Journal articles: 'Andrew Mousley'

1

Seyfried, Thomas N. "Mouse Brain Development. Andre M. Goffinet , Pasko Rakic." Quarterly Review of Biology 76, no. 2 (June 2001): 265–66. http://dx.doi.org/10.1086/393966.

Full text

APA, Harvard, Vancouver, ISO, and other styles

2

Miller, Malcolm. "Jerusalem, Music Centre: Andre Hajdu." Tempo 67, no. 264 (April 2013): 78. http://dx.doi.org/10.1017/s004029821300017x.

Full text

Abstract:

An 80th birthday concert full of the spirit of youthful exploration reflected the innovative interactive aesthetic of Andre Hajdu, the Hungarian-Israeli composer, whose oeuvre is gradually gaining wider international exposure. Presented by the Jerusalem Music Centre on 29 March 2012, the programme featured works from the last quarter of a century for chamber duo and solo piano, including two premières, culminating in an improvisational interactive jam session by an array of students and colleagues, joined by the composer himself at the piano. To begin was Hajdu's Sonatine for Flute and Cello (1990) ‘in the French style’ performed with panache by the flautist Yossi Arnheim and cellist Amir Eldan. It is an elegantly written work radiating the spirit of Hajdu's teachers Milhaud and (less overtly) Messiaen, with whom he studied in Paris in the 1950s and 60s. Beneath the light-hearted veneer of polyphonic textures is a serious, plangent expressiveness. The first movement, libre et gai, moves from the chirpy, Poulenc-like delicacy of a cat-and-mouse imitative chase, building tension towards a final stretto. In the second movement, molto moderato, Arnheim wove a lyrical cantilena for flute over gentle cello accompaniments, giving way to rarified high cello registers shadowed by eloquent lower lines of the flute. An exuberant dance-like finale, Libre mais un peu rythmé, increased in drama before receding to a tranquil conclusion.

APA, Harvard, Vancouver, ISO, and other styles

3

Woodfield, Sarah E., Roma H. Patel, Andres F. Espinoza, Richard S. Whitlock, Jessica Epps, Andrew Badachhape, Samuel R. Larson, et al. "Abstract PO013: Patient-derived xenograft mouse models of hepatoblastoma for a personalized medicine pipeline." Clinical Cancer Research 28, no. 17_Supplement (September 1, 2022): PO013. http://dx.doi.org/10.1158/1557-3265.liverca22-po013.

Full text

Abstract:

Abstract Introduction: Hepatoblastoma (HB) is the most common pediatric primary liver tumor and has the fastest rising incidence of all pediatric solid tumors. Patients with high-risk, treatment refractory, or relapse disease have a survival rate of less than 50%. The development of clinically relevant models of these aggressive tumors will facilitate studies to identify drugs that target these cells.Methods: Fresh, whole primary tumor samples were implanted into the livers of immunocompromised mice. Tumor growth was monitored with MRI and ELISA to measure serum human Alpha-fetoprotein (AFP), which is detectable in the blood of tumor-bearing animals. Tumors were validated with immunohistochemistry (IHC) for HB markers Glypican-3 (GPC3) and Beta-catenin; short tandem repeat (STR) DNA validation; next generation sequencing-based mutation profiling of 124 genes involved in pediatric solid tumors; RNA sequencing (RNA-seq), and single cell RNA-seq (scRNA-seq). Lung metastasis was also detected in models with serial sectioning and H&E staining. Cells derived from tumors were grown in vitro in adherent and spheroid conditions and used for high throughput drug screening of candidate agents. Tumors were serially passaged in animals for further in vivo drug testing of novel targeted agents.Results: Nine patient-derived xenograft (PDX) models were generated that represent low- and high-risk tumors, treatment refractory cases, and relapsed tumors. Passaging of these models showed consistent implantation rates at or above 80% with tumors detectable in 2 to 4 weeks. Eight of nine models secrete human serum AFP. All models mimic gene expression and histological patterns of their primary tumor counterparts as well as identical STR DNA profiles. The models also show gene expression consistent with an HB2/high-risk profile according to the Sumazin HB expression signature. Interestingly, two models represent unique sub-clones of a very aggressive HB relapse with different AFP secretion and transcriptomic expression. scRNA-seq of these two models indicated outgrowth of disparate disease sub-clones. The nine models also demonstrate a range of DNA mutations with three or four mutations per tumor; all variants present in the original clinical samples were conserved in the PDX models. Lung metastasis was evident in six of nine models. Two stable patient-derived cell lines (PDCLs) were developed from models, and these cell lines show expression of HB markers and secrete AFP with growth in culture. Drug screening of adherent and spheroid tumor cells support the efficacy of novel targeted agents and indicate a spectrum of sensitivity to cisplatin, a frontline standard chemotherapy agent. Importantly, the models replicate the chemotherapy responses of the corresponding patients. Additional in vitro and in vivo work showed the efficacy of a histone deacetylase inhibitor, panobinostat.Conclusions: These novel orthotopic PDX models of HB fully recapitulate the primary tumors and represent a platform for clinically relevant drug screening and testing. Citation Format: Sarah E Woodfield, Roma H Patel, Andres F Espinoza, Richard S Whitlock, Jessica Epps, Andrew Badachhape, Samuel R Larson, Rohit K Srivastava, Aayushi P Shah, Saiabhiroop R Govindu, Barry Zorman, Brandon J Mistretta, Kevin E Fisher, Ilavarasi Gandhi, Jacquelyn Reuther, Martin Urbicain, Aryana M Ibarra, Sakuni Rankothgedera, Kimberly R Holloway, Stephen F Sarabia, Andras Heczey, Ketan B Ghaghada, Kalyani R Patel, Dolores Lopez-Terrada, Angshumoy Roy, Preethi H Gunaratne, Pavel Sumazin, Sanjeev A Vasudevan. Patient-derived xenograft mouse models of hepatoblastoma for a personalized medicine pipeline [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO013.

APA, Harvard, Vancouver, ISO, and other styles

4

Kim, Rina, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, et al. "Abstract C046: Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment." Cancer Research 82, no. 22_Supplement (November 15, 2022): C046. http://dx.doi.org/10.1158/1538-7445.panca22-c046.

Full text

Abstract:

Abstract Myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) function as an immunosuppressive shield that protects the tumor from the host’s immune system and considered a barrier to effective immunotherapy. Here, we focused on polymorphonuclear (PMN)-MDSCs, the most prevalent MDSCs in the TME, to identify mechanisms regulating their maintenance, turnover, and accumulation. Using four mouse models of cancer including autochthonous pancreatic adenocarcinoma from KPC genetically engineered mice (KrasG12D/p53R172H, PdxCre), we found that PMN-MDSCs spontaneously die by ferroptosis, a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Only PMN-MDSCs within the TME were observed to spontaneously undergo ferroptosis. In mice, ferroptosis-related gene expression in CD11b+L6ClowLy6G+ PMN-MDSC isolated from bone marrow, spleen, and tumor demonstrated tumor-specific ferroptosis across tumor models. In humans, whole transcriptomic analysis of PMN-MDSC sorted from tumors and matched blood of lung cancer patients vs blood of healthy donors revealed up-regulation of genes involved in the regulation of ferroptosis in tumor PMN-MDSC. Ferroptosis gene signatures correlated with the PMN-MDSC signatures in pancreatic cancer patients and was associated with worse overall survival. Thus, ferroptosis is an unappreciated, prominent pathway of cell death of PMN-MDSCs in cancer linked to clinical outcome in patients with pancreatic cancer. Citation Format: Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Gozde Kar, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Yulia Nefedova, Valerian E. Kagan, Robert H. Vonderheide, Dmitry Gabrilovich. Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C046.

APA, Harvard, Vancouver, ISO, and other styles

5

Bowman, John C. "Douglas Scott Falconer. 10 March 1913 – 23 February 2004." Biographical Memoirs of Fellows of the Royal Society 51 (January 2005): 119–33. http://dx.doi.org/10.1098/rsbm.2005.0008.

Full text

Abstract:

Douglas Scott Falconer obtained a first–class honours degree in Zoology at St Andrews University followed by a PhD at Cambridge for research on wireworms. He then worked with R. A. (later Sir Ronald) Fisher FRS, as a prelude to joining the ARC Genetics Section of its Animal Breeding and Genetics Research Organisation at Edinburgh University. There he spent the rest of his career, later becoming Head of Unit and a personal professor in the university.His research interests fell into three main categories: the formal genetics of the mouse, quantitative genetics, and the genetics of human diseases. His work on mouse mutants and gene linkage was a major contribution to mapping the mouse genome, and his research in quantitative genetics produced theoretical and practical findings that have been of much benefit to animal breeders and to human geneticists as well as to the understanding of traits of complex inheritance.From his research and teaching he developed his acclaimed textbook Introduction to quantitative genetics , which ran to four editions in 36 years. The book is used as a foundation text worldwide.Douglas was much admired as a stimulating and innovative scientist, a considerate and polite colleague, and family gentleman.

