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1. Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

Author

Geva, Ravit, Vieito, Maria, Ramon, Jorge, Perets, Ruth, Pedregal, Manuel, Corral, Elena, Doger, Bernard, Calvo, Emiliano, Bardina, Jorge, Garralda, Elena, Brown, Regina J., Greger, James G., Wu, Shujian, Steinbach, Douglas, Yao, Tsun-Wen Sheena, Cao, Yu, Lauring, Josh, Chaudhary, Ruchi, Patel, Jaymala, Patel, Bharvin, and Moreno, Victor

Published
2024
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3. Clinical Benefit to an Aurora A Kinase Inhibitor in a Patient with Metastatic Integrase Interactor 1‐Deficient Carcinoma

Author

Karantanos, Theodoros, Rooper, Lisa, Kang, Youme, Lin, Cheng Ting, Wenga, Pawla, Sagorsky, Sarah, Lauring, Josh, and Kang, Hyunseok

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, Orphan Drug, Biotechnology, Human Genome, Rare Diseases, Breast Cancer, Adult, Aurora Kinase A, Carcinoma, Female, Humans, Neoplasm Metastasis, SMARCB1 Protein, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor. Next-generation-sequencing-based targeted cancer-related gene assay confirmed SMARCB1 loss and revealed other mutations in breast cancer 1 gene and checkpoint kinase 2 gene, which may have impacted her clinical course. After discussion at the molecular tumor board, she was offered alisertib, an aurora A kinase inhibitor, on a single-patient expanded-use program and achieved prolonged disease stabilization. Aurora A kinase inhibition may have an important role in the management of patients with INI-1-deficient tumors, warranting further evaluation in clinical studies. KEY POINTS: Loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene (SMARCB1), which encodes integrase interactor 1 (INI-1), is associated with various mesenchymal malignancies, but a few carcinomas with rhabdoid features have been recently described as a distinct entity.INI-1-deficient carcinoma can be very aggressive, and there is no known treatment option available.There are encouraging preliminary data with an enhancer of zeste homolog 2 inhibitor, tazematostat, in INI-1-deficient malignancies, including INI-1-deficient carcinomas.Loss of INI-1 can activate aurora A kinase (AurkA), and inhibition of AurkA by alisertib could be a viable option and warrants further investigation in this cancer.Clinical genomic profiling can confirm diagnosis of molecularly defined malignancy and provide insights on therapeutic options.

Published
2019

4. Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing

Author

Cushman-Vokoun, Allison, Lauring, Josh, Pfeifer, John, Olson, Damon R., Berry, Anna, Thorson, John, Voelkerding, Karl, Myles, Jonathan, Barbeau, James, Chandra, Pranil, Li, Marilyn, Vance, Gail H., Jensen, Brad W., Hansen, Molly Y., and Yohe, Sophia

Subjects
Cancer -- Genetic aspects -- Care and treatment, Genetic screening -- Methods, Health
Abstract

* Context.--Next-generation sequencing is a powerful clinical tool for cancer management but can produce incidental/secondary findings that require special consideration. Objective.--To discuss clinical and laboratory issues related to incidental or secondary germline findings in the clinical setting of tumor testing and inform future guidelines in this area. Design.--A College of American Pathologists workgroup including representation from the American Society of Clinical Oncology, the Association for Molecular Pathology, and the American College of Medical Genetics and Genomics created a review of items that should be considered when developing guidelines for incidental or secondary findings when performing clinical tumor testing. Results.--Testing recommendations should be cognizant of the differences among anticipated incidental, unanticipated incidental, and secondary findings, and whether normal tissue is also tested. In addition to defining which variants will be reported, robust recommendations must also take into account test design and validation, reimbursement, cost, infrastructure, impact on reflex testing, and maintenance of proficiency. Care providers need to consider the potential of a test to uncover incidental or secondary findings, the recommendation of upfront counseling, the need for consent, the timing of testing and counseling, and that the exact significance of a finding may not be clear. Conclusions.--As clinical oncology testing panels have become a mainstay of clinical cancer care, guidelines addressing the unique aspects of incidental and secondary findings in oncology testing are needed. This paper highlights clinical and laboratory considerations with regard to incidental/secondary findings and is a clarion call to create recommendations., Next-generation sequencing (NGS) has greatly improved upon traditional diagnostic molecular tests because of concurrent testing of many genes, resulting in improved efficiency and reduced costs. However, this expanded testing also [...]

