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1. The United States Department of Energy and National Institutes of Health Collaboration: Medical Care Advances via Discovery in Physical Sciences.

Author

Keppel, Cynthia, Weisenberger, Andrew, Atanasijevic, Tatjana, Wang, Shumin, Zubal, George, Buchsbaum, Jeffrey, Brechbiel, Martin, Capala, Jacek, Escorcia, Freddy, Obcemea, Ceferino, Boehnlein, Amber, Heyes, Graham, Bourne, Philip, Colby, Eric, El Fakhri, Georges, Gillo, Jehanne, Gropler, Robert, Gueye, Paul, Tourassi, Georgia, Peggs, Steve, Woody, Craig, and Cherry, Simon

Subjects
Department of Energy, National Institutes of Health, inter-agency collaboration, United States, Artificial Intelligence, National Institutes of Health (U.S.), Biomedical Research, Natural Science Disciplines, Laboratories
Abstract

Over several months, representatives from the U.S. Department of Energy (DOE) Office of Science and National Institutes of Health (NIH) had a number of meetings that lead to the conclusion that innovations in the Nations health care could be realized by more directed interactions between NIH and DOE. It became clear that the expertise amassed and instrumentation advances developed at the DOE physical science laboratories to enable cutting-edge research in particle physics could also feed innovation in medical healthcare. To meet their scientific mission, the DOE laboratories created advances in such technologies as particle beam generation, radioisotope production, high-energy particle detection and imaging, superconducting particle accelerators, superconducting magnets, cryogenics, high-speed electronics, artificial intelligence, and big data. To move forward, NIH and DOE initiated the process of convening a joint workshop which occurred on July 12th and 13th, 2021. This Special Report presents a summary of the findings of the collaborative workshop and introduces the goals of the next one.

Published
2023

2. Case-controlled field study of the ICD-11 clinical descriptions and diagnostic requirements for Bodily Distress Disorders

Author

Keeley, Jared, Reed, Geoffrey M., Rebello, Tahilia, Brechbiel, Julia, Garcia-Pacheco, Jose Angel, Adebayo, Kazeem, Esan, Oluyomi, Majekodunmi, Oluyinka, Ojagbemi, Akin, Onofa, Lucky, Robles, Rebeca, Matsumoto, Chihiro, Medina-Mora, Maria Elena, Kogan, Cary S., Kulygina, Maya, Gaebel, Wolfgang, Zhao, Min, Roberts, Michael C., Sharan, Pratap, Ayuso-Mateos, Jose Luis, Khoury, Brigitte, Stein, Dan J., Lovell, Anne M., Pike, Kathleen, Creed, Francis, and Gureje, Oye

Published
2023
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5. Accuracy of diagnostic classification and clinical utility assessment of ICD-11 compared to ICD-10 in 10 mental disorders: findings from a web-based field study

Author

Gaebel, Wolfgang, Stricker, Johannes, Riesbeck, Mathias, Zielasek, Jürgen, Kerst, Ariane, Meisenzahl-Lechner, Eva, Köllner, Volker, Rose, Matthias, Hofmann, Tobias, Schäfer, Ingo, Lotzin, Annett, Briken, Peer, Klein, Verena, Brunner, Franziska, Keeley, Jared W., Brechbiel, Julia, Rebello, Tahilia J., Andrews, Howard F., Reed, Geoffrey M., Vogel, Ulrich, Hasan, Alkomiet, and Falkai, Peter

Published
2020
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6. Case-controlled field study of the ICD-11 clinical descriptions and diagnostic requirements for Bodily Distress Disorders

Author

Jared Keeley, Geoffrey M. Reed, Tahilia Rebello, Julia Brechbiel, Jose Angel Garcia-Pacheco, Kazeem Adebayo, Oluyomi Esan, Oluyinka Majekodunmi, Akin Ojagbemi, Lucky Onofa, Rebeca Robles, Chihiro Matsumoto, Maria Elena Medina-Mora, Cary S. Kogan, Maya Kulygina, Wolfgang Gaebel, Min Zhao, Michael C. Roberts, Pratap Sharan, Jose Luis Ayuso-Mateos, Brigitte Khoury, Dan J. Stein, Anne M. Lovell, Kathleen Pike, Francis Creed, and Oye Gureje

Subjects
Psychiatry and Mental health, Clinical Psychology
Published
2023

8. General Method to Increase Carboxylic Acid Content on Nanodiamonds

Author

Ganesh Shenoy, Jessica Ettedgui, Chandrasekhar Mushti, Jennifer Hong, Kelly Lane, Burchelle Blackman, Hak-Sung Jung, Yasuharu Takagi, Yeonee Seol, Martin Brechbiel, Rolf E. Swenson, and Keir C. Neuman

Subjects
fluorescent nanodiamond, optical trapping, TIRF, rhodium catalysis, functionalization, Organic chemistry, QD241-441
Abstract

Carboxylic acid is a commonly utilized functional group for covalent surface conjugation of carbon nanoparticles that is typically generated by acid oxidation. However, acid oxidation generates additional oxygen containing groups, including epoxides, ketones, aldehydes, lactones, and alcohols. We present a method to specifically enrich the carboxylic acid content on fluorescent nanodiamond (FND) surfaces. Lithium aluminum hydride is used to reduce oxygen containing surface groups to alcohols. The alcohols are then converted to carboxylic acids through a rhodium (II) acetate catalyzed carbene insertion reaction with tert–butyl diazoacetate and subsequent ester cleavage with trifluoroacetic acid. This carboxylic acid enrichment process significantly enhanced nanodiamond homogeneity and improved the efficiency of functionalizing the FND surface. Biotin functionalized fluorescent nanodiamonds were demonstrated to be robust and stable single-molecule fluorescence and optical trapping probes.

