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18 results on '"Ruppert, Shannon M."'

1. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

Author

Larrayoz, Marta, Garcia-Barchino, Maria J., Celay, Jon, Etxebeste, Amaia, Jimenez, Maddalen, Perez, Cristina, Ordoñez, Raquel, Cobaleda, Cesar, Botta, Cirino, Fresquet, Vicente, Roa, Sergio, Goicoechea, Ibai, Maia, Catarina, Lasaga, Miren, Chesi, Marta, Bergsagel, P. Leif, Larrayoz, Maria J., Calasanz, Maria J., Campos-Sanchez, Elena, Martinez-Cano, Jorge, Panizo, Carlos, Rodriguez-Otero, Paula, Vicent, Silvestre, Roncador, Giovanna, Gonzalez, Patricia, Takahashi, Satoru, Katz, Samuel G., Walensky, Loren D., Ruppert, Shannon M., Lasater, Elisabeth A., Amann, Maria, Lozano, Teresa, Llopiz, Diana, Sarobe, Pablo, Lasarte, Juan J., Planell, Nuria, Gomez-Cabrero, David, Kudryashova, Olga, Kurilovich, Anna, Revuelta, Maria V., Cerchietti, Leandro, Agirre, Xabier, San Miguel, Jesus, Paiva, Bruno, Prosper, Felipe, and Martinez-Climent, Jose A.

Published
2023
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2. Phase I Study of Safety and Pharmacokinetics of RO7297089, an Anti-BCMA/CD16a Bispecific Antibody, in Patients with Relapsed, Refractory Multiple Myeloma

Author

Plesner, Torben, Harrison, Simon J., Quach, Hang, Lee, Cindy, Bryant, Adam, Vangsted, Annette, Estell, Jane, Delforge, Michel, Offner, Fritz, Twomey, Patrick, Choeurng, Voleak, Li, Junyi, Hendricks, Robert, Ruppert, Shannon M., Sumiyoshi, Teiko, Miller, Karen, Cho, Eunpi, and Schjesvold, Fredrik

Published
2023
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5. Case report: A persistently expanded T cell response in an exceptional responder to radiation and atezolizumab for metastatic non-small cell lung cancer

Author

Coffey, David G., primary, Xu, Yuexin, additional, Towlerton, Andrea M. H., additional, Kowanetz, Marcin, additional, Hegde, Priti, additional, Darwish, Martine, additional, Yadav, Mahesh, additional, Blanchette, Craig, additional, Ruppert, Shannon M., additional, Bertino, Sarah, additional, Xu, Qikai, additional, Ferretti, Andrew, additional, Weinheimer, Adam, additional, Hellmann, Matthew, additional, Qin, Angel, additional, Thomas, Dafydd, additional, Warren, Edus H., additional, and Ramnath, Nithya, additional

Published
2022
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6. OAB-033: Pre-clinical models of genetically heterogeneous multiple myeloma reveal mechanisms of immune escape and predict clinical immunotherapy outcomes

Author

Larrayoz, Marta, primary, Garcia-Barchino, Maria J., additional, Celay, Jon, additional, Etxebeste, Amaia, additional, Jimenez, Maddalen, additional, Perez, Cristina, additional, Ordoñez, Raquel, additional, Cobaleda, Cesar, additional, Chesi, Marta, additional, Bergsagel, Leif, additional, Rodríguez-Otero, Paula, additional, Takahashi, Satoru, additional, Katz, Samuel G., additional, Walensky, Loren D., additional, Ruppert, Shannon M., additional, Lasater, Elisabeth A., additional, Amann, Maria, additional, Lasarte, Juan J., additional, Kurilovich, Anna, additional, Cerchietti, Leandro, additional, Agirre, Xabier, additional, San-Miguel, Jesus, additional, Paiva, Bruno, additional, Prosper, Felipe, additional, and Martinez-Climent, Jose A., additional

Published
2022
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11. The Immune Response to Chronic Pseudomonas aeruginosa Wound Infection in Immunocompetent Mice

Author

Sweere, Johanna M., primary, Ishak, Heather, additional, Sunkari, Vivekananda, additional, Bach, Michelle S., additional, Manasherob, Robert, additional, Yadava, Koshika, additional, Ruppert, Shannon M., additional, Sen, Chandan K., additional, Balaji, Swathi, additional, Keswani, Sundeep G., additional, Secor, Patrick R., additional, and Bollyky, Paul L., additional

Published
2020
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12. 4-Methylumbelliferyl glucuronide contributes to hyaluronan synthesis inhibition