Published
2022
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5. Personalized Medicine in the Oncology Clinic: Implementation and Outcomes of the Johns Hopkins Molecular Tumor Board

Author

Dalton, W Brian, Forde, Patrick M, Kang, Hyunseok, Connolly, Roisin M, Stearns, Vered, Gocke, Christopher D, Eshleman, James R, Axilbund, Jennifer, Petry, Dana, Geoghegan, Cindy, Wolff, Antonio C, Loeb, David M, Pratilas, Christine A, Meyer, Christian F, Christenson, Eric S, Slater, Shannon A, Ensminger, Jennifer, Parsons, Heather A, Park, Ben H, and Lauring, Josh

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Patient Safety, Clinical Research, Cancer, Brain Cancer, Brain Disorders, Genetics, Clinical Trials and Supportive Activities, Rare Diseases, Good Health and Well Being, Oncology and carcinogenesis
Abstract

Tumor genomic profiling for personalized oncology therapy is being widely applied in clinical practice even as it is being evaluated more formally in clinical trials. Given the complexities of genomic data and its application to clinical use, molecular tumor boards with diverse expertise can provide guidance to oncologists and patients seeking to implement personalized genetically targeted therapy in practice. A multidisciplinary molecular tumor board reviewed tumor molecular profiling reports from consecutive referrals at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins over a 3-year period. The tumor board weighed evidence for actionability of genomic alterations identified by molecular profiling and provided recommendations including US Food and Drug Administration-approved drug therapy, clinical trials of matched targeted therapy, off-label use of such therapy, and additional tumor or germline genetic testing. One hundred fifty-five patients were reviewed. Actionable genomic alterations were identified in 132 patients (85%). Off-label therapies were recommended in 37 patients (24%). Eleven patients were treated off-label, and 13 patients were enrolled onto clinical trials of matched targeted therapies. Median progression-free survival of patients treated with matched therapies was 5 months (95% CI, 2.9 months to not reached), and the progression-free survival probability at 6 months was 43%(95% CI, 26% to 71%). Lack of locally available clinical trials was the major limitation on clinical actionability of tumor profiling reports. The molecular tumor board recommended off-label targeted therapies for a quarter of all patients reviewed. Outcomes were heterogeneous, although 43% of patients receiving genomically matched therapy derived clinical benefit lasting at least 6 months. Until more data become available from precision oncology trials, molecular tumor boards can help guide appropriate use of tumor molecular testing to direct therapy.

Published
2017

6. Phosphoinositide 3-Kinase Regulates Glycolysis through Mobilization of Aldolase from the Actin Cytoskeleton

Author

Hu, Hai, Juvekar, Ashish, Lyssiotis, Costas A, Lien, Evan C, Albeck, John G, Oh, Doogie, Varma, Gopal, Hung, Yin Pun, Ullas, Soumya, Lauring, Josh, Seth, Pankaj, Lundquist, Mark R, Tolan, Dean R, Grant, Aaron K, Needleman, Daniel J, Asara, John M, Cantley, Lewis C, and Wulf, Gerburg M

Subjects
Underpinning research, 1.1 Normal biological development and functioning, Animals, Breast Neoplasms, Cell Line, Tumor, Cytoskeleton, Cytosol, Disease Models, Animal, Epithelial Cells, Fructose-Bisphosphate Aldolase, Glycolysis, Humans, Insulin, Mice, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Signal Transduction, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The phosphoinositide 3-kinase (PI3K) pathway regulates multiple steps in glucose metabolism and also cytoskeletal functions, such as cell movement and attachment. Here, we show that PI3K directly coordinates glycolysis with cytoskeletal dynamics in an AKT-independent manner. Growth factors or insulin stimulate the PI3K-dependent activation of Rac, leading to disruption of the actin cytoskeleton, release of filamentous actin-bound aldolase A, and an increase in aldolase activity. Consistently, PI3K inhibitors, but not AKT, SGK, or mTOR inhibitors, cause a significant decrease in glycolysis at the step catalyzed by aldolase, while activating PIK3CA mutations have the opposite effect. These results point toward a master regulatory function of PI3K that integrates an epithelial cell's metabolism and its form, shape, and function, coordinating glycolysis with the energy-intensive dynamics of actin remodeling.