Published
2022
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12. Primary brain tumor representation in the post-traumatic growth literature: A scoping review.

Author

Brechbiel, Julia K, Willis, Kelcie D, Reid, Morgan P, Lanoye, Autumn, Aslanzadeh, Farah J, Fox, Amber M, Braun, Sarah Ellen, and Loughan, Ashlee R

Subjects
*POSTTRAUMATIC growth, *PATIENT experience, *POST-traumatic stress, *MATURATION (Psychology), *PATIENTS' attitudes, *BRAIN tumors
Abstract

Background Post-traumatic growth (PTG) has been extensively explored within general oncology, yet little is known about the experience of PTG in neuro-oncology. This study aimed to determine the representation of patients with primary brain tumors (PBT) in the PTG literature. Methods PsycINFO, PubMed, and CINAHL were systematically searched from inception to December 2022. Search terms were related to personal growth and positive reactions to cancer. Articles were first screened by titles and abstracts, then full texts were reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method. Results A total of 382 articles met the inclusion criteria. Of those, 13 included patients with PBT. Over 100 000 cancer patients were represented, with 0.79% having a PBT. Most research focused on low-grade gliomas. PTG negatively correlated with post-traumatic stress symptoms and avoidant coping. In the sole longitudinal study, patients with PBT demonstrated improved PTG after 1 year. Three quasi-experimental studies investigated the effect of mindfulness-based interventions with mixed-cancer samples and demonstrated improvement in PTG. Conclusions The inclusion rate of patients with PBT in the PTG literature was significantly lower than the population prevalence rate (1.3% of cancer diagnoses). Relatively few studies focused exclusively on how patients with PBT experience PTG (k = 5), and those that did only included low-grade glioma. The experience of PTG in those with high-grade glioma remains unknown. Patients with PBT are scarcely included in research on PTG interventions. Few studies examined the relationship between PTG and medical, cognitive, or psychological characteristics. Our understanding of the PTG experience in neuro-oncology remains extremely limited. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Targeted α-Particle Radiation Therapy of HER1-Positive Disseminated Intraperitoneal Disease: An Investigation of the Human Anti-EGFR Monoclonal Antibody, Panitumumab

Author

Diane E. Milenic, Kwamena E. Baidoo, Young-Seung Kim, Rachel Barkley, and Martin W. Brechbiel

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Identifying molecular targets and an appropriate targeting vehicle, i.e., monoclonal antibodies (mAb) and their various forms, for radioimmunotherapy (RIT) remains an active area of research. Panitumumab, a fully human and less immunogenic mAb that binds to the epidermal growth factor receptor (Erb1; HER1), was evaluated for targeted α-particle radiation therapy using 212Pb, an in vivo α generator. A single dose of 212Pb-panitumumab administered to athymic mice bearing LS-174T intraperitoneal (i.p.) tumor xenografts was found to have greater therapeutic efficacy when directly compared with 212Pb-trastuzumab, which binds to HER2. A dose escalation study determined a maximum effective working dose of 212Pb-panitumumab to be 20 μCi with a median survival of 35 days versus 25 days for the untreated controls. Pretreatment of tumor-bearing mice with paclitaxel and gemcitabine 24 hours prior to injection of 212Pb-pantiumumab at 10 or 20 μCi resulted in the greatest enhanced therapeutic response at the higher dose with median survivals of 106 versus 192 days, respectively. The greatest therapeutic impact, however, was observed in the animals that were treated with topotecan 24 hours prior to RIT and then again 24 hours after RIT; the best response from this combination was also obtained with the lower 10-μCi dose of 212Pb-panitumumab (median survival >280 days). In summary, 212Pb-panitumumab is an excellent candidate for the treatment of HER1-positive disseminated i.p. disease. Furthermore, the potentiation of the therapeutic impact of 212Pb-pantiumumab by chemotherapeutics confirms and validates the importance of developing a multimodal therapy regimen.

Published
2017
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16. Supplementary Figure S3 from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Burvenich, Ingrid J.G., primary, Lee, Fook T., primary, Cartwright, Glenn A., primary, O'Keefe, Graeme J., primary, Makris, Dahna, primary, Cao, Diana, primary, Gong, Sylvia, primary, Chueh, Anderly C., primary, Mariadason, John M., primary, Brechbiel, Martin W., primary, Beckman, Robert A., primary, Fujiwara, Kosaku, primary, von Roemeling, Reinhard, primary, and Scott, Andrew M., primary

Published
2023
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17. Supplementary Data from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Burvenich, Ingrid J.G., primary, Lee, Fook T., primary, Cartwright, Glenn A., primary, O'Keefe, Graeme J., primary, Makris, Dahna, primary, Cao, Diana, primary, Gong, Sylvia, primary, Chueh, Anderly C., primary, Mariadason, John M., primary, Brechbiel, Martin W., primary, Beckman, Robert A., primary, Fujiwara, Kosaku, primary, von Roemeling, Reinhard, primary, and Scott, Andrew M., primary

Published
2023
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18. Supplementary Legend from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Burvenich, Ingrid J.G., primary, Lee, Fook T., primary, Cartwright, Glenn A., primary, O'Keefe, Graeme J., primary, Makris, Dahna, primary, Cao, Diana, primary, Gong, Sylvia, primary, Chueh, Anderly C., primary, Mariadason, John M., primary, Brechbiel, Martin W., primary, Beckman, Robert A., primary, Fujiwara, Kosaku, primary, von Roemeling, Reinhard, primary, and Scott, Andrew M., primary

Published
2023
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19. Supplementary Tables from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Burvenich, Ingrid J.G., primary, Lee, Fook T., primary, Cartwright, Glenn A., primary, O'Keefe, Graeme J., primary, Makris, Dahna, primary, Cao, Diana, primary, Gong, Sylvia, primary, Chueh, Anderly C., primary, Mariadason, John M., primary, Brechbiel, Martin W., primary, Beckman, Robert A., primary, Fujiwara, Kosaku, primary, von Roemeling, Reinhard, primary, and Scott, Andrew M., primary