APA, Harvard, Vancouver, ISO, and other styles

6

Choi, Sung Hee, Alicia Aguilar, Jay Myers, Byung-Gyu Kim, Saada Eid, Suzanne Tomchuck, Daniel Kingsley, and Alex Huang. "Mechanosensory channel Piezo1 is essential in pathogenic T cell-mediated intestinal inflammation." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 113.16. http://dx.doi.org/10.4049/jimmunol.208.supp.113.16.

Full text

Abstract:

Abstract Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the gastrointestinal tract. CD4+ T cells are especially known to be the main drivers of IBD when they show an elevated level of activation. Elevation of intracellular Ca2+ is one of the key triggering signals for T cell activation. Piezo1 is a mechanosensitive nonselective Ca2+-permeable cation channel, which is broadly expressed in mammalian cells. However, the role of Piezo1 in the pathogenesis of T cell-mediated colitis remains unknown. We have generated T cell-specific Piezo1 knockout (Piezo1fl/flxCD4-cre) mice and observed that loss of Piezo1 in CD4+ T cell increased Th1 and Th17 cell polarization. RNA-sequence analysis of Piezo1fl/flxCD4-cre T cells identified elevated pathogenic Th17 cell pathway, IFN-γ signaling pathways and inflammatory response gene signature compared to that of wild type. These results suggest that Piezo1 controls the inflammatory response of pathogenic T cells. Next, we examined the function of Piezo1 on intestinal inflammation in vivo using acute and chronic colitis mouse model. For the acute colitis mouse model, we used a chemically induced mouse model of colitis using DSS in drinking water. Piezo1fl/flxCD4-cre mice with DSS developed severe colitis compared to Piezo1fl/fl mice with DSS. However, in chronic colitis mouse model, which is the adaptive transfer of naïve CD4+ T cells (CD4+CD45RBhigh) from Piezo1fl/fl or Piezo1fl/flxCD4cre into Rag1−/− mice, T cells from Piezo1fl/flxCD4cre mice failed to induce colon inflammation, while mice that received T cells from Piezo1fl/fl mice developed severe intestinal inflammation. Thus, our data demonstrate a critical role of Piezo1 in CD4+ T cell-mediated intestinal inflammation. Supported by R03 CA230840, P30 CA043703, St. Baldrick’s Foundation, Hyundai Hope-on-Wheels Scholar Hope Grant, Andrew McDonough B+ Foundation, Curing Kids Cancer, Center for Pediatric Immunotherapy at Rainbow

APA, Harvard, Vancouver, ISO, and other styles

7

Kim, Jin, Woo-Sung Kwon, Md Saidur Rahman, June-Sub Lee, Sung-Jae Yoon, Yoo-Jin Park, Young-Ah You, and Myung-Geol Pang. "Effect of sodium fluoride on male mouse fertility." Andrology 3, no. 3 (April 8, 2015): 544–51. http://dx.doi.org/10.1111/andr.12006.

Full text

APA, Harvard, Vancouver, ISO, and other styles

8

Dai, J., C. Zhan, W. Xu, Z. Wang, D. Nie, X. Zhao, D. Zhang, et al. "Nicotine elevates sperm motility and inducesPfn1promoter hypomethylation in mouse testis." Andrology 3, no. 5 (August 20, 2015): 967–78. http://dx.doi.org/10.1111/andr.12072.

Full text

APA, Harvard, Vancouver, ISO, and other styles

9

Brock, Andrew A., Katherine Powell, Thomas D. Schmittgen, and Lorenzo F. Sempere. "Abstract 5821: Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer." Cancer Research 82, no. 12_Supplement (June 15, 2022): 5821. http://dx.doi.org/10.1158/1538-7445.am2022-5821.

Full text

Abstract:

Abstract Pancreatic ductal adenocarcinoma (PDAC) originates from both ductal and acinar cells of the pancreas. The highly abundant and acinar cell-enriched miR-216a is reduced during in vitro acinar ductal metaplasia (ADM), throughout PanIN progression, during the development of pancreatitis in mice and humans, and during development of mouse and human PDAC. To investigate the contribution of miR-216a in the development of PDAC, we generated a miR-216a germline knockout mouse (216aKO) via CRISPR genetic editing of a minimal and precise deletion of the miR-216a precursor sequence without affecting the host gene. We crossed this 216aKO mouse to the LSL-KrasG12D; LSL-Trp53Flox/+; Pdx1Cre/+ (KPC) mice to produce a transgenic mouse with an activating Kras mutation, p53 deletion, and knockout of miR-216a (referred to here as miR216aKPC). miR216aKPC displayed an increase in tumor progression compared to KPC and had reduced survival - median 15 weeks miR216aKPC vs. 25 weeks for KPC. miR216aKPC produced lung metastasis by 12 weeks of age which were not present in the lungs of similarly aged KPC mice. Transfection of miR-216a mimetic oligo into cell lines derived from KPC or 216aKPC mice did not reduce viability or alter cellular morphology, suggesting that a potential tumor suppressive role of miR-216a functions during the early stages of PDAC development. A three dimensional ADM assay using acinar cells derived from both mouse and human pancreata will be applied to investigate the contributions of miR-216a on the development of ADM and cell polarity. To discover miR-216a target genes that are responsible for the increased tumorigenesis, cell lines derived from miR216aKPC will be transfected with miR-216a mimetic or scrambled control oligo followed by RNA sequencing. Our results thus far suggest a tumor suppressive role for miR-216a in the early development of PDAC and future studies will investigate molecular and cellular mechanisms driving acinar cell-induced PDAC. Citation Format: Andrew A. Brock, Katherine Powell, Thomas D. Schmittgen, Lorenzo F. Sempere. Enhanced tumorigenesis in a novel miR-216a knockout/KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5821.

APA, Harvard, Vancouver, ISO, and other styles

10

Raza, Qanber, Michael Cohen, Smriti Kala, Liang Lim, Geneve Awong, Andrew Quong, and Christina Loh. "Abstract 2035: Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2035. http://dx.doi.org/10.1158/1538-7445.am2022-2035.

Full text

Abstract:

Abstract Imaging Mass Cytometry™ (IMC™) is a vital tool to deeply characterize the complexity and diversity of any tissue without disrupting spatial context. The Hyperion™ Imaging System utilizes IMC, based on CyTOF® technology, to simultaneously assess up to 40 individual structural and functional markers in tissues, providing unprecedented insight into the organization and function of tissue microenvironment. We have previously demonstrated the application of IMC in combination with Maxpar® panel kits to highlight cellular composition of human tissues. Here, we showcase the recently released Maxpar OnDemand Antibodies for IMC application on mouse tissue. We introduced 11 additional biomarkers to our existing mouse antibody catalog, providing the basis for the use of high-multiplex imaging in preclinical investigations. To demonstrate the IMC workflow on mouse tissue, we analyzed a normal mouse tissue microarray using IMC spatial proteomic analysis. Tissues were stained with a 20-marker panel designed to highlight tissue architecture and major immune lineage markers combined with our IMC Cell Segmentation Kit*. The IMC Cell Segmentation Kit facilitates identification of cellular borders using plasma membrane markers that lead to improved nucleus and plasma membrane demarcation. We generated a detailed spatial map of the heterogeneous tissue architecture and successfully identified immune, epithelial, and stromal cell populations in various mouse tissues. Additionally, we classified the activation state of immune cell populations, adhesion state of epithelial cells, and molecular composition of the extracellular matrix.Overall, this work demonstrates the capability of IMC to identify subcellular localization of cellular and structural markers in the mouse tissue microenvironment. Information gained from IMC studies will enable in-depth high-throughput phenotypic characterization of the tissue microenvironment in various mouse models of development and disease, and thus accelerate preclinical discoveries. *The IMC Cell Segmentation Kit is part of the Innovative Solutions menu of custom-made reagents and workflows developed and tested by Fluidigm scientists to give faster access to new cutting-edge solutions for high-multiplex single-cell analysis. Innovative Solutions are not part of the Maxpar catalog. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Qanber Raza, Michael Cohen, Smriti Kala, Liang Lim, Geneve Awong, Andrew Quong, Christina Loh. Imaging mass cytometry identifies structural and cellular composition of the mouse tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2035.

APA, Harvard, Vancouver, ISO, and other styles

11

Shahreza, Fatemeh Dehghan, Mehdi Hajian, Parvis Gharagozloo, Joël R. Drevet, and Mohammad Hossein Nasr‐Esfahani. "Impact of vitamin D deficiency on mouse sperm structure and function." Andrology 8, no. 5 (June 14, 2020): 1442–55. http://dx.doi.org/10.1111/andr.12820.

Full text

APA, Harvard, Vancouver, ISO, and other styles

12

Micati, D. J., G. R. Hime, E. A. McLaughlin, H. E. Abud, and K. L. Loveland. "Differential expression profiles of conserved Snail transcription factors in the mouse testis." Andrology 6, no. 2 (January 30, 2018): 362–73. http://dx.doi.org/10.1111/andr.12465.