Published
2016

7. Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation

Author

Dalton, W. Brian, Helmenstine, Eric, Walsh, Noel, Gondek, Lukasz P., Kelkar, Dhanashree S., Read, Abigail, Natrajan, Rachael, Christenson, Eric S., Roman, Barbara, Das, Samarjit, Zhao, Liang, Leone, Robert D., Shinn, Daniel, Groginski, Taylor, Madugundu, Anil K., Patil, Arun, Zabransky, Daniel J., Medford, Arielle, Lee, Justin, Cole, Alex J., Rosen, Marc, Thakar, Maya, Ambinder, Alexander, Donaldson, Joshua, DeZern, Amy E., Cravero, Karen, Chu, David, Madero-Marroquin, Rafael, Pandey, Akhilesh, Hurley, Paula J., Lauring, Josh, and Park, Ben Ho

Subjects
Thermo Fisher Scientific Inc., Metabolites -- Health aspects -- Physiological aspects -- Genetic aspects, Genes -- Health aspects -- Physiological aspects -- Genetic aspects, Cells (Biology) -- Health aspects -- Physiological aspects -- Genetic aspects, Enzymes -- Health aspects -- Physiological aspects -- Genetic aspects, Serine -- Health aspects -- Physiological aspects -- Genetic aspects, Messenger RNA -- Health aspects -- Physiological aspects -- Genetic aspects, Glycine -- Health aspects -- Physiological aspects, Scientific equipment industry -- Health aspects -- Physiological aspects -- Genetic aspects, Amino acids, Cancer, RNA, Health care industry, Gene Ontology. Gene Ontology Consortium, Johns Hopkins University. School of Medicine
Abstract

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of [SF3B1.sup.MUT] xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against [SF3B1.sup.MUT] cancers., Introduction Since their identification in 2011, mutations in spliceosome genes have been found in numerous human malignancies (1). Among the most broadly implicated genes is SF3B1, recurrently mutated in myelodysplastic [...]

Published
2019
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8. Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Advanced Solid Tumors

Author

Vieito, Maria, primary, Moreno, Victor, additional, Spreafico, Anna, additional, Brana, Irene, additional, Wang, Judy S., additional, Preis, Meir, additional, Hernandez-Guerrero, Tatiana, additional, Genta, Sofia, additional, Hansen, Aaron R., additional, Doger, Bernard, additional, Galvao, Vladimir, additional, Lenox, Laurie, additional, Brown, Regina J., additional, Kalota, Anna, additional, Mehta, Jaydeep, additional, Pastore, Friederike, additional, Patel, Bharvin, additional, Mistry, Pankaj, additional, Gu, Junchen, additional, Lauring, Josh, additional, and Patel, Manish R., additional

Published
2023
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9. Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes

Author

Janssen Research and Development, Haque, Tamanna, López-Cadenas, Félix, Xicoy, Blanca, Alfonso-Pierola, Ana, Platzbecker, Uwe, Avivi, Irit, Brunner, Andrew M., Chromik, Jöerg, Morillo, Daniel, Patel, Manish R., Falantes-González, José Francisco, Leitch, Heather A., Germing, Ulrich, Preis, Meir, Lenox, Laurie, Lauring, Josh, Brown, Regina J., Kalota, Anna, Mehta, Jaydeep, Pastore, Friederike, Gu, Junchen, Mistry, Pankaj, Valcárcel, David, Janssen Research and Development, Haque, Tamanna, López-Cadenas, Félix, Xicoy, Blanca, Alfonso-Pierola, Ana, Platzbecker, Uwe, Avivi, Irit, Brunner, Andrew M., Chromik, Jöerg, Morillo, Daniel, Patel, Manish R., Falantes-González, José Francisco, Leitch, Heather A., Germing, Ulrich, Preis, Meir, Lenox, Laurie, Lauring, Josh, Brown, Regina J., Kalota, Anna, Mehta, Jaydeep, Pastore, Friederike, Gu, Junchen, Mistry, Pankaj, and Valcárcel, David

Abstract

Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03–6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.