Published
2023
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20. Supplementary Data and Figure Legends from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Vearing, Christopher, primary, Lee, Fook-Thean, primary, Wimmer-Kleikamp, Sabine, primary, Spirkoska, Violeta, primary, To, Catherine, primary, Stylianou, Con, primary, Spanevello, Mark, primary, Brechbiel, Martin, primary, Boyd, Andrew W., primary, Scott, Andrew M., primary, and Lackmann, Martin, primary

Published
2023
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21. Supplementary Figures 1 and 2 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Vearing, Christopher, primary, Lee, Fook-Thean, primary, Wimmer-Kleikamp, Sabine, primary, Spirkoska, Violeta, primary, To, Catherine, primary, Stylianou, Con, primary, Spanevello, Mark, primary, Brechbiel, Martin, primary, Boyd, Andrew W., primary, Scott, Andrew M., primary, and Lackmann, Martin, primary

Published
2023
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22. Data from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Vearing, Christopher, primary, Lee, Fook-Thean, primary, Wimmer-Kleikamp, Sabine, primary, Spirkoska, Violeta, primary, To, Catherine, primary, Stylianou, Con, primary, Spanevello, Mark, primary, Brechbiel, Martin, primary, Boyd, Andrew W., primary, Scott, Andrew M., primary, and Lackmann, Martin, primary

Published
2023
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23. Supplementary Figure 3 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Vearing, Christopher, primary, Lee, Fook-Thean, primary, Wimmer-Kleikamp, Sabine, primary, Spirkoska, Violeta, primary, To, Catherine, primary, Stylianou, Con, primary, Spanevello, Mark, primary, Brechbiel, Martin, primary, Boyd, Andrew W., primary, Scott, Andrew M., primary, and Lackmann, Martin, primary

Published
2023
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24. Supplementary Figure S3 from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Andrew M. Scott, Reinhard von Roemeling, Kosaku Fujiwara, Robert A. Beckman, Martin W. Brechbiel, John M. Mariadason, Anderly C. Chueh, Sylvia Gong, Diana Cao, Dahna Makris, Graeme J. O'Keefe, Glenn A. Cartwright, Fook T. Lee, and Ingrid J.G. Burvenich

Abstract

Supplementary Figure S3 - PDF file 489K, In vivo saturation of 111In-CHX-A"-DTPA-CS-1008 in WiDr tumors demonstrated by planar gamma camera imaging (A, 0.2 mg/kg; B, 0.5 mg/kg and C, 10 mg/kg). Representative whole body images (left), surface-rendered CT (middle) and fused images (right) are shown. Dorsal 20-minute images were collected

Published
2023

27. Data from Molecular Imaging of Death Receptor 5 Occupancy and Saturation Kinetics In Vivo by Humanized Monoclonal Antibody CS-1008

Author

Andrew M. Scott, Reinhard von Roemeling, Kosaku Fujiwara, Robert A. Beckman, Martin W. Brechbiel, John M. Mariadason, Anderly C. Chueh, Sylvia Gong, Diana Cao, Dahna Makris, Graeme J. O'Keefe, Glenn A. Cartwright, Fook T. Lee, and Ingrid J.G. Burvenich

Abstract

Purpose: CS-1008 (tigatuzumab; phase I/II), an antihuman death receptor 5 (DR5) agonist, induces apoptosis and has cytotoxic activity against human cancer cell lines. This study reports on the preclinical validation of 111In-labeled anti-DR5 humanized antibody CS-1008 as a diagnostic tool to study the DR5 occupancy in patients with cancer and establish dose ranges for receptor saturation kinetics in vivo.Experimental Design: CS-1008 was radiolabeled and characterized for DR5 binding and labeling efficiency on TRAIL-sensitive DR5–positive colorectal cancer cells (COLO 205 and WiDr). Pharmacokinetic and biodistribution studies were conducted in BALB/c nu/nu mice bearing COLO 205, WiDr, or DR5-negative CT26 colon tumors. Planar gamma camera imaging and computerized tomography (CT) images were obtained to study receptor occupancy in vivo.Results: Scatchard analysis showed high and specific binding affinity (Kd, 1.05 ± 0.12 nmol/L) of 111In-labeled CS-1008. 111In-labeled CS-1008 was specifically taken up in mice bearing COLO 205 and WiDr tumors with prolonged tumor retention (26.25 ± 2.85%ID/g vs. 12.20 ± 2.24 at 168 hours post injection; n = 5, SD), and uptake correlated both with DR5 expression on tumor cells and antitumor activity. DR5 saturation was shown in vivo via both biodistribution studies and planar gamma camera imaging/CT imaging of 111In-labeled CS-1008. Saturation of DR5 corresponded to maximal in vivo antitumor efficacy.Conclusions: Imaging of DR5 receptor occupancy in vivo correlates with tumor concentration and in vivo efficacy, and is a novel molecular imaging technique that can be used to determine receptor occupancy and effective dose levels of DR5 agonist antibodies in the clinic. Clin Cancer Res; 19(21); 5984–93. ©2013 AACR.