Full text

APA, Harvard, Vancouver, ISO, and other styles

13

Le, W., L. Qi, C. Xu, Z. Xiang, Z. Mao, J. Zhang, J. Xu, and D. Wu. "Preliminary study of the homologous recombination repair pathway in mouse spermatogonial stem cells." Andrology 6, no. 3 (March 25, 2018): 488–97. http://dx.doi.org/10.1111/andr.12481.

Full text

APA, Harvard, Vancouver, ISO, and other styles

14

Pan, D., D. Feng, H. Ding, X. Zheng, Z. Ma, B. Yang, and M. Xie. "Effects of bisphenol A exposure on DNA integrity and protamination of mouse spermatozoa." Andrology 8, no. 2 (September 5, 2019): 486–96. http://dx.doi.org/10.1111/andr.12694.

Full text

APA, Harvard, Vancouver, ISO, and other styles

15

Hu, S. G., A. J. Liang, G. X. Yao, X. Q. Li, M. Zou, J. W. Liu, and Y. Sun. "The dynamic metabolomic changes throughout mouse epididymal lumen fluid potentially contribute to sperm maturation." Andrology 6, no. 1 (December 1, 2017): 247–55. http://dx.doi.org/10.1111/andr.12434.

Full text

APA, Harvard, Vancouver, ISO, and other styles

16

Di-Luoffo, M., C. Brousseau, and J. J. Tremblay. "MEF2 and NR2F2 cooperate to regulate Akr1c14 gene expression in mouse MA-10 Leydig cells." Andrology 4, no. 2 (January 8, 2016): 335–44. http://dx.doi.org/10.1111/andr.12150.

Full text

APA, Harvard, Vancouver, ISO, and other styles

17

Andrews, Nancy C. "Understanding the Transferrin Receptor and Cellular Iron Deficiency Outside the Erythron." Blood 130, Suppl_1 (December 7, 2017): SCI—42—SCI—42. http://dx.doi.org/10.1182/blood.v130.suppl_1.sci-42.sci-42.

Full text

Abstract:

Our laboratory showed that mouse embryos lacking the classical transferrin receptor, Tfrc, experienced anemia, pericardial effusion and a kinking of the neural tube, but otherwise appeared to be developing normally, suggesting that Tfrc was not needed by most tissues (Levy et al. 1999). Subsequently, we reported that Tfrc was essential for hematopoiesis but seemed to be dispensable in other tissues (Ned et al., 2003). A recent paper showing that a missense mutation in the TFRC internalization motif resulted in immunodeficiency without other clinical manifestations was consistent with this idea (Jabara et al., 2016). Nonetheless, we were not entirely convinced. More than thirty years ago, Larrick and Hyman described a patient with an anti-TFRC autoantibody who suffered from a broader range of clinical problems, suggesting that TFRC might have other roles (Larrick and Hyman, 1984). To help resolve the issue, we developed mice carrying an allele of Tfrc that can be conditionally inactivated, and used Cre/lox-mediated recombination to disrupt that allele in vivo, in several key cell types. We asked two questions: (1) is Tfrc important in those cell types and, if so, (2) what are the cellular consequences of Tfrc loss? We found that some cell types do not need Tfrc but others are highly dependent upon it. Those cell types that depend upon Tfrc generally need it for iron uptake, as expected, with one exception. Tfrc is critically important for normal development of the intestinal epithelium, but our data indicate that its essential role does not involve iron uptake. While surprising in view of our earlier results, the roles of Tfrc that we have unmasked through conditional knockout experiments would not have been apparent prior to the death of global Tfrc knockout embryos in mid-gestation. Nonetheless those roles are important, and our results give insight into why iron deficiency exacerbates heart failure, how muscle iron deficiency leads to disruption of systemic carbon metabolism, and how iron deficiency, rather than iron excess, may play a role in the pathogenesis of neurodegenerative disorders. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396-9. Ned RM, Swat W, Andrews NC. Transferrin receptor 1 is differentially required in lymphocyte development. Blood. 2003;102:3711-8. Jabara HH, Boyden SE, Chou J et al. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016;48:74-8. Larrick JW, Hyman ES. Acquired iron-deficiency anemia caused by an antibody against the transferrin receptor. N Engl J Med. 1984;311:214-8. Disclosures Andrews: Novartis: Membership on an entity's Board of Directors or advisory committees.

APA, Harvard, Vancouver, ISO, and other styles

18

Michaelis, Marten, Alexander Sobczak, Carolin Ludwig, Hana Marvanová, Martina Langhammer, Jennifer Schön, and Joachim M. Weitzel. "Altered testicular cell type composition in males of two outbred mouse lines selected for high fertility." Andrology 8, no. 5 (May 16, 2020): 1419–27. http://dx.doi.org/10.1111/andr.12802.

Full text

APA, Harvard, Vancouver, ISO, and other styles

19

de Boer, P., M. de Vries, and L. Ramos. "A mutation study of sperm head shape and motility in the mouse: lessons for the clinic." Andrology 3, no. 2 (December 16, 2014): 174–202. http://dx.doi.org/10.1111/andr.300.

Full text

APA, Harvard, Vancouver, ISO, and other styles

20

Mukherjee, A., S. Koli, and K. V. R. Reddy. "Rapamycin (Sirolimus) alters mechanistic target of rapamycin pathway regulation and microRNA expression in mouse meiotic spermatocytes." Andrology 3, no. 5 (August 20, 2015): 979–90. http://dx.doi.org/10.1111/andr.12075.

Full text

APA, Harvard, Vancouver, ISO, and other styles

21

Ryu, J. K., D. H. Kim, K. M. Song, D. S. Ryu, S. N. Kim, D. H. Shin, T. Yi, J. K. Suh, and S. U. Song. "Intracavernous delivery of clonal mesenchymal stem cells rescues erectile function in the streptozotocin-induced diabetic mouse." Andrology 4, no. 1 (December 29, 2015): 172–84. http://dx.doi.org/10.1111/andr.12138.

Full text

APA, Harvard, Vancouver, ISO, and other styles

22

Asnagli, H., A. Novak, L. Birch, R. Lane, N. Minet, D. Laughton, P. George, et al. "OP0034 STP938, A NOVEL, POTENT AND SELECTIVE INHIBITOR OF CTP SYNTHASE 1 (CTPS1) DEMONSTRATES EFFICACY IN RODENT MODELS OF INFLAMMATION AND ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 18.1–19. http://dx.doi.org/10.1136/annrheumdis-2021-eular.148.

Full text

Abstract:

Background:The final rate-limiting step in pyrimidine synthesis is the conversion of UTP to CTP which is catalyzed by cytidine triphosphate synthase 1 (CTPS1) or CTPS2. A hypomorphic mutation in the CTPS1 gene has highlighted the essential and non-redundant role of CTPS1 in T and B lymphocyte proliferation1. These patients exhibit no effects on non-hematopoietic tissues. Thus, selective inhibition of CTPS1 represents a novel targeted approach to dampen pathological T- and B-cell lympho-proliferation. STP938 is an orally bioavailable, small molecular weight, selective inhibitor of CTPS1 developed by Step Pharma.Objectives:To demonstrate the in vitro effects of CTPS1 inhibition on T and B cell proliferation and the therapeutic potential of STP938 using in vivo models of disease.Methods:The in vitro anti-proliferative activity of STP938 was investigated using cell lines and primary human PBMCs. STP938 was assessed in vivo using the DTH-KLH rat model and the mouse collagen-induced arthritis (CIA) model. For the KLH-DTH model, Lewis rats were immunized with KLH, a week later, challenged locally at the ear with KLH antigen, ear swelling was assessed after 24 hours. Blood samples were collected for detection of KLH-specific IgG levels at day 8. STP938 was given orally one-hour prior to immunization and then b.i.d. for 7 days. For the CIA model, DBA-1 mice were immunized with Collagen type II and complete Freund’s adjuvant and received a booster immunization three weeks later. STP938 was administered to mice developing signs of arthritis from Day 28 to 45 orally daily b.i.d.Results:STP938 inhibited in vitro proliferation of HEKwt but not HEK-CTPS1KO cells as well as Jurkat and human PBMCs. STP938 demonstrated a significant and dose-dependent inhibition of KLH-specific T and B cell responses in vivo. STP938 significantly reduced the disease severity in the CIA model in a dose-dependent manner as determined by clinical and histopathological readouts.Conclusion:Our preliminary in vitro and in vivo results indicate that inhibition of CTPS1 specifically blocks proliferation of cells derived from the lymphocyte lineage and reduces the T cell driven inflammatory response. These data highlight the therapeutical potential of STP938 in treating patients with autoimmune diseases such as rheumatoid arthritis.References:[1]Martin et al, JCI Insight. 2020, 12;5(5):133880Disclosure of Interests:Hélène ASNAGLI Employee of: Step Pharma, Andrew Novak: None declared, Louise Birch Shareholder of: Step Pharma, Rebecca Lane: None declared, Norbert Minet Employee of: employee as Ph D student under CIFRE grant, David Laughton: None declared, Pascal George Shareholder of: Step Pharma, Geoffroy de Ribains Shareholder of: as former employee of Step Pharma, Employee of: former employee of Step Pharma, Sylvain Latour: None declared, Alain Fischer: None declared, Tim Bourne Shareholder of: UCB, Step Pharma, Sitryx Therapeutics, Consultant of: a range of biotech companies, Employee of: former employee of Step Pharma and Sitryx Therapeutics, Andrew Parker Employee of: Step Pharma

APA, Harvard, Vancouver, ISO, and other styles

23

Raspa, Marcello, Sabrina Putti, Renata Paoletti, Barbara Barboni, Marina Ramal‐Sanchez, Paola Lanuti, Marco Marchisio, et al. "The impact of five years storage/biobanking at −80°C on mouse spermatozoa fertility, physiology, and function." Andrology 9, no. 3 (February 17, 2021): 989–99. http://dx.doi.org/10.1111/andr.12971.

