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2. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Author

Kennedy, Alyssa L, Myers, Kasiani C, Bowman, James, Gibson, Christopher J, Camarda, Nicholas D, Furutani, Elissa, Muscato, Gwen M, Klein, Robert H, Ballotti, Kaitlyn, Liu, Shanshan, Harris, Chad E, Galvin, Ashley, Malsch, Maggie, Dale, David, Gansner, John M, Nakano, Taizo A, Bertuch, Alison, Vlachos, Adrianna, Lipton, Jeffrey M, Castillo, Paul, Connelly, James, Churpek, Jane, Edwards, John R, Hijiya, Nobuko, Ho, Richard H, Hofmann, Inga, Huang, James N, Keel, Siobán, Lamble, Adam, Lau, Bonnie W, Norkin, Maxim, Stieglitz, Elliot, Stock, Wendy, Walkovich, Kelly, Boettcher, Steffen, Brendel, Christian, Fleming, Mark D, Davies, Stella M, Weller, Edie A, Bahl, Christopher, Carter, Scott L, Shimamura, Akiko, and Lindsley, R Coleman

Subjects
Ribosomes, Humans, Bone Marrow Diseases, Eukaryotic Initiation Factors, Mutation, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Female, Male, Tumor Suppressor Protein p53, Young Adult, Shwachman-Diamond Syndrome, Clonal Hematopoiesis, Preschool
Abstract

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Published
2021

3. Mineralocorticoid Receptor in Endothelial Cells Contributes to Vascular Endothelial Growth Factor Receptor Inhibitor-Induced Vascular and Kidney Damage.

Author

Camarda, Nicholas D, Lu, Qing, Tesfu, Angelina F, Liu, Rui R, Ibarrola, Jaime, and Jaffe, Iris Z

Subjects
VASCULAR endothelial growth factor receptors, VASCULAR endothelial growth factor antagonists, VASCULAR endothelial cells, MINERALOCORTICOID receptors, CELL receptors, SORAFENIB
Abstract

BACKGROUND Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer patient survival by inhibiting tumor angiogenesis. However, VEGFRis induce treatment-limiting hypertension which has been associated with impaired vascular endothelial cell (EC) function and kidney damage. The mineralocorticoid receptor (MR) regulates blood pressure (BP) via its effects on the vasculature and the kidney. Thus, we interrogated the role of the MR in EC dysfunction, renal impairment, and hypertension in a mouse model of VEGFRi-induced hypertension using sorafenib. METHODS EC dysfunction in mesenteric arterioles was assessed by immunoblotting for phosphorylation of endothelial nitric oxide synthase (eNOS) at serine 1177. Renal damage was measured by assessing glomerular endotheliosis histologically. BP was measured using implanted radiotelemetry. RESULTS Six days of sorafenib treatment significantly impaired mesenteric resistance vessel EC function, induced renal damage, and increased BP. Pharmacologic MR blockade with spironolactone prevented the sorafenib-induced decline in eNOS phosphorylation and renal glomerular endotheliosis, without affecting systolic BP (SBP) or diastolic BP. Mice with the MR knocked out specifically in ECs (EC-MR-KO) were protected from sorafenib-induced EC dysfunction and glomerular endotheliosis, whereas smooth muscle cell-specific MR (SMC-MR) knockout mice were not. Neither EC-MR nor SMC-MR knockout affected the degree to which sorafenib increased SBP or diastolic BP. CONCLUSIONS These results reveal that the MR, specifically in EC but not in SMCs, is necessary for VEGFRi-induced renal and vascular injury. While ineffective at lowering SBP, these data suggest potential therapeutic benefits of MR antagonists, like spironolactone, to protect the vasculature and the kidneys from VEGFRi-induced injury. [ABSTRACT FROM AUTHOR]

Published
2025
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4. Detection of Mutations in Barrett’s Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma

Author

Stachler, Matthew D, Camarda, Nicholas D, Deitrick, Christopher, Kim, Anthony, Agoston, Agoston T, Odze, Robert D, Hornick, Jason L, Nag, Anwesha, Thorner, Aaron R, Ducar, Matthew, Noffsinger, Amy, Lash, Richard H, Redston, Mark, Carter, Scott L, Davison, Jon M, and Bass, Adam J

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Human Genome, Rare Diseases, Prevention, Clinical Research, Digestive Diseases, Genetics, Cancer, Good Health and Well Being, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Barrett Esophagus, Biopsy, Case-Control Studies, Disease Progression, Esophageal Neoplasms, Esophagoscopy, Female, Humans, Male, Middle Aged, Mutation, Precancerous Conditions, Prognosis, Retrospective Studies, Tumor Suppressor Protein p53, Esophageal Cancer, Preneoplastic, Esophagus, Neurosciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology, Clinical sciences, Nutrition and dietetics
Abstract

Background & aimsBarrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress.MethodsWe performed a retrospective case-control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non-progressors.ResultsTP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy).ConclusionsIn genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number.