Published
2023

29. Supplementary Figures 1 and 2 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Martin Lackmann, Andrew M. Scott, Andrew W. Boyd, Martin Brechbiel, Mark Spanevello, Con Stylianou, Catherine To, Violeta Spirkoska, Sabine Wimmer-Kleikamp, Fook-Thean Lee, and Christopher Vearing

Abstract

Supplementary Figures 1 and 2 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Published
2023

30. Data from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Martin Lackmann, Andrew M. Scott, Andrew W. Boyd, Martin Brechbiel, Mark Spanevello, Con Stylianou, Catherine To, Violeta Spirkoska, Sabine Wimmer-Kleikamp, Fook-Thean Lee, and Christopher Vearing

Abstract

The Eph receptor tyrosine kinases and their membrane-bound ephrin ligands form a unique cell-cell contact–mediated system for controlling cell localization and organization. Their high expression in a wide variety of human tumors indicates a role in tumor progression, and relatively low Eph and ephrin levels in normal tissues make these proteins potential targets for anticancer therapies. The monoclonal antibody IIIA4, previously used to isolate EphA3, binds with subnanomolar affinity to a conformation-specific epitope within the ephrin-binding domain that is closely adjacent to the “low-affinity” ephrin-A5 heterotetramerization site. We show that similar to ephrin-A5, preclustered IIIA4 effectively triggers EphA3 activation, contraction of the cytoskeleton, and cell rounding. BIAcore analysis, immunoblot, and confocal microscopy of wild-type and mutant EphA3 with compromised ephrin-A5 or IIIA4-binding capacities indicate that IIIA4 binding triggers an EphA3 conformation which is permissive for the assembly of EphA3/ephrin-A5-type signaling clusters. Furthermore, unclustered IIIA4 and ephrin-A5 Fc applied in combination initiate greatly enhanced EphA3 signaling. Radiometal conjugates of ephrin-A5 and IIIA4 retain their affinity, and in mouse xenografts localize to, and are internalized rapidly into EphA3-positive, human tumors. These findings show the biological importance of EphA3/ephrin-A5 interactions and that ephrin-A5 and IIIA4 have great potential as tumor targeting reagents.

Published
2023

31. Supplementary Data and Figure Legends from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Martin Lackmann, Andrew M. Scott, Andrew W. Boyd, Martin Brechbiel, Mark Spanevello, Con Stylianou, Catherine To, Violeta Spirkoska, Sabine Wimmer-Kleikamp, Fook-Thean Lee, and Christopher Vearing

Abstract

Supplementary Data and Figure Legends from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Published
2023

32. Supplementary Figure 3 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Author

Martin Lackmann, Andrew M. Scott, Andrew W. Boyd, Martin Brechbiel, Mark Spanevello, Con Stylianou, Catherine To, Violeta Spirkoska, Sabine Wimmer-Kleikamp, Fook-Thean Lee, and Christopher Vearing

Abstract

Supplementary Figure 3 from Concurrent Binding of Anti-EphA3 Antibody and Ephrin-A5 Amplifies EphA3 Signaling and Downstream Responses: Potential as EphA3-Specific Tumor-Targeting Reagents

Published
2023

33. The United States Department of Energy and National Institutes of Health Collaboration: Medical Care Advances via Discovery in Physical Sciences

Author

Cynthia Keppel, Andrew Weisenberger, Tatjana Atanasijevic, Shumin Wang, George Zubal, Jeffrey Buchsbaum, Martin Brechbiel, Jacek Capala, Freddy Escorcia, Ceferino Obcemea, Amber Boehnlein, Graham Heyes, Philip Bourne, Simon Cherry, Eric Colby, Georges El Fakhri, Jehanne Gillo, Robert Gropler, Paul Gueye, Georgia Tourassi, Steve Peggs, and Craig Woody

Subjects
General Medicine
Published
2023

34. 90 Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Author

Janik, John E., Morris, John C., O’Mahony, Deirdre, Pittaluga, Stefania, Jaffe, Elaine S., Redon, Christophe E., Bonner, William M., Brechbiel, Martin W., Paik, Chang H., Whatley, Millie, Chen, Clara, Lee, Jae-Ho, Fleisher, Thomas A., Brown, Maggie, White, Jeffrey D., Stewart, Donn M., Fioravanti, Suzanne, Lee, Cathryn C., Goldman, Carolyn K., Bryant, Bonita R., Junghans, Richard P., Carrasquillo, Jorge A., Worthy, Tat’Yana, Corcoran, Erin, Conlon, Kevin C., and Waldmann, Thomas A.

Published
2015

37. Application of 212Pb for Targeted α-particle Therapy (TAT): Pre-clinical and Mechanistic Understanding through to Clinical Translation

Author

Kwon Yong and Martin Brechbiel

Subjects
targeted α-therapy (TAT), 212Pb-Radioimmunotherapy (RIT), bio-vector, trastuzumab, cancer, Medicine (General), R5-920
Abstract

Targeted α-particle therapy (TAT), in which an α-particle emitting radionuclide is specifically directed to a biological target, is gaining more attention to treat cancers as new targets are validated. Bio-vectors such as monoclonal antibodies are able to selectively transport α-particles to destroy targeted cancer cells. TAT has the potential for an improved therapeutic ratio over β-particle targeted conjugate therapy. The short path length and the intense ionization path generated render α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking. 212Pb is the longer-lived parent radionuclide of 212Bi and serves as an in vivo generator of 212Bi. 212Pb has demonstrated significant utility in both in vitro and in vivo models. Recent evaluation of 212Pb-TCMC-trastuzumab in a Phase I clinical trial has demonstrated the feasibility of 212Pb in TAT for the treatment of ovarian cancer patients. This review highlights progress in radionuclide production, radiolabeling chemistry, molecular mechanisms, and application of 212Pb to targeted pre-clinical and clinical radiation therapy for the management and treatment of cancer.