Full text

APA, Harvard, Vancouver, ISO, and other styles

24

Kamińska, A., L. Pardyak, S. Marek, K. Wróbel, M. Kotula‐Balak, B. Bilińska, and A. Hejmej. "Notch signaling regulates nuclear androgen receptor AR and membrane androgen receptor ZIP 9 in mouse Sertoli cells." Andrology 8, no. 2 (August 29, 2019): 457–72. http://dx.doi.org/10.1111/andr.12691.

Full text

APA, Harvard, Vancouver, ISO, and other styles

25

Hays, E., N. Majchrzak, V. Daniel, Z. Ferguson, S. Brown, K. Hathorne, and S. La Salle. "Spermatogenesis associated 22 is required for DNA repair and synapsis of homologous chromosomes in mouse germ cells." Andrology 5, no. 2 (March 2017): 299–312. http://dx.doi.org/10.1111/andr.12315.

Full text

APA, Harvard, Vancouver, ISO, and other styles

26

Mayekar, Manasi, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, et al. "Abstract 2197: Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2197. http://dx.doi.org/10.1158/1538-7445.am2022-2197.

Full text

Abstract:

Abstract Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2197.

APA, Harvard, Vancouver, ISO, and other styles

27

Song, Kang‐Moon, Woo‐Jean Kim, Min‐Ji Choi, Anita Limanjaya, Kalyan Ghatak, Nguyen Nhat Minh, Jiyeon Ock, et al. "Intracavernous delivery of Dickkopf3 gene or peptide rescues erectile function through enhanced cavernous angiogenesis in the diabetic mouse." Andrology 8, no. 5 (April 10, 2020): 1387–97. http://dx.doi.org/10.1111/andr.12784.

Full text

APA, Harvard, Vancouver, ISO, and other styles

28

Chihara, M., T. Nakamura, S. Otsuka-Kanazawa, O. Ichii, Y. H. A. Elewa, and Y. Kon. "Genetic factors derived from the MRL/MpJ mouse function to maintain the integrity of spermatogenesis after heat exposure." Andrology 3, no. 5 (August 20, 2015): 991–99. http://dx.doi.org/10.1111/andr.12082.

Full text

APA, Harvard, Vancouver, ISO, and other styles

29

Bergeron, F., A. Boulende Sab, M. F. Bouchard, H. Taniguchi, O. Souchkova, C. Brousseau, J. J. Tremblay, N. Pilon, and R. S. Viger. "Phosphorylation of GATA 4 serine 105 but not serine 261 is required for testosterone production in the male mouse." Andrology 7, no. 3 (February 22, 2019): 357–72. http://dx.doi.org/10.1111/andr.12601.

Full text

APA, Harvard, Vancouver, ISO, and other styles

30

Taniguchi, H., T. Katano, K. Nishida, H. Kinoshita, T. Matsuda, and S. Ito. "Elucidation of the mechanism of suppressed steroidogenesis during androgen deprivation therapy of prostate cancer patients using a mouse model." Andrology 4, no. 5 (May 27, 2016): 964–71. http://dx.doi.org/10.1111/andr.12213.

Full text

APA, Harvard, Vancouver, ISO, and other styles

31

Loewendorf, Andrea, Corinna Krüger, Eva Maria Borst, Markus Wagner, Ursula Just, and Martin Messerle. "Identification of a Mouse Cytomegalovirus Gene Selectively Targeting CD86 Expression on Antigen-Presenting Cells." Journal of Virology 78, no. 23 (December 1, 2004): 13062–71. http://dx.doi.org/10.1128/jvi.78.23.13062-13071.2004.

Full text

Abstract:

ABSTRACT We and others have shown that infection of dendritic cells with murine cytomegalovirus (MCMV) leads to severe functional impairment of these antigen-presenting cells (D. M. Andrews, C. E. Andoniou, F. Granucci, P. Ricciardi-Castagnoli, and M. A. Degli-Esposti, Nat. Immunol. 2:1077-1084, 2001; S. Mathys, T. Schroeder, J. Ellwart, U. H. Koszinowski, M. Messerle, and U. Just, J. Infect. Dis. 187:988-999, 2003). Phenotypically, reduced surface expression of costimulatory molecules and major histocompatibility complex molecules was detected. In order to identify the molecular basis for the observed effects, we generated MCMV mutants with large deletions of nonessential genes. The study was facilitated by the finding that a monocyte-macrophage cell line displayed similar phenotypic alterations after MCMV infection. By analyzing the expression of cell surface molecules on infected cells, we identified a mutant virus which is no longer able to downmodulate the expression of the costimulatory molecule CD86. Additional mutants with smaller deletions allowed us to pin down the responsible gene to a certain genomic region. RNA analysis led to the identification of the spliced gene m147.5, encoding a protein with 145 amino acids. Experiments with an m147.5 mutant revealed that the protein affects CD86 expression only, suggesting that additional MCMV genes are responsible for downmodulation of the other surface molecules. Identification of viral gene products interfering with functionally important proteins of antigen-presenting cells will provide the basis to dissect the complex interaction of CMV with these important cells and to evaluate the biological importance of these viral genes in vivo.

APA, Harvard, Vancouver, ISO, and other styles

32

Weitz, Jonathan, Tatiana Hurtado de Mendoza, Herve Tiriac, Joel Baumgartner, Kaitlyn Kelly, Jula Veerapong, and Andrew Lowy. "Abstract 289: A novel ex-vivo organotypic culture platform for functional interrogation of human appendiceal neoplasms." Cancer Research 82, no. 12_Supplement (June 15, 2022): 289. http://dx.doi.org/10.1158/1538-7445.am2022-289.

Full text

Abstract:

Abstract Appendiceal neoplasms are rare and often clinically present with peritoneal metastasis. While surgical tumor resection is effective for some types of primary appendiceal cancers, patients with metastatic disease have poor prognostic outcomes. Models to study appendix cancer biology are limited, given that 1) no mouse models exist and 2) reliable in vitro models are unavailable. As such, we have developed an ex-vivo organotypic slice model to examine cellular interactions between tumor cells and their local microenvironment. Tumor specimens from human appendiceal cancer patients were cut using a vibratome to make 200 μm organotypic slices. Slices were cultured on transwell inserts and tested for changes in morphological, cellular and functional characteristics over a seven-day period. Organotypic slices maintained their cellular composition in regard to the proportion of epithelial, immune cells and fibroblasts. Live cell [Ca2+]i imaging of long term cultured slices confirmed that immune cells remain functionally active when stimulated with extracellular ATP. Lasty, using tumor biopsies from human donors, we have identified a diverse immunological profile of appendiceal tumors not previously identified. Our study illustrates a novel approach for studying the pathophysiology of appendiceal cancer, a notoriously difficult disease to model. Citation Format: Jonathan Weitz, Tatiana Hurtado de Mendoza, Herve Tiriac, Joel Baumgartner, Kaitlyn Kelly, Jula Veerapong, Andrew Lowy. A novel ex-vivo organotypic culture platform for functional interrogation of human appendiceal neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 289.

APA, Harvard, Vancouver, ISO, and other styles

33

Wormsbaecher, Clarissa, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Jonathan W. Song, and Craig J. Burd. "Abstract 2687: The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2687. http://dx.doi.org/10.1158/1538-7445.am2022-2687.