Published
2018

6. Genomic characterization of human brain metastases identifies drivers of metastatic lung adenocarcinoma

Author

Shih, David J. H., Nayyar, Naema, Bihun, Ivanna, Dagogo-Jack, Ibiayi, Gill, Corey M., Aquilanti, Elisa, Bertalan, Mia, Kaplan, Alexander, D’Andrea, Megan R., Chukwueke, Ugonma, Ippen, Franziska Maria, Alvarez-Breckenridge, Christopher, Camarda, Nicholas D., Lastrapes, Matthew, McCabe, Devin, Kuter, Ben, Kaufman, Benjamin, Strickland, Matthew R., Martinez-Gutierrez, Juan Carlos, Nagabhushan, Deepika, De Sauvage, Magali, White, Michael D., Castro, Brandyn A., Hoang, Kaitlin, Kaneb, Andrew, Batchelor, Emily D., Paek, Sun Ha, Park, Sun Hye, Martinez-Lage, Maria, Berghoff, Anna S., Merrill, Parker, Gerstner, Elizabeth R., Batchelor, Tracy T., Frosch, Matthew P., Frazier, Ryan P., Borger, Darrell R., Iafrate, A. John, Johnson, Bruce E., Santagata, Sandro, Preusser, Matthias, Cahill, Daniel P., Carter, Scott L., and Brastianos, Priscilla K.

Published
2020
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7. Identifying mitigating strategies for endothelial cell dysfunction and hypertension in response to VEGF receptor inhibitors.

Author

Camarda, Nicholas D., Qing Lu, Meola, Dawn M., Man, Joshua J., Zeyuan Song, Travers, Richard J., Lopez, Katherine E., Powers, Sarah N., Papanastasiou, Malvina, DeRuff, Katherine C., Mullahoo, James, Egri, Shawn B., Davison, Desiree, Sebastiani, Paola, Eblen, Scott T., Buchsbaum, Rachel, Huggins, Gordon S., London, Cheryl A., Jaffe, Jacob D., and Upshaw, Jenica N.

Subjects
*VASCULAR endothelial growth factor receptors, *VASCULAR endothelial growth factor antagonists, *SYSTOLIC blood pressure, *LISINOPRIL, *ENDOTHELIUM diseases
Abstract

Vascular endothelial growth factor receptor inhibitors (VEGFRis) improve cancer survival but are associated with treatment-limiting hypertension, often attributed to endothelial cell (EC) dysfunction. Using phosphoproteomic profiling of VEGFRi-treated ECs, drugs were screened for mitigators of VEGFRi-induced EC dysfunction and validated in primary aortic ECs, mice, and canine cancer patients. VEGFRi treatment significantly raised systolic blood pressure (SBP) and increased markers of endothelial and renal dysfunction in mice and canine cancer patients. a-Adrenergic-antagonists were identified as drugs that most oppose the VEGFRi proteomic signature. Doxazosin, one such a-antagonist, prevented EC dysfunction in murine, canine, and human aortic ECs. In mice with sorafenib-induced-hypertension, doxazosin mitigated EC dysfunction but not hypertension or glomerular endotheliosis, while lisinopril mitigated hypertension and glomerular endotheliosis without impacting EC function. Hence, reversing EC dysfunction was insufficient to mitigate VEGFRi-induced-hypertension in this mouse model. Canine cancer patients with VEGFRi-induced-hypertension were randomized to doxazosin or lisinopril and both agents significantly decreased SBP. The canine clinical trial supports safety and efficacy of doxazosin and lisinopril as antihypertensives for VEGFRi-induced-hypertension and the potential of trials in canines with spontaneous cancer to accelerate translation. The overall findings demonstrate the utility of phosphoproteomics to identify EC-protective agents to mitigate cardio-oncology side effects. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Data from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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10. MAF file for CNVs from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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11. Supplementary Table S3 from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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12. Supplementary Experimental Methods from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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13. MAF file for mutations from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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14. Supplementary Figures from Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., primary, Camarda, Nicholas D., primary, Moffitt, Richard A., primary, Ghazani, Arezou A., primary, Hazar-Rethinam, Mehlika, primary, Raghavan, Srivatsan, primary, Kim, Jaegil, primary, Brais, Lauren K., primary, Ragon, Dorisanne, primary, Welch, Marisa W., primary, Reilly, Emma, primary, McCabe, Devin, primary, Marini, Lori, primary, Anderka, Kristin, primary, Helvie, Karla, primary, Oliver, Nelly, primary, Babic, Ana, primary, Da Silva, Annacarolina, primary, Nadres, Brandon, primary, Van Seventer, Emily E., primary, Shahzade, Heather A., primary, St. Pierre, Joseph P., primary, Burke, Kelly P., primary, Clancy, Thomas, primary, Cleary, James M., primary, Doyle, Leona A., primary, Jajoo, Kunal, primary, McCleary, Nadine J., primary, Meyerhardt, Jeffrey A., primary, Murphy, Janet E., primary, Ng, Kimmie, primary, Patel, Anuj K., primary, Perez, Kimberly, primary, Rosenthal, Michael H., primary, Rubinson, Douglas A., primary, Ryou, Marvin, primary, Shapiro, Geoffrey I., primary, Sicinska, Ewa, primary, Silverman, Stuart G., primary, Nagy, Rebecca J., primary, Lanman, Richard B., primary, Knoerzer, Deborah, primary, Welsch, Dean J., primary, Yurgelun, Matthew B., primary, Fuchs, Charles S., primary, Garraway, Levi A., primary, Getz, Gad, primary, Hornick, Jason L., primary, Johnson, Bruce E., primary, Kulke, Matthew H., primary, Mayer, Robert J., primary, Miller, Jeffrey W., primary, Shyn, Paul B., primary, Tuveson, David A., primary, Wagle, Nikhil, primary, Yeh, Jen Jen, primary, Hahn, William C., primary, Corcoran, Ryan B., primary, Carter, Scott L., primary, and Wolpin, Brian M., primary