Published
2015
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38. Bench to Bedside: Stability Studies of GMP Produced Trastuzumab-TCMC in Support of a Clinical Trial

Author

Diane E. Milenic, Kwamena E. Baidoo, and Martin W. Brechbiel

Subjects
monoclonal antibody, Pb-212, HER2, trastuzumab, radioimmunotherapy, FDA, stability, Medicine, Pharmacy and materia medica, RS1-441
Abstract

The first-in-human phase 1 clinical radioimmunotherapy (RIT) trial with 212Pb-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane-trastuzumab (212Pb-TCMC-trastuzumab) was completed in October 2014 as a joint effort at the University of Alabama (UAB) and the University of California San Diego Moores Cancer Center. The preliminary reports indicate that after five dose-levels of intraperitoneally administered 212Pb-TCMC-trastuzumab, patients with carcinomatosis experienced minimal agent-related toxicity. This report presents the data accumulated to date on the stability of the clinical grade, produced according to current good manufacturing practices (cGMP), TCMC-trastuzumab conducted in support of that clinical trial. Of the eleven tests performed with the cGMP TCMC-trastuzumab all but one remained within specifications throughout the 5 year testing period. The protein concentration varied by 0.01 mg/mL at 48 months. Two other assays, ion-exchange high performance liquid chromatography (IEX-HPLC) and a competitive radioimmunoassay (RIA) indicated that the cGMP TCMC-trastuzumab integrity may be changing, although the change thus far is within specifications. Subsequent stability testing will confirm if a trend has truly developed. The cGMP TCMC-trastuzumab was also evaluated for tolerance to higher temperatures and the potential of storage at −80 °C. The immunoconjugate proved stable when subjected to the lower temperatures and to multiple freeze-thaw cycles. The size exclusion (SE) HPLC analysis of the 203Pb-TCMC-trastuzumab was the only indicator that cGMP TCMC-trastuzumab may be sensitive to storage at 37 °C for 3 months.

Published
2015
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39. Toxicological Studies of 212Pb Intravenously or Intraperitoneally Injected into Mice for a Phase 1 Trial

Author

Diane E. Milenic, Alfredo A. Molinolo, María S. Solivella, Eileen Banaga, Julien Torgue, Sarah Besnainou, Martin W. Brechbiel, and Kwamena E. Baidoo

Subjects
Pb-212, FDA toxicity study, radioimmunotherapy, targeted alpha-radiation, Medicine, Pharmacy and materia medica, RS1-441
Abstract

Faced with the novelty of a 212Pb-labeled monoclonal antibody (mAb) for clinical translation, concerns were expressed by the Food and Drug Administration (FDA) regarding 212Pb prematurely released from the mAb-chelate conjugate. The objective of this study was to simulate the worst case scenario of such a failure. Groups of Balb/c mice (n = 9–20) were administered 212Pb by intraperitoneal (0.0925–1.85 MBq) or intravenous (0.0925–1.11 MBq) injection and then euthanized at 7 or 90 days to assess acute or chronic effects. Weights were recorded prior to injection of the 212Pb and at the end of the observation periods. Blood samples were collected for clinical chemistry and blood cell analysis. Thirty tissues were harvested and formalin fixed for histopathological examination. Treatment related effects of the 212Pb were observed in the bone marrow, spleen, kidneys and the liver. Histological alterations in these organs were considered mild to moderate, indicating low grade toxicity, and not considered severe enough to affect function. This data was presented to the FDA and determined to be acceptable. The clinical trial with 212Pb-TCMC-trastuzumab was approved in January 2011 and the trial opened at the University of Alabama at Birmingham (UAB) in July.

Published
2015
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41. National Cancer Institute support for targeted alpha-emitter therapy

Author

Christie A Canaria, Frank I. Lin, Jeff Buchsbaum, C. Norman Coleman, Charles A. Kunos, Jacek Capala, Michael Graham Espey, Martin W. Brechbiel, Freddy E. Escorcia, Julie A Hong, and Deepa Narayanan

Subjects
medicine.medical_specialty, business.industry, Extramural, medicine.medical_treatment, Cancer, General Medicine, medicine.disease, Targeted therapy, Clinical trial, Cancer Therapy Evaluation Program, Intramural Program, Radiation oncology, Medicine, Radiology, Nuclear Medicine and imaging, Medical physics, business, Small Business Innovation Research
Abstract

Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. This article reviews National Cancer Institute (NCI)’s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)’s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI’s intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing “bench-to-bedside” efforts leverage the unique infrastructure of the National Institutes of Health’s (NIH) Clinical Center. Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

Published
2021

42. Death anxiety in patients with primary brain tumor: Measurement, prevalence, and determinants

Author

Gary Rodin, Mariya Husain, Scott G. Ravyts, Leroy R. Thacker, Julia Brechbiel, Ashlee R. Loughan, Kelcie D. Willis, Dace S. Svikis, Farah Aslanzadeh, and Sarah Braun

Subjects
Oncology, medicine.medical_specialty, business.industry, Brain tumor, General Medicine, medicine.disease, 03 medical and health sciences, Psychiatry and Mental health, Clinical Psychology, Death anxiety, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, In patient, 030212 general & internal medicine, business, General Nursing
Abstract

ObjectiveThis study investigated death anxiety in patients with primary brain tumor (PBT). We examined the psychometric properties of two validated death anxiety measures and determined the prevalence and possible determinants of death anxiety in this often-overlooked population.MethodsTwo cross-sectional studies in neuro-oncology were conducted. In Study 1, 81 patients with PBT completed psychological questionnaires, including the Templer Death Anxiety Scale (DAS). In Study 2, 109 patients with PBT completed similar questionnaires, including the Death and Dying Distress Scale (DADDS). Medical and disease-specific variables were collected across participants in both studies. Psychometric properties, including construct validity, internal consistency, and concurrent validity, were investigated. Levels of distress were analyzed using frequencies, and determinants of death anxiety were identified using logistic regression.ResultsThe DADDS was more psychometrically sound than the DAS in patients with PBT. Overall, 66% of PBT patients endorsed at least one symptom of distress about death and dying, with 48% experiencing moderate-severe death anxiety. Generalized anxiety symptoms and the fear of recurrence significantly predicted death anxiety.Significance of resultsThe DADDS is a more appropriate instrument than the DAS to assess death anxiety in neuro-oncology. The proportion of patients with PBT who experience death anxiety appears to be higher than in other advanced cancer populations. Death anxiety is a highly distressing symptom, especially when coupled with generalized anxiety and fears of disease progression, which appears to be the case in patients with PBT. Our findings call for routine monitoring and the treatment of death anxiety in neuro-oncology.