Author

Nagy, Nadine, primary, Gurevich, Irina, additional, Kuipers, Hedwich F., additional, Ruppert, Shannon M., additional, Marshall, Payton L., additional, Xie, Bryan J., additional, Sun, Wenchao, additional, Malkovskiy, Andrey V., additional, Rajadas, Jayakumar, additional, Grandoch, Maria, additional, Fischer, Jens W., additional, Frymoyer, Adam R., additional, Kaber, Gernot, additional, and Bollyky, Paul L., additional

Published
2019
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13. The Immune Response to Chronic Pseudomonas aeruginosaWound Infection in Immunocompetent Mice

Author

Sweere, Johanna M., Ishak, Heather, Sunkari, Vivekananda, Bach, Michelle S., Manasherob, Robert, Yadava, Koshika, Ruppert, Shannon M., Sen, Chandan K., Balaji, Swathi, Keswani, Sundeep G., Secor, Patrick R., and Bollyky, Paul L.

Abstract

Objective:Our goal was to develop a chronic wound model in mice that avoids implantation of foreign material or impaired immunity and to use this to characterize the local and systemic immune response associated with Pseudomonas aeruginosainfection.Approach:We generated bilateral full-thickness dermal wounds in healthy 10–12-week-old C57Bl6 mice. We waited 24 h to inoculate the developing wound eschar at these sites. We performed careful titration experiments with luminescent strains of P. aeruginosato identify bacterial inoculation concentrations that consistently established stable infections in these animals. We performed flow cytometry-based immunophenotyping of immune cell infiltrates at the wound site, spleen, and draining lymph nodes over time. Finally, we compared inflammatory responses seen in wound inoculation with planktonic bacteria, preformed biofilm, and heat-killed (HK) P. aeruginosa.Results:Using this delayed inoculation model and 7.5 ± 2.5 × 102CFU/mL of PAO1 we consistently established stable infections that lasted at 10 days in duration. During early infection, we detected a strong upregulation of inflammatory cytokines and neutrophil infiltration at the wound site, while natural killer (NK) cells and dendritic cells (DCs) were reduced. At the systemic level, only plasmacytoid DCs were increased early in infection. During later stages, there was systemic upregulation of B cells, T cells, and macrophages, whereas NK cells and interferon killer DCs were reduced. Infections with P. aeruginosabiofilms were not more virulent than infections with planktonic P. aeruginosa, whereas treatment with HK P. aeruginosaonly induces a short-term inflammatory state.Innovation:We describe a versatile wound model of chronic P. aeruginosainfection that lasts 10 days without causing sepsis or other excessive morbidity.Conclusion:This model may facilitate the study of chronic wound infections in immunocompetent mice. Our findings also highlight the induction of early innate immune cell populations during P. aeruginosainfection.

Published
2020
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17. 4-Methylumbelliferyl glucuronide contributes to hyaluronan synthesis inhibition.

Author

Nadine Nagy, Gurevich, Irina, Kuipers, Hedwich F., Ruppert, Shannon M., Marshall, Payton L., Xie, Bryan J., Wenchao Sun, Malkovskiy, Andrey V., Rajadas, Jayakumar, Grandoch, Maria, Fischer, Jens W., Frymoyer, Adam R., Kaber, Gernot, and Bollyky, Paul L.

Subjects
*HYALURONIC acid, *INHIBITION (Chemistry), *GLUCURONIDATION, *DRUG abuse, *PANCREAS, *BIOAVAILABILITY
Abstract

4-Methylumbelliferone (4-MU) inhibits hyaluronan (HA) synthesis and is an approved drug used for managing biliary spasm. However, rapid and efficient glucuronidation is thought to limit its utility for systemically inhibitingHAsynthesis. In particular,4-MU in mice has a short half-life, causing most of the drug to be present as the metabolite 4-methylumbelliferyl glucuronide (4-MUG), which makes it remarkable that 4-MU is effective at all. We report here that 4-MUG contributes to HA synthesis inhibition. We observed that oral administration of 4-MUG to mice inhibits HA synthesis, promotes FoxP3+ regulatory T-cell expansion, and prevents autoimmune diabetes. Mice fed either 4-MUG or 4-MU had equivalent4-MU:4-MUGratios in serum, liver, and pancreas, indicating that4-MUand4-MUGreachanequilibrium in these tissues. LC-tandem MS experiments revealed that 4-MUG is hydrolyzed to4-MUin serum, thereby greatly increasing the effective bioavailability of 4-MU. Moreover, using intravital 2-photon microscopy, wefound that4-MUG(a nonfluorescent molecule) undergoes conversion into4-MU(a fluorescent molecule)andthat4-MUis extensively tissue bound in the liver, fat, muscle, and pancreas of treated mice. 4-MUG also suppressed HA synthesis independently of its conversion into 4-MU and without depletion of the HA precursor UDP-glucuronic acid (GlcUA). Together, these results indicate that 4-MUG both directly and indirectly inhibitsHAsynthesis and that the effective bioavailability of 4-MU is higher than previously thought. These findings greatly alter the experimental and therapeutic possibilities for HA synthesis inhibition. [ABSTRACT FROM AUTHOR]