Full text

Abstract:

Abstract In utero exposure to estrogenic endocrine disrupting compounds (EDCs) increases a woman’s lifetime risk of breast cancer. Similarly, mice exposed in utero to the estrogenic EDC bisphenol A (BPA) have increased susceptibility to mammary gland tumors. It is unclear which BPA-induced alterations predispose the mammary gland to cancer transformation. There is a critical need to understand the mechanisms that drive increased cancer risk in order to assess the impact of BPA and BPA alternatives that retain estrogenic activity. We have utilized in utero BPA exposure as a model system for in utero estrogenic endocrine disruption to study the long-term consequences to the mouse mammary stroma. We found that BPA exposed fibroblasts showed significant transcriptional deregulation, with the extracellular matrix being the most altered cellular component and multiple collagen genes being more highly expressed. The fibroblasts from the BPA exposed mice decreased fluid permeability of the extracellular matrix, indicative of an increased density in the extracellular matrix. Also, in utero BPA exposure increased mammary gland stiffness. Changes to breast density, stiffness, and collagen deposition are all associated with breast cancer risk. Further, we test BPA alternative compounds with varying affinities for the estrogen receptor in our in utero model to assess the phenotypes in the mouse mammary stroma which are associated with breast cancer risk. Additionally, we use a mesenchymal estrogen receptor alpha (ERα) knockout mouse model to dissect the in utero cellular target of EDCs. Citation Format: Clarissa Wormsbaecher, Andrea R. Hindman, Alex Avendano, Marcos Cortes-Medina, Jonathan W. Song, Craig J. Burd. The estrogenic activities of endocrine disruptors alter the extracellular matrix and tissue stiffness in the mammary gland [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2687.

APA, Harvard, Vancouver, ISO, and other styles

34

Makvandi, A., R. Kowsar, M. Hajian, A. H. Mahdavi, N. Tanhaei Vash, and M. H. Nasr‐Esfahani. "Alpha lipoic acid reverses the negative effect of LPS on mouse spermatozoa and developmental competence of resultant embryos in vitro." Andrology 7, no. 3 (February 20, 2019): 350–56. http://dx.doi.org/10.1111/andr.12596.

Full text

APA, Harvard, Vancouver, ISO, and other styles

35

Raab, G., K. Kover, B. C. Paria, S. K. Dey, R. M. Ezzell, and M. Klagsbrun. "Mouse preimplantation blastocysts adhere to cells expressing the transmembrane form of heparin-binding EGF-like growth factor." Development 122, no. 2 (February 1, 1996): 637–45. http://dx.doi.org/10.1242/dev.122.2.637.

Full text

Abstract:

Previous studies have shown that heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) mRNA is synthesized in the mouse uterine luminal epithelium temporally, just prior to implantation, and spatially, only at the site of blastocyst apposition (Das, S. K., Wang, X. N., Paria, B. C., Damm, D., Abraham, J. A., Klagsbrun, M., Andrews, G. K. and Dey, S. K. (1994) Development 120, 1071–1083). HB-EGF is synthesized as a transmembrane protein (HB-EGF TM) that can be processed to release the soluble growth factor. An antibody that cross-reacts only with the transmembrane form detected HB-EGF TM in uterine luminal epithelium in a spatial manner similar to that of HB-EGF mRNA. HB-EGF TM is a juxtacrine growth factor that mediates cell-cell contact. To ascertain if HB-EGF TM could be an adhesion factor for blastocysts, a mouse cell line synthesizing human HB-EGF TM was co-cultured with mouse blastocysts. Cells synthesizing HB-EGF TM adhered to day-4 mouse blastocysts more extensively than parental cells or cells synthesizing a constitutively secreted form of HB-EGF. Adhesion of cells synthesizing HB-EGF TM to blastocysts was inhibited by excess recombinant HB-EGF but less so by TGF-alpha. Adhesion was also inhibited by the synthetic peptide P21 corresponding to the HB-EGF heparin binding domain, and by incubating the blastocysts with heparinase. In addition, adhesion to delayed implanting dormant blastocysts, which lack EGF receptor (EGFR), was diminished relative to normal blastocysts. These results suggested that adhesion between blastocysts and cells synthesizing HB-EGF TM was mediated via interaction with both blastocyst EGFR and heparan sulfate proteoglycan (HSPG). It was concluded that HB-EGF TM, which is synthesized exclusively in the luminal epithelium at the site of blastocyst apposition, and which is a juxtacrine adhesion factor for blastocysts, could be one of the mediators of blastocyst adhesion to the uterus in the process of implantation.

APA, Harvard, Vancouver, ISO, and other styles

36

Carstens, Julienne L., Sujuan Yang, Pedro Correa de Sampaio, Xiaofeng Zheng, Souptik Barua, Kathleen M. McAndrews, Arvind Rao, Jared K. Burks, Andrew D. Rhim, and Raghu Kalluri. "Abstract PO-059: Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis." Cancer Research 81, no. 22_Supplement (November 15, 2021): PO—059—PO—059. http://dx.doi.org/10.1158/1538-7445.panca21-po-059.

Full text

Abstract:

Abstract Metastatic pancreatic adenocarcinoma (PDAC) is the dominant clinical presentation and highly treatment-resistant. However, not all metastasis is equal with metastatic disease in the lung having improved outcomes over the liver. These clinical differences suggest a therapeutic opportunity and urge analysis of the molecular underpinnings of PDAC metastasis. The acquisition of mesenchymal features by epithelial cancer cells is commonly associated with solid tumor metastasis and has been linked to the pancreatic cancer basal subtype and its association with treatment resistance and poorer outcomes, but its impact on pancreatic cancer metastasis needs further understanding. We explored the impact on metastasis of stabilized epithelial, partial-mesenchymal and mesenchymal cancer cells by generating several genetic mouse models based on the lineage-traced KPC mouse model (KrasLSL-G12D;p53R172H; or p53LSL; PDX1-Cre;EYFPLSL). Using single-cell RNA-sequencing we confirmed the KPC mouse model recapitulates the spectrum of epithelial-mesenchymal phenotypes observed in patients and can be genetically engineered to stabilize specific phenotypes. The stabilization of epithelial phenotypes through the homozygous loss of the mesenchymal-driving transcription factors Snail and Twist (Snai1F/F;Twist1F/F) had no impact on primary tumor progression but increased liver colonization. This increase in liver colonization was supported by a second epithelial-stabilized mouse model based on the loss of Zeb1 (Zeb1F/F). The stabilization of mesenchymal features through the heterozygous or homozygous loss of the epithelial adherin junction E-cadherin (Cdh1F/+ or Cdh1F/F) promoted lung metastasis. Interestingly, epithelial plasticity was still required for efficient lung colonization, but not rare liver metastasis. Additionally, mesenchymal gene expression correlated with an improved patient survival as well as metastatic localization, supporting the clinical observations of improved survival in lung metastasis. Using gene expression analysis of sorted bulk cancer cells and single-cells, migration assays, and multiplexed-immunohistochemistry, we observed that the epithelial/mesenchymal status of the cancer cells dictated different mechanisms for motility and interaction with the immune system. Mesenchymal cancer cells migrate as single-cells and attract fewer T-cells where epithelial cancer cells migrate collectively and have increased immune regulation gene expression. These data suggest the epithelial/mesenchymal status of cancers cells dictate the where and how of metastatic disease and could inform therapeutic interventions. Citation Format: Julienne L. Carstens, Sujuan Yang, Pedro Correa de Sampaio, Xiaofeng Zheng, Souptik Barua, Kathleen M. McAndrews, Arvind Rao, Jared K. Burks, Andrew D. Rhim, Raghu Kalluri. Epithelial/mesenchymal identity dictates pancreatic cancer cell metastasis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-059.

APA, Harvard, Vancouver, ISO, and other styles

37

Gillette-Ferguson, Illona, Amy G. Hise, Helen F. McGarry, Joseph Turner, Andrew Esposito, Yan Sun, Eugenia Diaconu, Mark J. Taylor, and Eric Pearlman. "Wolbachia-Induced Neutrophil Activation in a Mouse Model of Ocular Onchocerciasis (River Blindness)." Infection and Immunity 72, no. 10 (October 2004): 5687–92. http://dx.doi.org/10.1128/iai.72.10.5687-5692.2004.

Full text

Abstract:

ABSTRACT Endosymbiotic Wolbachia bacteria are abundant in the filarial nematodes that cause onchocerciasis (river blindness), including the larvae (microfilariae) that migrate into the cornea. Using a mouse model of ocular onchocerciasis, we recently demonstrated that it is these endosymbiotic bacteria rather than the nematodes per se that induce neutrophil infiltration to the corneal stroma and loss of corneal clarity (Saint Andre et al., Science 295:1892-1895, 2002). To better understand the role of Wolbachia organisms in the pathogenesis of this disease, we examined the fate of these bacteria in the cornea by immunoelectron microscopy. Microfilariae harboring Wolbachia organisms were injected into mouse corneas, and bacteria were detected with antibody to Wolbachia surface protein. Within 18 h of injection, neutrophils completely surrounded the nematodes and were in close proximity to Wolbachia organisms. Wolbachia surface protein labeling was also prominent in neutrophil phagosomes, indicating neutrophil ingestion of Wolbachia organisms. Furthermore, the presence of numerous electron-dense granules around the phagosomes indicated that neutrophils were activated. To determine if Wolbachia organisms directly activate neutrophils, peritoneal neutrophils were incubated with either parasite extracts containing Wolbachia organisms, parasite extracts depleted of Wolbachia organisms (by antibiotic treatment of worms), or Wolbachia organisms isolated from filarial nematodes. After 18 h of incubation, we found that isolated Wolbachia organisms stimulated production of tumor necrosis factor alpha and CXC chemokines macrophage inflammatory protein 2 and KC by neutrophils in a dose-dependent manner. Similarly, these cytokines were induced by filarial extracts containing Wolbachia organisms but not by Wolbachia-depleted extracts. Taken together, these findings indicate that neutrophil activation is an important mechanism by which Wolbachia organisms contribute to the pathogenesis of ocular onchocerciasis.