Published
2021

44. 18th European Symposium on Radiopharmacy and Radiopharmaceuticals: Salzburg, Austria. 7-10 April 2016

Author

Radchenko, V., Engle, J. W., Roy, C., Griswold, J., Nortier, M. F., Birnbaum, E. R., Brugh, M., Mirzadeh, S., John, K. D., Fassbender, M. E., Zhai, Chuangyan, Franssen, Gerben M., Petrik, Milos, Laverman, Peter, Decristoforo, Clemens, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Brigitte, Guérin, Summer, D., Kroess, A., Rangger, C., Haas, H., Laverman, P., Gerben, F., von Guggenberg, E., Decristoforo, C., Bolzati, Cristina, Salvarese, Nicola, Refosco, Fiorenzo, Meléndez-Alafort, Laura, Carpanese, Debora, Rosato, Antonio, Saviano, Michele, Del Gatto, Annarita, Comegna, Daniela, Zaccaro, Laura, Billaud, Emilie, Ahamed, Muneer, Cleeren, Frederik, Shahbazali, Elnaz, Noël, Tim, Hessel, Volker, Verbruggen, Alfons, Bormans, Guy, Cleeren, F., Lecina, J., Koole, M., Verbruggen, A., Bormans, G., Lugatoa, B., Stucchia, S., Turollaa, E. A., Giulianoa, L., Toddea, S., Ferraboschib, P., Klok, R. P., Mooijer, M. P. J., Hendrikse, N. H., Windhorst, A. D., Collet, C., Petry, N., Chrétien, F., Karcher, G., Pellegrini-Moïse, N., Lamandé-Langle, S., Pfaff, Sarah, Philippe, Cecile, Mitterhauser, Markus, Hacker, Marcus, Wadsak, Wolfgang, Guérard, François, Lee, Yong-Sok, Gouard, Sébastien, Baidoo, Kwamena, Alliot, Cyrille, Chérel, Michel, Brechbiel, Martin W., Gestin, Jean-François, Lam, K., Chan, C., Reilly, R. M., Paillas, Salomé, Marshall, John, Pouget, Jean-Pierre, Sosabowski, Jane, Briard, Emmanuelle, Auberson, Yves P., Reilly, John, Healy, Mark, Sykes, David, Paulus, Andreas, Lichtenbelt, Wouter van Marken, Mottaghy, Felix, Bauwens, Matthias, Baranski, Ann-Christin, Schäfer, Martin, Bauder-Wüst, Ulrike, Haberkorn, Uwe, Eder, Matthias, Kopka, Klaus, Chaussard, M., Hosten, B., Vignal, N., Tsoupko-Sitnikov, V., Hernio, N., Hontonnou, F., Merlet, P., Poyet, J. L., Sarda-Mantel, L., Rizzo-Padoin, N., Cardinale, J., Schäfer, M., Benešová, M., Bauder-Wüst, U., Seibert, O., Giesel, F., Haberkorn, U., Eder, M., Kopka, K., Nematallah, Mansour, Michel, Paquette, Samia, Ait-Mohand, Véronique, Dumulon-Perreault, Roger, Lecomte, Brigitte, Guérin, Fernandez-Maza, L., Rivera-Marrero, S., Capote, A. Prats, Parrado-Gallego, A., Fernandez-Gomez, I., Balcerzyk, M., Sablon-Carrazana, M., Perera-Pintado, A., Merceron-Martinez, D., Acosta-Medina, E., Rodriguez-Tanty, C., Attili, Bala, Ahamed, Muneer, Bormans, Guy, Philippe, C., Zeilinger, M., Scherer, T., Fürnsinn, C., Dumanic, M., Wadsak, W., Hacker, M., Mitterhauser, M., Janssen, B., Vugts, D. J., Molenaar, G.T. T., Funke, U., Kruijer, P. S., Dollé, F., Bormans, G., Lammertsma, A. A., Windhorst, A. D., Vermeulen, Koen, Ahamed, Muneer, Schnekenburger, Michael, Froeyen, Mathy, Olberg, Dag Erlend, Diederich, Marc, Bormansa, Guy, Raaphorst, R. M., Luurtsema, G., Lammertsma, A. A., Elsinga, P. H., Windhorst, A D., Rotteveel, Lonneke, Funke, Uta, ten Dijke, Peter, Bogaard, Harm Jan, Lammertsma, Adriaan A., Windhorst, Albert D., Song, Lei, Able, Sarah, Falzone, Nadia, Kersemans, Veerle, Vallis, Katherine, Carta, Davide, Salvarese, Nicola, Sihver, Wiebke, Gao, Feng, Pietzsch, Hans Jürgen, Biondi, Barbara, Ruzza, Paolo, Refosco, Fiorenzo, Bolzati, Cristina, Haubner, Roland, Finkensted, Armin, Stegmair, Armin, Rangger, Christine, Decristoforo, Clemens, Zoller, Heinz, Virgolini, Irene J., Pooters, Ivo, Lotz, Maartje, Wierts, Roel, Mottaghy, Felix, Bauwens, Matthias, Forsback, Sarita, Jörgen, Bergman, Riikka, Kivelä, Karageorgou, M., Radović, M., Tsoukalas, C., Antic, B., Gazouli, M., Paravatou-Petsotas, M., Xanthopouls, S., Calamiotou, M., Stamopoulos, D., Vranješ-Durić, S., Bouziotis, P., Lunev, A. S., Larenkov, A. A., Petrosova, K. A., Klementyeva, O. E., Kodina, G. E., Kvernenes, O. H., Adamsen, T. C. H., Martin, René, Weidlich, Sebastian, Zerges, Anna-Maria, Gameiro, Cristiana, Lazarova, Neva, Müllera, Marco, Luurtsema, Gert, de Vries, Michèl, Ghyoot, Michel, van der Woude, Gina, Zijlma, Rolf, Dierckx, Rudi, Boersma, Hendrikus H., Elsinga, Philip H., Lambrecht, Fatma Yurt, Er, Ozge, Ince, Mine, Avci, Cıgır Biray, Gunduz, Cumhur, Sarı, Fatma Aslihan, Ocakoglu, Kasim, Er, Ozge, Ersoz, Onur Alp, Lambrecht, Fatma Yurt, Ince, Mine, Kayabasi, Cagla, Gunduz, Cumhur, Kniess, Torsten, Meister, Sebastian, Fischer, Steffen, Steinbach, Jörg, Ashfaq, Rabia, Iqbal, Saeed, ullah Khan, Irfan, Iglesias-Jerez, R., Martín-Banderas, L., Perera-Pintado, A., Borrego-Dorado, I., Farinha-Antunes, Ines, Kwizera, Chantal, Lacivita, Enza, Lucente, Ermelinda, Niso, Mauro, De Giorgio, Paola, Perrone, Roberto, Colabufo, Nicola A., Elsinga, Philip H., Leopoldo, Marcello, Vaulina, V. V., Fedorova, O. S., Orlovskaja, V. V., Chen, С. L., Li, G. Y., Meng, F. C., Liu, R. S., Wang, H. E., Krasikova, R. N., Meléndez-Alafort, Laura, Abozeid, Mohamed, Ferro-Flores, Guillermina, Negri, Anna, Bello, Michele, Uzunov, Nikolay, Paiusco, Martha, Esposito, Juan, Rosato, Antonio, Meléndez-Alafort, Laura, Bolzati, Cristina, Ferro-Flores, Guillermina, Salvarese, Nicola, Carpanese, Debora, Abozeid, Mohamed, Rosato, Antonio, Uzunov, Nikolay, Palmieri, L., Verbrugghen, T., Glassner, M., Hoogenboom, R., Staelens, S., Wyffels, L., Orlovskaja, V. V., Kuznetsova, O. F., Fedorova, O. S., Maleev, V. I., Belokon, Yu. N., Geolchanyan, A., Saghyan, A. S., Mu, L., Schibli, R., Ametamey, S. M., Krasikova, R. N., Revunov, Evgeny, Malmquist, Jonas, Johnström, Peter, Van Valkenburgh, Juno, Steele, Dalton, Halldin, Christer, Schou, Magnus, Osati, Samira, Paquette, Michel, Beaudoin, Simon, Ali, Hasrat, Guerin, Brigitte, Leyton, Jeffrey V., van Lier, Johan E., Di Iorio, V, Iori, M., Donati, C., Lanzetta, V., Capponi, P. C., Rubagotti, S., Dreger, T., Kunkel, F., Asti, M., Zhai, Chuangyan, Rangger, Christine, Summer, Dominik, Haas, Hubertus, Decristoforo, Clemens, Kijprayoon, Suphansa, Ruangma, Ananya, Ngokpol, Suthatip, Tuamputsha, Samart, Filp, Ulrike, Pees, Anna, Taddei, Carlotta, Pekošak, Aleksandra, Gee, Antony D., Poot, Alex J., Windhorst, Albert D., Gunay, Mine Silindir, Ozer, A. Yekta, Erdogan, Suna, Baysal, Ipek, Guilloteau, Denis, Chalon, Sylvie, Galli, Filippo, Artico, Marco, Taurone, Samanta, Bianchi, Enrica, Weintraub, Bruce D., Skudlinski, Mariusz, Signore, Alberto, Lepareur, Nicolas, Noiret, Nicolas, Hindré, François, Lacœuille, Franck, Benoist, Eric, Garin, Etienne, Trejo-Ballado, F., Zamora-Romo, E., Manrique-Arias, J. C., Gama-Romero, H M, Contreras-Castañon, G., Tecuapetla-Chantes, R. G., Avila-Rodriguez, M. A., Kvaternik, H., Hausberger, D., Zink, C., Rumpf, B., Aigner, R. M., Kvaternik, H., Hausberger, D., Rumpf, B., Aigner, R. M., Janković, Drina, Lakić, Mladen, Savić, Aleksandar, Ristić, Slavica, Nikolić, Nadežda, Vukadinović, Aleksandar, Sabo, Tibor J., Vranješ-Đurić, Sanja, Vranješ-Đurić, S., Radović, M., Janković, D., Nikolić, N., Goya, G. F., Calatayud, P., Spasojević, V., Antić, B., Goblet, David, Gameiro, Cristiana, Lazarova, Neva, Gameiro, Cristiana, Oxley, Ian, Abrunhosa, Antero, Kramer, Vasko, Vosjan, Maria, Spaans, Arnold, Vats, Kusum, Satpati, Drishty, Sarma, Haladhar D., Banerjee, Sharmila, Wojdowska, W., Pawlak, D. W., Parus, L. J., Garnuszek, P., Mikołajczak, R., Pijarowska-Kruszyna, J., Jaron, A., Kachniarz, A., Malkowski, B., Garnuszek, P., Mikolajczak, R., Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Ilem-Ozdemir, Derya, Caglayan-Orumlu, Oya, Asikoglu, Makbule, Eveliina, Arponen, Semi, Helin, Timo, Saarinen, Simo, Vauhkala, Esa, Kokkomäki, Pertti, Lehikoinen, De Simone, Mariarosaria, Pascali, Giancarlo, Carzoli, Ludovica, Quaglierini, Mauro, Telleschi, Mauro, Salvadori, Piero A., Lam, Phoebe, Aistleitner, Martina, Eichinger, Reinhard, Artner, Christoph, Nakka, Surendra, MC, Hemantha Kumara, Al-Qahtani, Mohammed, Al-Qahtani, Mohammed, Al-Malki, Yousif, Mambilima, N., Rubow, S. M., Berroterán-Infante, N., Hacker, M., Mitterhauser, M., Wadsak, W., Funke, Uta, Cleeren, Frederik, Lecina, Joan, Gallardo, Rodrigo, Verbruggen, Alfons M., Bormans, Guy, Ramos-Membrive, Rocío, Brotons, Ana, Quincoces, Gemma, Inchaurraga, Laura, de Redín, Inés Luis, Morán, Verónica, García-García, Berta, Irache, Juan Manuel, Peñuelas, Iván, Trabelsi, M., Cooper, M. S., Abella, Alejandra, Fuente, Teodomiro, Montellano, Antonio Jesús, Martínez, Teresa, Rabadan, Ruben, Meseguer-Olmo, Luis, Lehtiniemi, P., Yim, C., Mikkola, K., Nuutila, P., Solin, O., von Guggenberg, E., Rangger, C., Mair, C., Balogh, L., Pöstényi, Z., Pawlak, D., Mikołajczak, R., Socan, A., Peitl, P. Kolenc, Krošelj, M., Rangger, C., Decristoforo, C., Collet, C., Remy, S., Didier, R., Vergote, T., Karcher, G., Véran, N., Pawlak, D., Maurin, M., Garnuszek, P., Karczmarczyk, U., Mikołajczak, R., Fredericia, Pil, Severin, Gregory, Groesser, Torsten, Köster, Ulli, Jensen, Mikael, Leonte, R., Puicea, F. D., Raicu, A., Min, E. A., Serban, R., Manda, G., Niculae, D., Zerna, Marion, Schieferstein, Hanno, Müller, Andre, Berndt, Mathias, Yim, Cheng-Bin, Mikkola, Kirsi, Nuutila, Pirjo, Solin, Olof, Seifert, D., Ráliš, J., Lebeda, O., Selivanova, Svetlana V., Senta, Helena, Lavallée, Éric, Caouette, Lyne, Turcotte, Éric, Lecomte, Roger, Kochovska, Marina Zdraveska, Ivanovska, Emilija Janjevik, Jokic, Vesna Spasic, Ackova, Darinka Gjorgieva, Smilkov, Katarina, Makreski, Petre, Stafilov, Trajče, Janevik-Ivanovska, Emilija, Alemu, Aschalew, Muchira, Joel Munene, Wanjeh, David Mwanza, Janevik-Ivanovska, Emilija, Janevik-Ivanovska, Emilija, Zdravev, Zoran, Bhonsle, Uday, Alberto, Osso Júnior João, Duatti, Adriano, Angelovska, Bistra, Stojanovska, Zdenka, Sarafinovska, Zorica Arsova, Bosnakovski, Darko, Gorgieva-Ackova, Darinka, Smilkov, Katarina, Drakalska, Elena, Venkatesh, Meera, Gulaboski, Rubin, Colin, Didier J., Inkster, James A. H., Germain, Stéphane, Seimbille, Yann, Atiq-ur-Rehman, and Cayero-Otero

