics of innate immune molecules on AMs has been studied.
- Published
- 2020
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27. Antibody-Mediated Immune Subset Depletion Modulates the Immune Response in a Rabbit ( Oryctolagus cuniculus ) Model of Epstein-Barr Virus Infection.
- Author
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Osborne AJ, Atkins HM, Balogh KK, Brendle SA, Shearer DA, Hu J, Sample CE, and Christensen ND
- Subjects
- Animals, Antibodies, Viral, DNA, Viral, Guinea Pigs, Herpesvirus 4, Human genetics, Immunity, Mice, Rabbits, Epstein-Barr Virus Infections
- Abstract
Epstein-Barr Virus (EBV) is a γ-herpesvirus which infects over 90% of the adult human population. Most notably, this virus causes infectious mononucleosis but it is also associated with cancers such as Hodgkin and Burkitt lymphoma. EBV is a species-specific virus and has been studied in many animal models, including nonhuman primates, guinea pigs, humanized mice, and tree shrews. However, none of these animal models are considered the "gold standard" for EBV research. Recently, rabbits have emerged as a viable alternative model, as they are susceptible to EBV infection. In addition, the EBV infection progresses after immune suppression with cyclosporine A (CsA), modeling the reactivation of EBV after latency. We sought to refine this model for acute or active EBV infections by performing antibody-mediated depletion of certain immune subsets in rabbits. Fourteen 16 to 20-wk old, NZW rabbits were intravenously inoculated with EBV and concurrently treated with either anti-CD4 T-cell antibody, anti-pan-T-cell antibody (anti CD45), CSA, or, as a control, anti-HPV antibody. Rabbits that received the depleting antibodies were treated with CsA 3 times at a dose of 15 mg/kg SC once per day for 4 d starting at the time of EBV inoculation then the dose was increased to 20 mg/kg SC twice weekly for 2 wk. Weights, temperatures, and clinical signs were monitored, and rabbits were anesthetized once weekly for blood collection. When compared with the control group, anti-CD4-treated rabbits had fewer clinical signs and displayed higher levels of viral DNA via qPCR in splenocytes; however, flow cytometry results showed only a partial depletion of CD4 T-cells. Treatment with anti-pan-T-cell antibody did not result in noticeable T-cell depletion. These data suggest the EBV-infected rabbit is a promising model for testing antiviral medications and prophylactic vaccines for EBV.
- Published
- 2020
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28. Down-regulation of HtrA1 activates the epithelial-mesenchymal transition and ATM DNA damage response pathways.
- Author
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Wang N, Eckert KA, Zomorrodi AR, Xin P, Pan W, Shearer DA, Weisz J, Maranus CD, and Clawson GA
- Subjects
- Breast Neoplasms metabolism, Cell Line, Tumor, Epigenesis, Genetic, Female, Gene Silencing, High-Temperature Requirement A Serine Peptidase 1, Humans, Serine Endopeptidases metabolism, Breast Neoplasms genetics, DNA Damage physiology, Down-Regulation physiology, Epithelial-Mesenchymal Transition physiology, Gene Expression Regulation, Neoplastic, Serine Endopeptidases genetics
- Abstract
Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-to-mesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-to-mesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways.
- Published
- 2012
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29. Expression of UGT2B7, a UDP-glucuronosyltransferase implicated in the metabolism of 4-hydroxyestrone and all-trans retinoic acid, in normal human breast parenchyma and in invasive and in situ breast cancers.
- Author
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Gestl SA, Green MD, Shearer DA, Frauenhoffer E, Tephly TR, and Weisz J
- Subjects
- Female, Glucuronosyltransferase genetics, Humans, Immunoblotting, Immunohistochemistry, Neoplasm Invasiveness, RNA, Messenger metabolism, Reference Values, Reverse Transcriptase Polymerase Chain Reaction, Tissue Distribution, Breast metabolism, Breast Neoplasms metabolism, Breast Neoplasms pathology, Glucuronosyltransferase metabolism, Hydroxyestrones metabolism, Tretinoin metabolism
- Abstract
Glucuronidation, mediated by UDP-glucuronosyltransferases (UGTs), affects the actions and disposition of diverse endo- and xenobiotics. In the case of catecholestrogens (CEs), glucuronidation is likely to block their oxidation to quinone estrogens that are the putative mediators of CEs' actions as initiators of cancers. The goal of this study was to determine whether UGT2B7, the isoenzyme with a high affinity for 4-hydroxyestrone, is expressed in human breast parenchyma. Glucuronidation of 4-hydroxyestrone has relevance to breast carcinogenesis because quinone metabolites of 4-hydroxylated CEs can form potentially mutagenic depurinating DNA adducts, and because in breast tissue estrone is likely to be the predominant estrogen available for 4-hydroxylation. Using reverse transcriptase-polymerase chain reaction, immunocytochemistry, immunoblot analyses, and assays of glucuronidation of 4-hydroxyestrone, we show that UGT2B7 is expressed in human mammary epithelium, and that its expression is dramatically reduced in invasive breast cancers. In many in situ carcinomas, however, 4-hydroxyestrone immunostaining was not only preserved but even more intense than in normal mammary epithelium. The finding of reduced UGT2B7 protein and glucuronidation of 4-hydroxyestrone in invasive cancers suggests a tumor-suppressor function for the enzyme. Recent identification of all-trans retinoic acid as a substrate of UGT2B7 suggests that this function includes the generation of retinoyl-beta-glucuronide, a potent mediator of actions of retinoids important for maintaining epithelia in a differentiated state. Current knowledge does not provide any ready explanation for the apparent increase in UGT2B7 expression in carcinomas in situ. However, this finding, together with reduced immunostaining at loci showing breach of the basement membrane (microinvasion), suggests involvement of UGT2B7-catalyzed reaction(s) in protection against invasion of surrounding tissue by cancer cells.
- Published
- 2002
- Full Text
- View/download PDF
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