Published
2023
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15. Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia

Author

Biwer, Lauren A., primary, Lu, Qing, additional, Ibarrola, Jaime, additional, Stepanian, Alec, additional, Man, Joshua J., additional, Carvajal, Brigett V., additional, Camarda, Nicholas D., additional, Zsengeller, Zsuzsanna, additional, Skurnik, Geraldine, additional, Seely, Ellen W., additional, Karumanchi, S. Ananth, additional, and Jaffe, Iris Z., additional

Published
2023
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16. Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

Author

Kennedy, Alyssa L; https://orcid.org/0000-0001-7948-5933, Myers, Kasiani C; https://orcid.org/0000-0002-5528-4405, Bowman, James, Gibson, Christopher J, Camarda, Nicholas D; https://orcid.org/0000-0002-1853-0056, Furutani, Elissa, et al, Boettcher, Steffen; https://orcid.org/0000-0001-9937-0957, Kennedy, Alyssa L; https://orcid.org/0000-0001-7948-5933, Myers, Kasiani C; https://orcid.org/0000-0002-5528-4405, Bowman, James, Gibson, Christopher J, Camarda, Nicholas D; https://orcid.org/0000-0002-1853-0056, Furutani, Elissa, et al, and Boettcher, Steffen; https://orcid.org/0000-0001-9937-0957

Abstract

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

Published
2021

17. Distinct genetic pathways define pre-leukemic and compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

Author

Kennedy, Alyssa L., primary, Myers, Kasiani C., additional, Bowman, James, additional, Gibson, Christopher J., additional, Camarda, Nicholas D., additional, Furutani, Elissa, additional, Muscato, Gwen M., additional, Klein, Robert H., additional, Ballotti, Kaitlyn, additional, Liu, Shanshan, additional, Harris, Chad E., additional, Galvin, Ashley, additional, Malsch, Maggie, additional, Dale, David, additional, Gansner, John M., additional, Nakano, Taizo A., additional, Bertuch, Alison, additional, Vlachos, Adrianna, additional, Lipton, Jeffrey M., additional, Castillo, Paul, additional, Connelly, James, additional, Churpek, Jane, additional, Edward, John R., additional, Hijiya, Nobuko, additional, Ho, Richard H., additional, Hofmann, Inga, additional, Huang, James N., additional, Keel, Siobán, additional, Lamble, Adam, additional, Lau, Bonnie W., additional, Norkin, Maxim, additional, Stieglitz, Elliot, additional, Stock, Wendy, additional, Walkovich, Kelly, additional, Boettcher, Steffen, additional, Brendel, Christian, additional, Fleming, Mark D., additional, Davies, Stella M., additional, Weller, Edie A., additional, Bahl, Christopher, additional, Carter, Scott L., additional, Shimamura, Akiko, additional, and Lindsley, R. Coleman, additional