Published
2016
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49. Iron Chelation in Cancer Therapy

Author

Torti, Suzy V., Planalp, R. P., Brechbiel, M. W., Park, G., Torti, F. M., Abraham, Nader G., editor, Tabilio, Antonio, editor, Martelli, Massimo, editor, Asano, Shigetaka, editor, and Donfrancesco, Alberto, editor

Published
1999
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50. Cell Killing Mechanisms and Impact on Gene Expression by Gemcitabine and 212Pb-Trastuzumab Treatment in a Disseminated i.p. Tumor Model.

Author

Kwon Joong Yong, Diane E Milenic, Kwamena E Baidoo, and Martin W Brechbiel

Subjects
Medicine, Science
Abstract

In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using 212Pb-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to 212Pb-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes. The combination of Gem with α-radiation resulted in the differential expression of apoptotic genes (BRCA1, CIDEA, GADD45α, GADD45γ, IP6K3, PCBP4, RAD21, and p73), cell cycle regulatory genes (BRCA1, CHK1, CHK2, FANCG, GADD45α, GTSE1, PCBP4, MAP2K6, NBN, PCBP4, and SESN1), and damaged DNA binding and repair genes (BRCA1, BTG2, DMC1, ERCC1, EXO1, FANCG, FEN1, MSH2, MSH3, NBN, NTHL1, OGG1, PRKDC, RAD18, RAD21, RAD51B, SEMA4G, p73, UNG, XPC, and XRCC2). Of these genes, the expression of CHK1, GTSE1, EXO1, FANCG, RAD18, UNG and XRCC2 were specific to Gem/212Pb-trastuzumab administration. In addition, the present study demonstrates that increased stressful growth arrest conditions induced by Gem/212Pb-trastuzumab could suppress cell proliferation possibly by up-regulating genes involved in apoptosis such as p73, by down-regulating genes involved in cell cycle check point such as CHK1, and in damaged DNA repair such as RAD51 paralogs. These events may be mediated by genes such as BRCA1/MSH2, a member of BARC (BRCA-associated genome surveillance complex). The data suggest that up-regulation of genes involved in apoptosis, perturbation of checkpoint genes, and a failure to correctly perform HR-mediated DSB repair and mismatch-mediated SSB repair may correlate with the previously observed inability to maintain the G2/M arrest, leading to cell death.

Published
2016
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