Published
2023

10. HER2 missense mutations have distinct effects on oncogenic signaling and migration

Author

Zabransky, Daniel J., Yankaskas, Christopher L., Cochran, Rory L., Wong, Hong Yuen, Croessmann, Sarah, Chu, David, Kavuri, Shyam M., Brewer, Monica Red, Rosen, D. Marc, Dalton, W. Brian, Cimino-Mathews, Ashley, Cravero, Karen, Button, Berry, Kyker-Snowman, Kelly, Cidado, Justin, Erlanger, Bracha, Parsons, Heather A., Manto, Kristen M., Bose, Ron, Lauring, Josh, Arteaga, Carlos L., Konstantopoulos, Konstantinos, and Park, Ben Ho

Published
2015

11. NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability

Author

Croessmann, Sarah, Wong, Hong Yuen, Zabransky, Daniel J., Chu, David, Mendonca, Janet, Sharma, Anup, Mohseni, Morassa, Rosen, D. Marc, Scharpf, Robert B., Cidado, Justin, Cochran, Rory L., Parsons, Heather A., Dalton, W. Brian, Erlanger, Bracha, Button, Berry, Cravero, Karen, Kyker-Snowman, Kelly, Beaver, Julia A., Kachhap, Sushant, Hurley, Paula J., Lauring, Josh, and Park, Ben Ho

Published
2015

13. Abstract ND07: JNJ-78306358: A first-in-class bispecific T cell redirecting HLA-G antibody

Author

Obermajer, Nataša, primary, Zwolak, Adam, additional, Van De Ven, Kelly, additional, Versmissen, Shana, additional, Brajic, Aleksandra, additional, Petley, Ted, additional, Weinstock, Dan, additional, Aligo, Jason, additional, Yi, Fang, additional, Jarantow, Stephen, additional, Schutsky, Keith, additional, Tian, Ken, additional, Lorraine, Angelilo, additional, Arias, Diana Alvarez, additional, Buyens, Kristel, additional, Torti, Vince, additional, Menard, Krista, additional, Rogers, Katharine, additional, Geist, Brian, additional, Van Heerden, Marjolein, additional, Chu, Gerald, additional, Verbist, Bie, additional, Ongenaert, Maté, additional, Hasler, Julien, additional, Packman, Kathryn, additional, Shenton, Jacintha, additional, Brehmer, Dirk, additional, Lauring, Josh, additional, Brown, Regina J., additional, Greger, James, additional, Ryan, Daphne Salick, additional, Singh, Sanjaya, additional, Lorenzi, Matthew V., additional, Lenox, Laurie, additional, and Laquerre, Sylvie, additional

Published
2022
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14. Mutation of a single allele of the cancer susceptibility gene BRCA1 leads to genomic instability in human breast epithelial cells

Author

Konishi, Hiroyuki, Mohseni, Morassa, Tamaki, Akina, Garay, Joseph P., Croessmann, Sarah, Karnan, Sivasundaram, Ota, Akinobu, Wong, Hong Yuen, Konishi, Yuko, Karakas, Bedri, Tahir, Khola, Abukhdeir, Abde M., Gustin, John P., Cidado, Justin, Wang, Grace M., Cosgrove, David, Cochran, Rory, Jelovac, Danijela, Higgins, Michaela J., Arena, Sabrina, Hawkins, Lauren, Lauring, Josh, Gross, Amy L., Heaphy, Christopher M., Hosokawa, Yositaka, Gabrielson, Edward, Meeker, Alan K., Visvanathan, Kala, Argani, Pedram, Bachman, Kurtis E., and Park, Ben Ho

Published
2011

15. Knockin of Mutant PIK3CA Activates Multiple Oncogenic Pathways

Author

Gustin, John P., Karakas, Bedri, Weiss, Michele B., Abukhdeir, Abde M., Lauring, Josh, Garay, Joseph P., Cosgrove, David, Tamaki, Akina, Konishi, Hiroyuki, Konishi, Yuko, Mohseni, Morassa, Wang, Grace, Rosen, D. Marc, Denmeade, Samuel R., Higgins, Michaela J., Vitolo, Michele I., Bachman, Kurtis E., Park, Ben Ho, and Vogelstein, Bert

Published
2009
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16. Tamoxifen-Stimulated Growth of Breast Cancer due to p21 Loss

Author

Abukhdeir, Abde M., Vitolo, Michele I., Argani, Pedram, De Marzo, Angelo M., Karakas, Bedri, Konishi, Hiroyuki, Gustin, John P., Lauring, Josh, Garay, Joseph P., Pendleton, Courtney, Konishi, Yuko, Blair, Brian G., Brenner, Keith, Garrett-Mayer, Elizabeth, Carraway, Hetty, Bachman, Kurtis E., and Park, Ben Ho

Published
2008
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18. Phase I Study of JNJ-74699157 in Patients with Advanced Solid Tumors Harboring the KRAS G12C Mutation