APA, Harvard, Vancouver, ISO, and other styles

38

Hoyle, Rosalie G., Andrew Morris, Piyusha Pagare, Shadid Uz Zaman, Zhikun Ma, Yan Zhang, and Jiong Li. "Abstract 1862: Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1862. http://dx.doi.org/10.1158/1538-7445.am2022-1862.

Full text

Abstract:

Abstract In this study, we performed a structure-activity-relationship study of seven previously identified chloro-naphthoquinone analogs and evaluated their abilities to inhibit the Wnt/β-catenin signaling pathway. The Wnt/β-catenin signaling pathway plays essential roles in colorectal cancer (CRC) initiation, proliferation, and development. While targeting the Wnt/β-catenin pathway has been validated as a very promising approach for CRC treatment, developing a therapeutic for inhibition of this elusive pathway has been very challenging for researchers. Of the seven chloro-naphthoquinone analogues, we found that two compounds, Compound 3 and Compound 6, significantly inhibited Wnt target gene transcription and Wnt-induced colorectal tumorigenesis in vitro. Chromatin immunoprecipitation binding assays and computational modeling analysis revealed that Compound 3 and Compound 6 inhibit the Wnt/β-catenin pathway through disruption of the TCF4-DNA binding, a crucial step for the activation of the Wnt/β-catenin signaling pathway. Lastly, using a patient-derived organoid model and xenograft mouse model, we showed that these compounds inhibit CRC tumorigenesis. Taken together, this study demonstrates a novel mechanism of action for these chloro-naphthoquinone analogs, which can be further explored in future drug design and discovery efforts for small molecules targeting the TCF family proteins for inhibition of the Wnt/β-catenin signaling pathway. Citation Format: Rosalie G. Hoyle, Andrew Morris, Piyusha Pagare, Shadid Uz Zaman, Zhikun Ma, Yan Zhang, Jiong Li. Naphthoquinone analogues inhibit Wnt/β-catenin signaling and colorectal cancer tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1862.

APA, Harvard, Vancouver, ISO, and other styles

39

Rankin, Erinn B. "Genomics and molecular mechanisms of high grade serous ovarian cancer: the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium." International Journal of Gynecologic Cancer 29, Suppl 2 (August 2019): s7—s11. http://dx.doi.org/10.1136/ijgc-2019-000490.

Full text

Abstract:

ObjectiveThe aim of this study was to review current research efforts in genomics and molecular mechanisms of high grade serous ovarian cancer, presented at the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium, held at the University of Washington.MethodsThe 12th Biennial Rivkin Center Ovarian Cancer Research Symposium brought together leaders in the field to discuss recent advances in ovarian cancer research and therapy.ResultsThe genomics and molecular mechanisms of ovarian cancer session featured invited speaker presentations by Dr Alan D’ Andrea on ‘Deoxyribonucleic acid (DNA) repair in ovarian cancer’ and Dr Kathleen Cho on ‘Modeling the genomics of high grade serous carcinoma in the mouse’. Eight additional oral presentations and 46 poster presentations were selected from the submitted abstracts that highlighted current research efforts in p53, DNA repair, genomic instability and modeling disease in mice, and organoids in high grade serous ovarian cancer.ConclusionsNew technologies utilizing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (CAS9) approaches in mice, organoids, and cell based screens continue to advance our knowledge of key molecular drivers of ovarian cancer initiation, progression, and drug resistance. Improved understanding of the mechanisms of poly ADP ribose polymerase inhibitor resistance may lead to new therapeutic strategies to enhance outcomes in women with high grade serous ovarian cancer.

APA, Harvard, Vancouver, ISO, and other styles

40

Yan, Bing Chun, Ki-Yeon Yoo, Joon Ha Park, Choong Hyun Lee, Jung Hoon Choi, and Moo-Ho Won. "The high dosage of earthworm (Eisenia andrei) extract decreases cell proliferation and neuroblast differentiation in the mouse hippocampal dentate gyrus." Anatomy & Cell Biology 44, no. 3 (2011): 218. http://dx.doi.org/10.5115/acb.2011.44.3.218.

Full text

APA, Harvard, Vancouver, ISO, and other styles

41

Gofur, M. R., and K. Ogawa. "Compartments with predominant ephrin‐B1 and EphB2/B4 expression are present alternately along the excurrent duct system in the adult mouse testis and epididymis." Andrology 7, no. 6 (July 25, 2018): 888–901. http://dx.doi.org/10.1111/andr.12523.

Full text

APA, Harvard, Vancouver, ISO, and other styles

42

Daniels, Andrew, William Damsky, Meaghan McGeary, Akiko Iwasaki, and Marcus Bosenberg. "Abstract 1357: T cell memory and the critical effectors of successful anticancer immune response." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1357. http://dx.doi.org/10.1158/1538-7445.am2022-1357.

Full text

Abstract:

Abstract Despite the initial clinical success of immunotherapies in the treatment of melanoma, most patients fail to achieve long-term responses. While the majority of patients initially respond to these treatments, most go on to develop secondary resistance. The mechanisms underlying this failure of long-term response and successful responses is poorly understood. To better understand the factors contributing to successful long-term anti-cancer immune responses, we utilized the YUMMER1.7 (YR1.7) melanoma line to develop a novel model for the evaluation of immunologic memory. We found that mice engrafted with a YR1.7 tumor can be cured by resection, and that subsequent challenge of these mice with the same tumor, even at 20x the cell number, led to expeditious rejection. Using depleting antibodies, we found that memory response were dependent on CD8 and CD4 T cells, and that CD4 depletion alone does not compromise initial responses, but leads to eventual failure of memory. We found no effect of natural killer cell (NK) depletion. We performed single cell RNA sequencing on primary and rechallenge tumors from the same mouse, with the same tumor line. We found a phenotype of clonal replacement, in which the effective T cell clones seen in the memory response were non-overlapping with those found in the primary tumor. This implies an extra-tumoral location for these clones in the primary setting or the potential for additional priming of novel T cell clones upon re-challenge. Together, these findings suggest a novel insights on the manner and location of T cells needed for anti-cancer memory responses. Citation Format: Andrew Daniels, William Damsky, Meaghan McGeary, Akiko Iwasaki, Marcus Bosenberg. T cell memory and the critical effectors of successful anticancer immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1357.

APA, Harvard, Vancouver, ISO, and other styles

43

Thege, Fredrik Ivar, Dhwani N. Rupani, Bhargavi B. Barathi, Anirban Maitra, Andrew D. Rhim, and Sonja M. Wörmann. "Abstract 918: Development of a platform for programmable in vivo oncogene activation and screening using CRISPRa technology." Cancer Research 82, no. 12_Supplement (June 15, 2022): 918. http://dx.doi.org/10.1158/1538-7445.am2022-918.

Full text

Abstract:

Abstract Conventional genetically engineered mouse models (GEMMs) are time consuming, laborious and offer limited spatio-temporal control. We have developed a streamlined platform for in vivo gene activation using CRISPR activation (CRISPRa) technology. Our model system allows for flexible, sustained and timed activation of one or more target genes, in vitro or in vivo, using single or pooled lentiviral guides. Using Myc and Yap1 as model oncogenes, we implemented this platform to study the effect of oncogene activation on the tumorigenic potential of primary pancreatic organoids, as well as in an autochthonous model of lung adenocarcinoma. We found that Myc-activation in pancreatic organoids increased their tumorigenic potential and resulted in significantly shorter survival relative to controls when transplanted orthotopically. In vivo Myc activation in the lung accelerated tumor progression and resulted in significantly shorter overall survival relative to non-targeted tumor controls. Furthermore, we found that Myc-activation drives the acquisition of an immune suppressive “cold” tumor microenvironment. Through cross-species validation of our results, we were able to link MYC to a previously described, immunosuppressive transcriptomic subtype in patient tumors, thus identifying a patient cohort that may benefit from combined MYC/immune-targeted therapies. Our work demonstrates how CRISPRa can be used for rapid functional validation of putative oncogenes and may allow for the identification and evaluation of potential metastatic and oncogenic drivers through competitive screening. Citation Format: Fredrik Ivar Thege, Dhwani N. Rupani, Bhargavi B. Barathi, Anirban Maitra, Andrew D. Rhim, Sonja M. Wörmann. Development of a platform for programmable in vivo oncogene activation and screening using CRISPRa technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 918.