Published
2020
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19. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine

Author

Aguirre, Andrew J., primary, Nowak, Jonathan A., additional, Camarda, Nicholas D., additional, Moffitt, Richard A., additional, Ghazani, Arezou A., additional, Hazar-Rethinam, Mehlika, additional, Raghavan, Srivatsan, additional, Kim, Jaegil, additional, Brais, Lauren K., additional, Ragon, Dorisanne, additional, Welch, Marisa W., additional, Reilly, Emma, additional, McCabe, Devin, additional, Marini, Lori, additional, Anderka, Kristin, additional, Helvie, Karla, additional, Oliver, Nelly, additional, Babic, Ana, additional, Da Silva, Annacarolina, additional, Nadres, Brandon, additional, Van Seventer, Emily E., additional, Shahzade, Heather A., additional, St. Pierre, Joseph P., additional, Burke, Kelly P., additional, Clancy, Thomas, additional, Cleary, James M., additional, Doyle, Leona A., additional, Jajoo, Kunal, additional, McCleary, Nadine J., additional, Meyerhardt, Jeffrey A., additional, Murphy, Janet E., additional, Ng, Kimmie, additional, Patel, Anuj K., additional, Perez, Kimberly, additional, Rosenthal, Michael H., additional, Rubinson, Douglas A., additional, Ryou, Marvin, additional, Shapiro, Geoffrey I., additional, Sicinska, Ewa, additional, Silverman, Stuart G., additional, Nagy, Rebecca J., additional, Lanman, Richard B., additional, Knoerzer, Deborah, additional, Welsch, Dean J., additional, Yurgelun, Matthew B., additional, Fuchs, Charles S., additional, Garraway, Levi A., additional, Getz, Gad, additional, Hornick, Jason L., additional, Johnson, Bruce E., additional, Kulke, Matthew H., additional, Mayer, Robert J., additional, Miller, Jeffrey W., additional, Shyn, Paul B., additional, Tuveson, David A., additional, Wagle, Nikhil, additional, Yeh, Jen Jen, additional, Hahn, William C., additional, Corcoran, Ryan B., additional, Carter, Scott L., additional, and Wolpin, Brian M., additional

Published
2018
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21. ACKR3 Proximity Labeling Identifies Novel G protein- and β-arrestin-independent GPCR Interacting Proteins.

Author

Hicks C, Gardner J, Eiger DS, Camarda ND, Pham U, Dhar S, Rodriguez H, Chundi A, and Rajagopal S

Abstract

The canonical paradigm of GPCR signaling recognizes G proteins and β-arrestins as the two primary transducers that promote GPCR signaling. Recent evidence suggests the atypical chemokine receptor 3 (ACKR3) does not couple to G proteins, and β-arrestins are dispensable for some of its functions. Here, we employed proximity labeling to identify proteins that interact with ACKR3 in cells devoid of β-arrestin. We identified proteins involved in the endocytic machinery and evaluated a subset of proteins conserved across several GPCR-based proximity labeling experiments. We discovered that the bone morphogenic protein 2-inducible kinase (BMP2K) interacts with many different GPCRs with varying dependency on β-arrestin. Together, our work highlights the existence of modulators that can act independently of G proteins and β-arrestins to regulate GPCR signaling and provides important evidence for other targets that may regulate GPCR signaling., Competing Interests: DISCLOSURES None.

Published
2024
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22. PREDICTING SIGNIFICANCE OF UNKNOWN VARIANTS IN GLIAL TUMORS THROUGH SUB-CLASS ENRICHMENT.

Author

Fichtenholtz AM, Camarda ND, and Neumann EK

Subjects
Astrocytoma classification, Astrocytoma genetics, Biomarkers, Tumor genetics, DNA, Neoplasm genetics, Databases, Genetic statistics & numerical data, Genetic Variation, Glioblastoma classification, Glioblastoma genetics, Humans, Models, Genetic, Models, Statistical, Mutation, Oligodendroglioma classification, Oligodendroglioma genetics, Polymorphism, Single Nucleotide, Brain Neoplasms classification, Brain Neoplasms genetics, Computational Biology methods, Glioma classification, Glioma genetics
Abstract

Glial tumors have been heavily studied and sequenced, leading to scores of findings about altered genes. This explosion in knowledge has not been matched with clinical success, but efforts to understand the synergies between drivers of glial tumors may alleviate the situation. We present a novel molecular classification system that captures the combinatorial nature of relationships between alterations in these diseases. We use this classification to mine for enrichment of variants of unknown significance, and demonstrate a method for segregating unknown variants with functional importance from passengers and SNPs.

Published
2016

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