Author

Wang, Judy, primary, Martin-Romano, Patricia, additional, Cassier, Philippe, additional, Johnson, Melissa, additional, Haura, Eric, additional, Lenox, Laurie, additional, Guo, Yue, additional, Bandyopadhyay, Nibedita, additional, Russell, Michael, additional, Shearin, Elizabeth, additional, Lauring, Josh, additional, and Dahan, Laetitia, additional

Published
2022
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19. Phase 1 Study of JNJ-64619178, a Protein Arginine Methyltransferase 5 Inhibitor, in Patients with Lower-Risk Myelodysplastic Syndromes

Author

Haque, Tamanna, primary, Cadenas, Felix López, additional, Xicoy, Blanca, additional, Alfonso, Ana, additional, Platzbecker, Uwe, additional, Avivi, Irit, additional, Brunner, Andrew M., additional, Chromik, Jörg, additional, Morillo, Daniel, additional, Patel, Manish R., additional, Falantes, José F., additional, Leitch, Heather A., additional, Germing, Ulrich, additional, Preis, Meir, additional, Lavie, David, additional, Lenox, Laurie, additional, Lauring, Josh, additional, Kalota, Anna, additional, Brown, Regina, additional, Mehta, Jaydeep, additional, Pastore, Friederike, additional, Mistry, Pankaj, additional, and Valcarcel, David, additional

Published
2021
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21. Laboratory and Clinical Implications of Incidental and Secondary Germline Findings During Tumor Testing

Author

Cushman-Vokoun, Allison, primary, Lauring, Josh, additional, Pfeifer, John, additional, Olson, Damon R., additional, Berry, Anna, additional, Thorson, John, additional, Voelkerding, Karl, additional, Myles, Jonathan, additional, Barbeau, James, additional, Chandra, Pranil, additional, Li, Marilyn, additional, Vance, Gail H., additional, Jensen, Brad W., additional, Hansen, Molly Y., additional, and Yohe, Sophia, additional

Published
2021
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24. Abstract 1408: SF3B1 mutations induce proteome remodeling, metabolic reprogramming, and a novel kind of tumor surface antigen in human cells

Author

Dalton, William B., primary, Shinn, Daniel, additional, Walsh, Noel, additional, Christenson, Eric, additional, Groginski, Taylor, additional, Kelkar, Dhanashree, additional, Magugundu, Anil, additional, Patil, Arun, additional, Zabransky, Daniel, additional, Medford, Arielle, additional, Lee, Justin, additional, Cole, Alex, additional, Donaldson, Josh, additional, DeZern, Amy, additional, Cravero, Karen, additional, Chu, David, additional, Hunter, Natasha, additional, Pandey, Akhilesh, additional, Lauring, Josh, additional, and Park, Ben, additional

Published
2018
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26. Individualized Molecular Analyses Guide Efforts (IMAGE): A Prospective Study of Molecular Profiling of Tissue and Blood in Metastatic Triple-Negative Breast Cancer

Author

Parsons, Heather A., primary, Beaver, Julia A., additional, Cimino-Mathews, Ashley, additional, Ali, Siraj M., additional, Axilbund, Jennifer, additional, Chu, David, additional, Connolly, Roisin M., additional, Cochran, Rory L., additional, Croessmann, Sarah, additional, Clark, Travis A., additional, Gocke, Christopher D., additional, Jeter, Stacie C., additional, Kennedy, Mark R., additional, Lauring, Josh, additional, Lee, Justin, additional, Lipson, Doron, additional, Miller, Vincent A., additional, Otto, Geoff A., additional, Rosner, Gary L., additional, Ross, Jeffrey S., additional, Slater, Shannon, additional, Stephens, Philip J., additional, VanDenBerg, Dustin A., additional, Wolff, Antonio C., additional, Young, Lauren E., additional, Zabransky, Daniel J., additional, Zhang, Zhe, additional, Zorzi, Jane, additional, Stearns, Vered, additional, and Park, Ben H., additional

Published
2017
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27. ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients

Author

Chu, David, primary, Paoletti, Costanza, additional, Gersch, Christina, additional, VanDenBerg, Dustin A., additional, Zabransky, Daniel J., additional, Cochran, Rory L., additional, Wong, Hong Yuen, additional, Toro, Patricia Valda, additional, Cidado, Justin, additional, Croessmann, Sarah, additional, Erlanger, Bracha, additional, Cravero, Karen, additional, Kyker-Snowman, Kelly, additional, Button, Berry, additional, Parsons, Heather A., additional, Dalton, W. Brian, additional, Gillani, Riaz, additional, Medford, Arielle, additional, Aung, Kimberly, additional, Tokudome, Nahomi, additional, Chinnaiyan, Arul M., additional, Schott, Anne, additional, Robinson, Dan, additional, Jacks, Karen S., additional, Lauring, Josh, additional, Hurley, Paula J., additional, Hayes, Daniel F., additional, Rae, James M., additional, and Park, Ben Ho, additional

Published
2016
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28. Ki-67 is required for maintenance of cancer stem cells but not cell proliferation

Author

Cidado, Justin, primary, Wong, Hong Yuen, additional, Rosen, D. Marc, additional, Cimino-Mathews, Ashley, additional, Garay, Joseph P., additional, Fessler, Abigail G., additional, Rasheed, Zeshaan A., additional, Hicks, Jessica, additional, Cochran, Rory L., additional, Croessmann, Sarah, additional, Zabransky, Daniel J., additional, Mohseni, Morassa, additional, Beaver, Julia A., additional, Chu, David, additional, Cravero, Karen, additional, Christenson, Eric S., additional, Medford, Arielle, additional, Mattox, Austin, additional, De Marzo, Angelo M., additional, Argani, Pedram, additional, Chawla, Ajay, additional, Hurley, Paula J., additional, Lauring, Josh, additional, and Park, Ben Ho, additional

Published
2016
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29. TMSB4Yis a candidate tumor suppressor on the Y chromosome and is deleted in male breast cancer

Author

Wong, Hong Yuen, primary, Wang, Grace M., additional, Croessmann, Sarah, additional, Zabransky, Daniel J., additional, Chu, David, additional, Garay, Joseph P., additional, Cidado, Justin, additional, Cochran, Rory L., additional, Beaver, Julia A., additional, Aggarwal, Anita, additional, Liu, Min-Ling, additional, Argani, Pedram, additional, Meeker, Alan, additional, Hurley, Paula J., additional, Lauring, Josh, additional, and Park, Ben Ho, additional

Published
2015
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31. Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes

Author

Cochran, Rory L., primary, Cidado, Justin, additional, Kim, Minsoo, additional, Zabransky, Daniel J., additional, Croessmann, Sarah, additional, Chu, David, additional, Wong, Hong Yuen, additional, Beaver, Julia A., additional, Cravero, Karen, additional, Erlanger, Bracha, additional, Parsons, Heather, additional, Heaphy, Christopher M., additional, Meeker, Alan K., additional, Lauring, Josh, additional, and Park, Ben Ho, additional

Published
2015
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32. Multiple Cooperating Oncogenes Drive Recurrent Breast Cancer-Associated Chromosomal Amplifications: Creation of Isogenic Human Cell Line Models

Author

JOHNS HOPKINS UNIV BALTIMORE MD, Lauring, Josh, JOHNS HOPKINS UNIV BALTIMORE MD, and Lauring, Josh

Abstract

Human breast cancers, like other cancers, frequently harbor amplifications of chromosomal regions containing multiple genes. Many such multi-gene amplifications are recurrent across many individual instances of breast cancer, suggesting they contain oncogenes critical for breast cancer development or progression. In some cases, traditional laboratory methods have identified more than one candidate driver oncogene within usuch amplified regions. This research proposal is designed to test the hypothesis that some recurrent amplicons actually function through the concerted action of multiple simultaneously overexpressed oncogenes. We are testing this hypothesis by attempting to create cell line models of such multigene amplifications, prospectively. We have designed an experimental strategy to target a dominantly selectable IMPDH gene to specific chromosomal regions using gene targeting technology. Targeted cells will then be selected in increasing concentrations of the IMPDH inhibitors mycophenolic acid and mizoribine to provide selective pressure for the targeted cells to amplify the targeted region, co-amplifying multiple genes simultaneously. Here we report the design of a functional, efficient gene targeting vector and the successful delivery of the IMPDH selection marker to two different chromosomal loci, ZNF703 and ERBB2, in two different human breast cancer cell lines, MCF-7, and T47D. In MCF-7, we have succeeded in creating subclones with focal, overlapping amplification of regions of chromosome 8p11-12, where ZNF703 is located. We demonstrate amplification by array CGH, digital PCR, and fluorescent in situ hybridization. Amplification is shown to cause coordinate overexpression of co-amplified genes at the mRNA and protein level., The original document contains color images.