APA, Harvard, Vancouver, ISO, and other styles

44

Hao, Xue, Bo Zhao, Martina Towers, Liping Liao, Hsin Yao Tang, Aaron Havas, Andrew V. Kossenkov, et al. "Abstract PR011: TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation." Cancer Research 83, no. 2_Supplement_1 (January 15, 2023): PR011. http://dx.doi.org/10.1158/1538-7445.agca22-pr011.

Full text

Abstract:

Abstract Cellular senescence regulates cancer and tissue aging in part through the secretion of proinflammatory factors known as the senescence-associated secretory phenotype (SASP). For example, sterile inflammation or ‘inflammaging’ is a hallmark of tissue aging. Thioredoxin reductase 1 (TXNRD1) genetic variability is associated with aging and is often upregulated in human cancers. TXNRD1’s role in regulating tissue aging and cancer has been attributed to its enzymatic role in regulating cellular redox. Here we show that TXNRD1 drives the SASP and inflammation through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments (CCF) and interacts with cGAS in a senescence status dependent manner, which is required for the SASP. Biochemically, TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune-surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse tumor models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not an inhibitor of its enzymatic activity alone, downregulated inflammaging in several tissues. In summary, our results report TXNRD1 promotes inflammation via activating the innate immune response in a manner depending on its interaction with cGAS but not its enzymatic activity. Our findings have important implications for both tissue aging and cancer. Citation Format: Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Hsin Yao Tang, Aaron Havas, Andrew V. Kossenkov, Shelley Berger, Peter D. Adams, David W. Speicher, Rugang Zhang. TXNRD1 drives innate immune response in senescent cells to promote tumor immune surveillance and age-associated inflammation [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR011.

APA, Harvard, Vancouver, ISO, and other styles

45

Michael, Simon K., Jo Hilgers, Christine Kozak, J. Barry Whitney, and Eugene F. Howard. "Characterization and mapping of DNA sequence homologous to mouse U1a1 snRNA: Localization on chromosome 11 near theDlb-1 andRe loci." Somatic Cell and Molecular Genetics 12, no. 3 (May 1986): 215–23. http://dx.doi.org/10.1007/bf01570780.

Full text

APA, Harvard, Vancouver, ISO, and other styles

46

Gulay, Kevin Christian M., Edgar Esparza, Xinlian Zhang, Evangeline S. Mose, Jonathan Weitz, Minya Pu, Karen Messer, Andrew M. Lowy, and Herve Tiriac. "Abstract A072: Strategies to improve KRAS G12D inhibitor (MRTX1133) therapy in pancreatic ductal adenocarcinoma." Cancer Research 82, no. 22_Supplement (November 15, 2022): A072. http://dx.doi.org/10.1158/1538-7445.panca22-a072.

Full text

Abstract:

Abstract Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor oncogenic KRAS, with KRAS G12D being the predominant mutation. Recently, a novel KRAS G12D inhibitor, MRTX-1133, has been developed, potentially revolutionizing PDAC treatment. However, clinical studies on KRAS G12C inhibitors suggest that there may be intrinsic resistance to KRAS inhibitors (KRASi) and acquired resistance can develop rapidly in patients. Moreover, our preliminary data suggest that acquired resistance mechanisms to chemotherapy can also confer partial resistance to KRASi. We hypothesize that effective killing of tumor cells with KRASi will require a rationally designed combinatorial treatment. Methods: We tested chemotherapy and targeted pathway inhibitors which can inhibit signaling upstream and downstream of KRAS to identify drugs that synergize with MRTX-1133. We treated resected human PDAC and mouse tumors from Kras-G12D; P53-R172H; PDX-Cre (KPC) prepared as organotypic slice cultures to test our identified drug combinations. We orthotopically inoculated KPC PDAC cells and treated mice with vehicle, single-agent drugs (MRTX1133 or Afatinib), or combination therapy. We established MRTX-1133-resistant (MRTXR) models in human SUIT2 cells, human organoids and mouse KPC cell lines to study the mechanisms of KRASi resistance. We performed RNA-seq and Reverse Phase Protein Array in these resistance models to identify pathways differentially activated during resistance development. Results: We found that irreversible ErbB inhibitors, Afatinib and Neratinib, had the greatest synergy with MRTX-1133 in parental and in MRTXR cells. We found that combination therapy with MRTX-1133 and Afatinib decreased the number of proliferating cells compared to the control or single-agent treatment in the human and mouse slice cultures. Combination therapy with MRTX1133 and Afatinib significantly reduced tumor growth in mice compared to the vehicle or single-agent controls. We also found that resistant cells demonstrated increased EGFR and HER2 phosphorylation compared to parental cells and that the MRTX-1133 and Afatinib drug combo synergistically decreased EGFR and HER2 phosphorylation. We identified and mapped the differentially expressed pathways and genes involved in KRASi resistance using RNA-seq and RPPA analyses. Conclusion: We identified a likely pathway of resistance to novel KRAS G12D inhibitors, and we demonstrate that this resistance can be effectively targeted using existing therapeutics targeting the ErbB pathway. Citation Format: Kevin Christian M. Gulay, Edgar Esparza, Xinlian Zhang, Evangeline S. Mose, Jonathan Weitz, Minya Pu, Karen Messer, Andrew M. Lowy, Herve Tiriac. Strategies to improve KRAS G12D inhibitor (MRTX1133) therapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A072.

APA, Harvard, Vancouver, ISO, and other styles

47

Purde, Mette-Triin, Fabienne Hartmann, Jovana Cupovic, Sarah Schmidt, David Bomze, Felix Stemeseder, Alexander Lercher, et al. "Abstract 3298: Propagation competence of a self-antigen-targeting arenavirus vector based cancer therapy determines antitumor efficacy in mouse melanoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 3298. http://dx.doi.org/10.1158/1538-7445.am2022-3298.

Full text

Abstract:

Abstract Breaking self-tolerance and inducing a robust immune response targeting tumor cell derived self-antigens by therapeutic vaccines has remained challenging. We have generated a replicating viral vector based on the arenavirus lymphocytic choriomeningitis virus expressing the melanoma tissue-specific self-antigen Trp2 (artLCMV-Trp2) and show that a single immunization of mice bearing established melanoma with this vector can break tolerance against this self antigen and induces high levels of tumor-infiltrating TRP2+ CD8+ T cells. These T cells express the effector cytokines IFNγ and TNFα, lack markers of T cell exhaustion, and their appearance coincides with marked inhibition of tumor growth and significant survival benefit. artLCMV-TRP2 induced a strong type I interferon response that resulted in transient type I-dependent Treg inhibition that was necessary for the generation of optimal antitumoral T cell responses. Moreover, artLCMV-TRP2 vaccination proved able to induce complete tumor remission when combined with infusion of exogenous TRP2-specific T cells into mice. In conclusion, replication competence is a key property of artLCMV-TRP2 that enabled effective anti-cancer immunity and therapeutic effect. Citation Format: Mette-Triin Purde, Fabienne Hartmann, Jovana Cupovic, Sarah Schmidt, David Bomze, Felix Stemeseder, Alexander Lercher, Lenka Besse, Fiamma Berner, Thomas Tüting, Andreas Bergthaler, Andrea Schietinger, Stefan Kochanek, Burkhard Ludewig, Klaus K. Orlinger, Tobias Bald, Sandra S. Ring, Lukas Flatz. Propagation competence of a self-antigen-targeting arenavirus vector based cancer therapy determines antitumor efficacy in mouse melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3298.

APA, Harvard, Vancouver, ISO, and other styles

48

Truong, Andrew S., Mi Zhou, Michael S. Sturdivant, John D. Raupp, Ujjawal Manocha, and William Y. Kim. "Abstract 919: APOBEC3 promotes tumor progression, squamous differentiation and metastasis in bladder cancer mouse model." Cancer Research 82, no. 12_Supplement (June 15, 2022): 919. http://dx.doi.org/10.1158/1538-7445.am2022-919.