Published
2019
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18. Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma

Author

Marta Larrayoz, Maria J. Garcia-Barchino, Jon Celay, Amaia Etxebeste, Maddalen Jimenez, Cristina Perez, Raquel Ordoñez, Cesar Cobaleda, Cirino Botta, Vicente Fresquet, Sergio Roa, Ibai Goicoechea, Catarina Maia, Miren Lasaga, Marta Chesi, P. Leif Bergsagel, Maria J. Larrayoz, Maria J. Calasanz, Elena Campos-Sanchez, Jorge Martinez-Cano, Carlos Panizo, Paula Rodriguez-Otero, Silvestre Vicent, Giovanna Roncador, Patricia Gonzalez, Satoru Takahashi, Samuel G. Katz, Loren D. Walensky, Shannon M. Ruppert, Elisabeth A. Lasater, Maria Amann, Teresa Lozano, Diana Llopiz, Pablo Sarobe, Juan J. Lasarte, Nuria Planell, David Gomez-Cabrero, Olga Kudryashova, Anna Kurilovich, Maria V. Revuelta, Leandro Cerchietti, Xabier Agirre, Jesus San Miguel, Bruno Paiva, Felipe Prosper, Jose A. Martinez-Climent, Larrayoz, Marta, Garcia-Barchino, Maria J, Celay, Jon, Etxebeste, Amaia, Jimenez, Maddalen, Perez, Cristina, Ordoñez, Raquel, Cobaleda, Cesar, Botta, Cirino, Fresquet, Vicente, Roa, Sergio, Goicoechea, Ibai, Maia, Catarina, Lasaga, Miren, Chesi, Marta, Bergsagel, P Leif, Larrayoz, Maria J, Calasanz, Maria J, Campos-Sanchez, Elena, Martinez-Cano, Jorge, Panizo, Carlo, Rodriguez-Otero, Paula, Vicent, Silvestre, Roncador, Giovanna, Gonzalez, Patricia, Takahashi, Satoru, Katz, Samuel G, Walensky, Loren D, Ruppert, Shannon M, Lasater, Elisabeth A, Amann, Maria, Lozano, Teresa, Llopiz, Diana, Sarobe, Pablo, Lasarte, Juan J, Planell, Nuria, Gomez-Cabrero, David, Kudryashova, Olga, Kurilovich, Anna, Revuelta, Maria V, Cerchietti, Leandro, Agirre, Xabier, San Miguel, Jesu, Paiva, Bruno, Prosper, Felipe, and Martinez-Climent, Jose A

Subjects
multiple myeloma, mouse model, immune system, immunotherapy, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract

The historical lack of preclinical models reflecting the genetic heterogeneity of multiple myeloma (MM) hampers the advance of therapeutic discoveries. To circumvent this limitation, we screened mice engineered to carry eight MM lesions (NF-κB, KRAS, MYC, TP53, BCL2, cyclin D1, MMSET/NSD2 and c-MAF) combinatorially activated in B lymphocytes following T cell-driven immunization. Fifteen genetically diverse models developed bone marrow (BM) tumors fulfilling MM pathogenesis. Integrative analyses of ∼500 mice and ∼1,000 patients revealed a common MAPK–MYC genetic pathway that accelerated time to progression from precursor states across genetically heterogeneous MM. MYC-dependent time to progression conditioned immune evasion mechanisms that remodeled the BM microenvironment differently. Rapid MYC-driven progressors exhibited a high number of activated/exhausted CD8+ T cells with reduced immunosuppressive regulatory T (Treg) cells, while late MYC acquisition in slow progressors was associated with lower CD8+ T cell infiltration and more abundant Treg cells. Single-cell transcriptomics and functional assays defined a high ratio of CD8+ T cells versus Treg cells as a predictor of response to immune checkpoint blockade (ICB). In clinical series, high CD8+ T/Treg cell ratios underlie early progression in untreated smoldering MM, and correlated with early relapse in newly diagnosed patients with MM under Len/Dex therapy. In ICB-refractory MM models, increasing CD8+ T cell cytotoxicity or depleting Treg cells reversed immunotherapy resistance and yielded prolonged MM control. Our experimental models enable the correlation of MM genetic and immunological traits with preclinical therapy responses, which may inform the next-generation immunotherapy trials.

Published
2023

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