Published
2014

33. Detection of Cancer DNA in Plasma of Patients with Early-Stage Breast Cancer

Author

Beaver, Julia A., primary, Jelovac, Danijela, additional, Balukrishna, Sasidharan, additional, Cochran, Rory L., additional, Croessmann, Sarah, additional, Zabransky, Daniel J., additional, Wong, Hong Yuen, additional, Valda Toro, Patricia, additional, Cidado, Justin, additional, Blair, Brian G., additional, Chu, David, additional, Burns, Timothy, additional, Higgins, Michaela J., additional, Stearns, Vered, additional, Jacobs, Lisa, additional, Habibi, Mehran, additional, Lange, Julie, additional, Hurley, Paula J., additional, Lauring, Josh, additional, VanDenBerg, Dustin A., additional, Kessler, Jill, additional, Jeter, Stacie, additional, Samuels, Michael L., additional, Maar, Dianna, additional, Cope, Leslie, additional, Cimino-Mathews, Ashley, additional, Argani, Pedram, additional, Wolff, Antonio C., additional, and Park, Ben Ho, additional

Published
2014
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34. Multiple Cooperating Oncogenes Drive Recurrent Breast Cancer-Associated Chromosomal Amplifications: Creation of Isogenic Human Cell Line Models

Author

JOHNS HOPKINS UNIV BALTIMORE MD, Lauring, Josh, JOHNS HOPKINS UNIV BALTIMORE MD, and Lauring, Josh

Abstract

Targeted therapy for cancer is based upon the notion that tumors have characteristics that are quantitatively or qualitatively different from normal tissues, or that tumor cells are uniquely dependent, or addicted , to certain of these characteristic differences. Genetic changes including somatic mutation, gene amplification, and chromosomal translocation often serve as irreversible drivers of tumor growth and survival making them attractive targets for therapy. The amplification of ERBB2/Her-2 on chromosome 17q12 in 15% of breast cancers led to the identification of Her-2 as a driver oncogene and successful target for therapy. Other chromosomal regions are recurrently amplified in breast cancer almost as frequently as 17q12: these include 8p11-12 and 11q13. Amplification of 8p11-12 has been shown to confer a high risk of metastasis after primary breast cancer surgery and adjuvant therapy, and it is therefore critical to identify the oncogene(s) driving this aggressive behavior., The original document contains color images.

Published
2013

36. Single Copies of Mutant KRAS and Mutant PIK3CA Cooperate in Immortalized Human Epithelial Cells to Induce Tumor Formation

Author

Wang, Grace M., primary, Wong, Hong Yuen, additional, Konishi, Hiroyuki, additional, Blair, Brian G., additional, Abukhdeir, Abde M., additional, Gustin, John P., additional, Rosen, D. Marc, additional, Denmeade, Samuel Ray, additional, Rasheed, Zeshaan, additional, Matsui, William, additional, Garay, Joseph P., additional, Mohseni, Morassa, additional, Higgins, Michaela J., additional, Cidado, Justin, additional, Jelovac, Danijela, additional, Croessmann, Sarah, additional, Cochran, Rory L., additional, Karnan, Sivasundaram, additional, Konishi, Yuko, additional, Ota, Akinobu, additional, Hosokawa, Yoshitaka, additional, Argani, Pedram, additional, Lauring, Josh, additional, and Park, Ben Ho, additional

Published
2013
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38. The growth response to androgen receptor signaling in ERα-negative human breast cells is dependent on p21 and mediated by MAPK activation

Author

Garay, Joseph P, primary, Karakas, Bedri, additional, Abukhdeir, Abde M, additional, Cosgrove, David P, additional, Gustin, John P, additional, Higgins, Michaela J, additional, Konishi, Hiroyuki, additional, Konishi, Yuko, additional, Lauring, Josh, additional, Mohseni, Morassa, additional, Wang, Grace M, additional, Jelovac, Danijela, additional, Weeraratna, Ashani, additional, Sherman Baust, Cheryl A, additional, Morin, Patrice J, additional, Toubaji, Antoun, additional, Meeker, Alan, additional, De Marzo, Angelo M, additional, Lewis, Gloria, additional, Subhawong, Andrea, additional, Argani, Pedram, additional, and Park, Ben H, additional

Published
2012
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40. PIK3CAmutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells

Author

Higgins, Michaela J., primary, Beaver, Julia A., additional, Wong, Hong Yuen, additional, Gustin, John P., additional, Lauring, Josh D., additional, Garay, Joseph P., additional, Konishi, Hiroyuki, additional, Mohseni, Morassa, additional, Wang, Grace M., additional, Cidado, Justin, additional, Jelovac, Danijela, additional, Cosgrove, David P., additional, Tamaki, Akina, additional, Abukhdeir, Abde M., additional, and Park, Ben Ho, additional

Published
2011
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48. The multiple myeloma–associated MMSETgene contributes to cellular adhesion, clonogenic growth, and tumorigenicity

Author

Lauring, Josh, Abukhdeir, Abde M., Konishi, Hiroyuki, Garay, Joseph P., Gustin, John P., Wang, Qiuju, Arceci, Robert J., Matsui, William, and Park, Ben Ho

Abstract

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by recurrent chromosomal translocations. Patients with t(4;14)(p16;q32) are the worst prognostic subgroup in MM, although the basis for this poor prognosis is unknown. The t(4;14) is unusual in that it involves 2 potential target genes: fibroblast growth factor receptor 3 (FGFR3) and multiple myeloma SET domain (MMSET). MMSET is universally overexpressed in t(4;14) MM, whereas FGFR3 expression is lost in one-third of cases. Nonetheless, the role of MMSET in t(4;14) MM has remained unclear. Here we demonstrate a role for MMSET in t(4;14) MM cells. Down-regulation of MMSET expression in MM cell lines by RNA interference and by selective disruption of the translocated MMSETallele using gene targeting dramatically reduced colony formation in methylcellulose but had only modest effects in liquid culture. In addition, MMSET knockdown led to cell-cycle arrest of adherent MM cells and reduced the ability of MM cells to adhere to extracellular matrix. Finally, MMSET knockdown and knockout reduced tumor formation by MM xenografts. These results provide the first direct evidence that MMSET plays a significant role in t(4;14) MM and suggest that therapies targeting this gene could impact this particular subset of poor-prognosis patients.

Published
2008
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49. Distinct Factors Regulate the MurineRAG-2Promoter in B- and T-Cell Lines

Author

Lauring, Josh and Schlissel, Mark S.

Abstract

ABSTRACTThe recombination activating genes RAG-1andRAG-2are expressed in a lymphoid-cell-specific and developmentally regulated fashion. To understand the transcriptional basis for this regulation, we have cloned and characterized the murineRAG-2promoter. The promoter was lymphoid cell specific, showing activity in various B- and T-cell lines but little activity in nonlymphoid cells. To our surprise, however, the promoter was regulated differently in B and T cells. Using nuclear extracts from B-cell lines, we found that the B-cell-specific transcription factor BSAP (Pax-5) could bind to a conserved sequence critical for promoter activity. BSAP activated the promoter in transfected cells, and the BSAP site was occupied in a tissue-specific manner in vivo. An overlapping DNA sequence binding to a distinct factor was necessary for promoter activity in T cells. Full promoter activity in T cells was also dependent on a more distal DNA sequence whose disruption had no effect on B-cell activity. The unexpected finding that a B-cell-specific factor regulates the RAG-2promoter may explain some of the recently observed differences in the regulation of RAGtranscription between B and T cells.

Published
1999
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50. Distinct Factors Regulate the Murine RAG-2Promoter in B- and T-Cell Lines

Author

Lauring, Josh and Schlissel, Mark S.

Abstract

The recombination activating genes RAG-1and RAG-2are expressed in a lymphoid-cell-specific and developmentally regulated fashion. To understand the transcriptional basis for this regulation, we have cloned and characterized the murine RAG-2promoter. The promoter was lymphoid cell specific, showing activity in various B- and T-cell lines but little activity in nonlymphoid cells. To our surprise, however, the promoter was regulated differently in B and T cells. Using nuclear extracts from B-cell lines, we found that the B-cell-specific transcription factor BSAP (Pax-5) could bind to a conserved sequence critical for promoter activity. BSAP activated the promoter in transfected cells, and the BSAP site was occupied in a tissue-specific manner in vivo. An overlapping DNA sequence binding to a distinct factor was necessary for promoter activity in T cells. Full promoter activity in T cells was also dependent on a more distal DNA sequence whose disruption had no effect on B-cell activity. The unexpected finding that a B-cell-specific factor regulates the RAG-2promoter may explain some of the recently observed differences in the regulation of RAGtranscription between B and T cells.

Published
1999
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