Full text

Abstract:

Abstract Bladder cancer is the sixth most common type of cancer in the United States. In 2021, there are an estimated 83,730 new cases and 17,200 deaths from bladder cancer. Only about 15% of patients with metastatic disease survive past five years. The apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) is overexpressed in bladder tumors compared to corresponding healthy tissues. This enzyme catalyzes the conversion of cytidine to uracil playing an important physiologic role in restricting viral replication. When aberrantly over-expressed, APOBEC3B can damage single-stranded DNA present during DNA replication and transcription, resulting in an increased tumor mutational burden. Strikingly, APOBEC mutagenesis accounts for 70% of all single-nucleotide variants found in bladder cancer. Despite the strong evidence of APOBEC mutagenesis in bladder cancer, the effects of APOBEC3B on the disease progression remain unclear. To address this question, we generated the UPPA (urothelial specific over-expression of mouse Apobec3 along with Pten and p53 knock-out) and control UPP mouse models to interrogate the role Apobec3 in bladder cancer progression. Apobec3 over-expression shortened tumor latency in the UPPA model with the median tumor free survival time of 43.3 weeks compared to 53.6 weeks in the UPP model. Histological analysis showed that bladder epithelial cells in the UPPA mice underwent squamous differentiation which is associated with aggressive disease in human. Additionally, immunofluorescence analysis showed up-regulation of krt6a (a squamous marker) in UPPA urothelium compared to a complete lack of krt6a signal in the urothelium of UPP mice. Necropsy revealed the presence of metastatic nodules in lung, liver and peritoneum in UPPA mice. Cell lines derived from a matched pair of UPPA primary tumor and peritoneal metastatic tumor formed lung and liver nodules in wild-type C57BL/6J mice via tail vein injection. Our results so far suggest that Apobec3 promotes tumor progression, squamous differentiation and metastasis. Additional work utilizing bladder organoids and scRNAseq are underway to unravel the mechanism by which Apobec3 promotes these observed phenotypes. Currently, single-cell RNAseq analysis on primary UPPA tumor demonstrated high degree to T cell infiltration. Approximately 60% of cells sequenced were annotated as T-cells and natural killer T-cells by SingleR. We treated mice bearing UPPA primary bladder tumors with anti-PD-1 antibody and observed significant tumor growth inhibition. Citation Format: Andrew S. Truong, Mi Zhou, Michael S. Sturdivant, John D. Raupp, Ujjawal Manocha, William Y. Kim. APOBEC3 promotes tumor progression, squamous differentiation and metastasis in bladder cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 919.

APA, Harvard, Vancouver, ISO, and other styles

49

Tsai, Daniel E., Yvette Robbins, Angel Huynh, Andrew Sinkoe, Cem Sievers, Madhavi Murali, Xiaolin Luo, Clint T. Allen, and Vassiliki Saloura. "Abstract 6250: Investigating the immunomodulatory mechanisms of Smyd3 depletion in HPV-negative head and neck squamous cell carcinoma." Cancer Research 82, no. 12_Supplement (June 15, 2022): 6250. http://dx.doi.org/10.1158/1538-7445.am2022-6250.

Full text

Abstract:

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, with Human Papilloma virus (HPV)-negative patients having a ~50% recurrence rate and poor median overall survival of ~13 months in the recurrent/metastatic setting. Pembrolizumab, a programmed-death-1 (PD-1) checkpoint inhibitor is active but with a response rate as low as 19%. Our preliminary work has identified SET and MYND Domain containing 3 (SMYD3) as a chromatin modifier that is significantly overexpressed in HPV-negative HNSCC tumor tissues compared to normal epithelium and is associated with low CD8+ T-cell infiltration in HPV-negative HNSCC. Furthermore, we have shown that knockdown of human SMYD3 upregulates the expression of multiple type I IFN response and antigen presentation machinery (APM) genes. This study aims to investigate whether Smyd3 depletion potentiates immune-mediated antitumor efficacy in anti-PD-1 resistant syngeneic mouse models of HPV-negative HNSCC (MOC1), as well as relevant mechanisms. SiRNA-mediated knockdown of Smyd3 in mouse HPV-negative MOC1 cells followed by RNA-seq revealed upregulation of multiple type I IFN response and APM genes in vitro. Multicolor flow cytometry of MOC1 tumors treated with control anti-sense oligonucleotides (ASOs) or Smyd3 ASOs showed that Smyd3 depletion in a syngeneic, heterotopic mouse model (C57BL/6) of flank MOC1 tumors induced intratumoral infiltration of CD8+ T-cells, as well as upregulation of H2-Kb (MHC class I) and mouse Pd-l1 in MOC1 cells. Combined treatment of Smyd3 ASOs with anti-PD-1 induced complete regressions of flank MOC1 tumors in 4/8 treated mice and significant tumor growth restriction in 2/8 mice, while 2/8 tumors “escaped” the treatment effect. Single-cell RNA seq of MOC1 tumors treated with control or Smyd3 ASOs is ongoing to evaluate the effects of Smyd3 depletion on MOC1 cancer cells and immune cell subsets of the tumor microenvironment and to identify potential mechanisms of resistance of Smyd3 ASO + anti-PD-1 combination treatment. Genome-wide mapping of Smyd3 and the repressive mark H4K20me3, which is known to be written by Smyd3, in MOC1 cells using CUT&RUN assays is also ongoing and aims to decipher whether Smyd3 directly binds to and regulates the expression of immune-related genes through H4K20me3. Ex-vivo cytotoxicity assays aim to evaluate whether CRISPR Smyd3 KO in MOC1 cells sensitizes cancer cells to TIL-mediated cytotoxicity. Smyd3 depletion induces an inflamed tumor microenvironment and may potentiate the immune-mediated antitumor efficacy of anti-PD-1 in syngeneic mouse models of HPV-negative HNSCC. This work may lay the biological rationale to combine SMYD3 inhibition with T-cell based immunotherapeutic approaches in HPV-negative HNSCC. Citation Format: Daniel E. Tsai, Yvette Robbins, Angel Huynh, Andrew Sinkoe, Cem Sievers, Madhavi Murali, Xiaolin Luo, Clint T. Allen, Vassiliki Saloura. Investigating the immunomodulatory mechanisms of Smyd3 depletion in HPV-negative head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6250.

APA, Harvard, Vancouver, ISO, and other styles

50

Garg, Bharti, Shweta Sharma, Sohini Khan, Edgar Esparza, Sarah Sass, Dawn Jacquish, Evangeline Mose, Herve Tiriac, and Andrew Lowy. "Abstract C044: MICAL2 expression in pancreatic cancer cells modulates the tumor microenvironment through the TGF beta pathway." Cancer Research 82, no. 22_Supplement (November 15, 2022): C044. http://dx.doi.org/10.1158/1538-7445.panca22-c044.

Full text

Abstract:

Abstract Introduction: Pancreatic cancer is characterized by a desmoplastic, fibroinflammatory stroma. The crosstalk between cancer cells and their surrounding tumor microenvironment (TME) promotes disease progression, metastasis, and chemoresistance. We identified MICAL2 as a super-enhancer associated gene in pancreatic cancer. MICAL2 (molecule interacting with Cas-L) proteins are Flavin monooxygenases that promotes actin depolymerization and indirectly regulate SRF transcription. In other work, we have found that MICAL2 promotes pancreatic cancer growth and progression. In this study, we evaluated how MICAL2 pancreatic cancer cell expression modulates the PDAC tumor microenvironment. Methods: RNA-Seq analysis performed on human pancreas cancer cells (AsPC) before and after MICAL2 knockdown revealed differential regulation of TGF-β and other proinflammatory cytokines. We validated the expression of TGF-β and other potent cytokines in multiple human and mouse pancreas cancer cell lines by q-PCR. We next exposed human and mouse pancreatic stellate cells (PSCs) to conditioned media from cancer cells before and after MICAL2 knockdown and checked the expression of TGF-β responsive genes by qPCR. KrasG12D/+; Trp53R172H/+; Pdx1-cre (KPC) cells with and without MICAL2 were orthotopically injected to assess the in vivo tumor growth and metastasis. We sorted epithelial cells and CAFs from KPC orthotopic tumors with and without MICAL2 by using EPCAM, PDGFR, and PDPN markers. Results: MICAL2 knockdown (KD) resulted in downregulation of TGF-β gene in both human and mouse pancreas cancer cell lines (50% reduction, p<0.05). Human hPSCs and mouse mPSCs co-cultured with pancreatic cancer cells showed a significant downregulation of myofibroblastic and inflammatory CAFs genes including a-SMA, fibronectin, IL1α and IL6 upon MICAL2 KD as compared to hPSCs and mPSCs co-cultured with shcontrol cells. Orthotopic injections of KPC MICAL2 KD cells led to decreased tumor growth as compared to shcontrol (0.26 gm vs. 1 gm, p = 0.008). Our Immunofluorescence revealed less collagen deposition and α-SMA expression and reduced secretion of IL6 by stromal cells in MICAL2 KD tumors. Flow sorting showed less percentage of epithelial and CAF population in MICAL2 KD orthotopic tumors as compared to Shcontrol tumors. A qPCR analysis of the sorted populations showed less expression of TGF-β on epithelial cells and reduced expression of IL6 on PDGFRα/PDPN+ CAFs extracted from MICAL2 KD tumors as compared to control tumors. Conclusion: These data reveal that MICAL2 expression mediates tumor-stromal crosstalk through TGF- β. Ongoing work is focused on dissecting the role of MICAL2 in priming the metastatic niche through remodeling of the TME. Citation Format: Bharti Garg, Shweta Sharma, Sohini Khan, Edgar Esparza, Sarah Sass, Dawn Jacquish, Evangeline Mose, Herve Tiriac, Andrew Lowy. MICAL2 expression in pancreatic cancer cells modulates the tumor microenvironment through the TGF beta pathway [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C044.

APA, Harvard, Vancouver, ISO, and other styles

Journal articles on the topic 'Andrew Mousley'

Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles