tbuckley/cabot-search huggingface dataset:
Myocarditis in the Setting of Cancer Therapeutics
Authors: Marc P. Bonaca, Benjamin A. Olenchock, Joe-Elie Salem, Stephen D. Wiviott, Stephane Ederhy, Ariel Cohen, Garrick C. Stewart, Toni K. Choueiri, Marcelo Di Carli, Yves Allenbach, Dharam J. Kumbhani, Lucie Heinzerling, Laleh Amiri-Kordestani, Alexander R. Lyon, Paaladinesh Thavendiranathan, Robert Padera, Andrew Lichtman, Peter P. Liu, Douglas B. Johnson, Javid Moslehi
Journal: Circulation (2019)

Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
Abstract 1447: Predicting immunogenic neoepitopes with biology-aware machine learning
Authors: Giovanni Mazzocco, Iga Niemiec, Oleksandr Myronov, Edyta Kowalczyk, Jan Kaczmarczyk, Anna Sanecka-Duin, Piotr Stepniak
Journal: Cancer Research (2019)

Abstract Introduction: The purpose of this study is to present a novel method for neoepitope prediction, along with extensive benchmarks to existing solutions and identification of the most predictive constituent biological features. The accurate prediction of neoepitope immunogenicity represents an invaluable tool for the design of personalized cancer vaccines with effective treatment outcomes. The effectiveness of the host’s adaptive immune response against cancer relies on the correct HLA-mediated neoepitope presentation and the recognition by specific CD8+ clones. Cancer immunotherapies act by boosting the activity of these effector T-cells. Methods: The proposed AI-driven bioinformatics solution allows to perform an accurate prediction of HLA I-restricted neoepitope immunogenicity by including several analytical modules simulating biological processes leading to the activation of CD8+ T-cells. These modules can be flexibly composed on the basis of the data available and include: (i) selection of potential neoepitope based on cancer NGS data, (ii) expression of neoepitope-associated genes, (iii) similarity to self, (iv) prediction of neoepitope-HLA binding affinity and stability, (v) effect of post-translational modification on neoepitope presentation and TCR recognition, (vi) prediction of neoepitope:TCR recognition probability based on neoepitope-HLA:TCR structural-derived features and TCR CDR3 sequence similarities. The model was trained on a curated dataset joining records of multiple studies containing neoepitopes experimentally validated for their ability to elicit adaptive immune response. Results: We present the results of a benchmarking study where we compare the performance of widely used methods for the assessment of neoepitope immunogenicity along with our solution. We investigate the predictive power of each analytical module to determine the individual information gain and determine the most informative ones. All the methods included in the benchmarking study were tested using the dataset provided by Chowell et al. 2015. As the metric for performance evaluation we use ROC AUC and the overall percentage of correctly detected immunogenic neoepitopes (precision). Conclusion: The results present the utility of the compared methods for personalized cancer vaccine design and the importance of modules related to biological processes underlying the neoepitope presentation and immunogenicity. Citation Format: Giovanni Mazzocco, Iga Niemiec, Oleksandr Myronov, Edyta Kowalczyk, Jan Kaczmarczyk, Anna Sanecka-Duin, Piotr Stepniak. Predicting immunogenic neoepitopes with biology-aware machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1447.
A Universal Influenza Nanovaccine for “Mixing Vessel” Hosts Confers Potential Ability to Block Cross‐Species Transmission
Authors: Peiyang Ding, Qianyue Jin, Wen Zhou, Yongxiao Chai, Xiao Liu, Yao Wang, Xinxin Chen, Junqing Guo, Ruiguang Deng, George F. Gao, Gaiping Zhang
Journal: Advanced Healthcare Materials (2019)

Abstract Influenza A virus (IAV), a deadly zoonotic pathogen, poses a tremendous threat and burden to global health systems. Pigs act as “mixing vessel” hosts to support and generate new pandemic viruses. Preventing the spread of IAV in pigs effectively can delay or even block cross‐species transmission. Universal vaccines based on the highly conserved ectodomain of influenza matrix protein 2 (M2e) have been widely reported, but have not been applied due to inadequate protection. Porcine circovirus type 2 (PCV2) causes immunosuppression and promotes swine influenza virus (SIV) infection. Here, M2e is inserted into capsid protein of PCV2 without burying the neutralizing epitopes and self‐assembles to form a bivalent nanovaccine. Inoculation with the nanovaccine induces robust M2e‐ and PCV2‐specific immune responses. The nanovaccine confers protection against lethal challenges of IAV from different species in mice, and significantly reduces SIV titers in pigs' respiratory tract and blocks SIV transmission. These results indicate that the nanovaccine is an economical and promising PCV2 and universal IAV bivalent vaccine, and it will synergistically and powerfully offer potential ability to block IAV cross‐species reassortment and transmission.
Abstract 4819: Sacituzumab Govitecan (IMMU-132) in uterine serous carcinoma
Authors: Salvatore Lopez, Chanhee Han, Burak Zeybek, Elena Bonazzoli, Anna Bianchi, Paola Manara, Stefania Bellone, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro, Gary Altwerger, Alessandro D. Santin
Journal: Cancer Research (2019)

Abstract Objective: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with poor prognosis. Sacituzumab govitecan (IMMU-132) is a novel antibody-drug conjugate (ADC) targeting trophoblast antigen 2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors including USC, to deliver SN-38, the active metabolite of irinotecan. The objective of this study was to preclinically evaluate the efficacy of IMMU-132 against primary USC cell lines and xenografts. Methods: Trop-2 expression in primary tumor cell lines and USC cell viability after exposure to IMMU-132 ADC (hRS7-CL2A-SN-38), non-targeting control ADC (h679-CL2A-SN-38), and naked antibody hRS7 IgG were evaluated using RT-PCR and flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2- USC cell lines was evaluated in vitro using 4 hr Chromium release assays. Finally, in vivo activity of Sacituzumab govitecan was tested against Trop-2+ USC xenografts by 3 twice-a-week retro-orbital injection of 500 μg of IMMU-132, control-ADC, and hRS7 naked-IgG. Results: Overexpression of Trop-2 was detected in 67% (8 out of 12) of primary USC cell lines. Primary tumors overexpressing Trop-2 were significantly more sensitive (ie, lower IC50) to IMMU-132 (hRS7-CL2A-SN-38) when compared to control ADC (h679-CL2A-SN-38). Both sacituzumab govitecan (IMMU-132) and the naked antibody hRS7 induced high level of ADCC against Trop2+ USC cell lines while no cytotoxicity was detected against Trop-2 negative tumors. In vivo experiments comparing IMMU-132 activity to control ADC and hRS7 showed a dramatically improved tumor suppression and increased survival in IMMU-132 treated mice when compared to controls (P = 0.0001 and P = 0.0002, respectively). Conclusion: IMMU-132 demonstrated remarkable antitumor activity against biologically aggressive USC overexpressing Trop-2. Our preclinical results combined with the dramatic clinical response recently reported in an USC patient treated with IMMU-132 (https://doi.org/10.1016/j.gore.2018.05.009) strongly supports further clinical development of sacituzumab govitecan in USC patients with advanced/recurrent disease. (ie, clinical trial IND 140394). Furthermore, due to a cleavable linker that can cause bystander effect, sacituzumab govitecan could be also effective in tumors with heterogenous TROP-2 expression. Citation Format: Salvatore Lopez, Chanhee Han, Burak Zeybek, Elena Bonazzoli, Anna Bianchi, Paola Manara, Stefania Bellone, Aranzazu Manzano, Emanuele Perrone, Luca Zammataro, Gary Altwerger, Alessandro D. Santin. Sacituzumab Govitecan (IMMU-132) in uterine serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4819.
Abstract CT028: Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ)
Authors: Jennifer E. Amengual, Gary K. Schwartz, Lora Inclan, Abhijeet Kumar, Patricia Robles-Medina, Shahnaz Singh-Kandah, Benjamin Suttle, Melissa Beelen, Daniel Persky
Journal: Cancer Research (2019)

Abstract TAZ, a selective, oral EZH2 inhibitor, is in the phase 2 clinical investigation stage for the treatment of advanced solid tumors (AdvST) and B-cell non-Hodgkin lymphoma (NHL). Drug-drug interaction (DDI) potential of TAZ was investigated in study EZH-105, a phase 1, open-label, 2-part study in adults with AdvST or NHL. In Part A, patients received TAZ 400 mg twice-daily (BID) days 1-24, then 800 mg BID continuously. Moderate CYP3A inhibitor fluconazole 400 mg was administered once daily (QD) days 16-19. Serial blood samples for pharmacokinetic analysis were collected on days 15 and 19. Patients in Part B received TAZ 800 mg BID continuously starting day 2. The CYP2C8 probe repaglinide 0.25 mg and CYP2C19 probe omeprazole 20 mg were administered on day 1 and 1 hour following TAZ administration on day 16. Omeprazole 20 mg QD continued days 17-19. Serial blood samples were collected on days 1, 16, and 19. DDIs were evaluated based on AUC and Cmax. Other primary endpoints included safety of TAZ. As of August 14, 2018, 27 patients were enrolled (n=17 AdvST, n=10 NHL). Median age was 60 years. Preliminary pharmacokinetic results are displayed in the Table. Median treatment exposure was 70 days in Part A and 57 days in Part B. Two patients, both in Part B, discontinued due to treatment emergent adverse events (TEAEs). Grade ≥3 TEAEs were reported in 12 patients. The most frequent treatment-related TEAEs (any grade) included diarrhea (n=6), fatigue (n=6), and nausea (n=3). In conclusion, the likelihood of a clinically significant DDI in the presence of TAZ is minimal. Table.Preliminary study EZH-105 PK resultsPart A. The effect of fluconazole on TAZParameterTAZ alone Day 15 Mean (%CV)TAZ + fluconazole Day 19 Mean (%CV)TAZ, n=14Cmax, ng/ml426 (95)968 (80)AUC0-12h, ng*h/mL1590 (81)5180 (66)Part B. The effect of TAZ on REP and OMPREP + OMP Day 1 Mean (%CV)REP + OMP + TAZ Day 16 Mean (%CV)REP, n=12Cmax, ng/ml5 (109)10 (78)AUC0-7h, ng*h/mL9 (110)17 (65)OMP, n=12Cmax, ng/ml263 (266)220 (250)AUC0-7h, ng*h/mL677 (340)558 (231)Part B. The effect of OMP on TAZTAZ prior to OMP Day 16 Mean (%CV)TAZ + OMP Day 19 Mean (%CV)TAZ, n=9Cmax, ng/ml613 (91)663 (68)AUC0-12h, ng*h/mL2200 (58)2820 (62)AUC, area under the concentration curve; CI, confidence interval; Cmax, maximum plasma concentration; CV, coefficient of variation; REP, repaglinide; OMP, omeprazole; PK, pharmacokinetic; TAZ, tazemetostat. Citation Format: Jennifer E. Amengual, Gary K. Schwartz, Lora Inclan, Abhijeet Kumar, Patricia Robles-Medina, Shahnaz Singh-Kandah, Benjamin Suttle, Melissa Beelen, Daniel Persky. Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT028.
LaSalle Leffall: groundbreaking American surgeon and educator
Authors: Bob Roehr
Journal: BMJ (2019)

Picture credit: LaSalle Leffall/NLM/NIM

Racism was a fact of life in the southern US in the mid-20th century. There were stores downtown that you knew you couldn’t go in as a black person, LaSalle Leffall recounted in an oral history interview with the US Library of Congress.1 Public accommodations such as drinking fountains and bus waiting rooms were clearly labelled for either “white” or “colored” people.

But Leffall never let that impede his advancement. He became a noted cancer surgeon and educator, the first African-American president of the American Cancer Society, and the first to lead the American College of Surgeons, among many other firsts throughout his career.

Still, he began life with several advantages. His father had graduated from college at a time when less than 5% of Americans had access to higher education; for minorities the number was smaller still. His father, LaSalle Doheny Leffall Sr, was principal of the blacks-only high school in the town of Quincy, near Tallahassee, Florida. That position ensured the family largely avoided the direct ravages of the Great Depression.

“With a good education and hard work, combined with honesty and integrity, there are no boundaries,” his father would tell young LaSalle. And the lad took that to heart, graduating from high school …
Abstract 88: Stable luciferase expressing cell lines for <i>in vivo x</i>enograft and syngeneic tumor model bioluminescence imaging
Authors: John Foulke, Luping Chen, Alexei Miagkov, Elizabeth Turner-Gillies, Lysa-Anne Volpe, Fang Tian
Journal: Cancer Research (2019)

Abstract Human and mouse cancer cell lines are used in xenograft and syngeneic models, respectively, for the in vivo study of tumor formation and development, metastases, measuring tumor burden in whole animals and monitoring response to therapeutic treatment. Whole animal in vivo imaging has been widely applied by researchers due to the ease of operation in visualizing in vivo biological events, eliminating the requirement for animal subject sacrifice, allowing for continual monitoring/imaging of a single individual animal and reducing the amount of inter-animal variation. Luciferase reporters provide a relatively simple, robust, and highly sensitive means to measure biological processes and to assess drug efficacy in animal models through in vivo bioluminescence imaging. Here we report on the generation of a large panel of cell lines which express high levels of luciferase and -have broad applications for in vitro and in vivo studies. The panel includes human and mouse cell lines, which represent various common cancer and tissue types, such as breast, colon, lung, pancreas, prostate, and skin. After introduction of a Lenti-LUC2 luciferase reporter into the parental cell lines, single cell cloning was performed to isolate stable clones with high luciferase expression. We quantified both the relative and absolute in vitro bioluminescence signals within the cells and analyzed the signal-to-noise ratio. In addition, the cell lines were characterized and authenticated using cell morphology, growth kinetics, and STR analysis. In addition, luciferase labeled human cell lines were administered into immune-deficient mice either by subcutaneous or orthotropic injection to establish xenograft models. Luciferase labeled mouse cell lines were tested in the associated breed of mice to evaluate tumor growth in the syngeneic mouse model. The bioluminescence live imaging was performed using the Xenogen IVIS imaging system and the in vivo bioluminescent radiance was analyzed. Although growth can be evaluated by both traditional caliper measurement and bioluminescence in subcutaneous mouse models, only live bioluminescent imaging enables continuous monitoring tumor metastasis or analysis of tumor growth of the intracranial brain tumor models. In summary, luciferase expressing cell lines are valuable tools for elucidating mechanisms involved in tumorigenesis, studying tumors in vivo, and screening anti-cancer compounds for drug discovery and development. Citation Format: John Foulke, Luping Chen, Alexei Miagkov, Elizabeth Turner-Gillies, Lysa-Anne Volpe, Fang Tian. Stable luciferase expressing cell lines for in vivo xenograft and syngeneic tumor model bioluminescence imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 88.
A New Brain Mass in an Immunocompromised Woman
Authors: Michelle H. Lee, Emily Wilding, Jennie Y. Law
Journal: JAMA Oncology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Abstract SY42-03: Systematic interrogation of cancer dependencies and synthetic lethal interactions
Authors: William C. Hahn
Journal: Cancer Research (2019)

Abstract Although molecular profiling of human tumors is becoming increasingly routine, the use of this data to guide remains limited to a subset of patients. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed systematic studies to interrogate rare alleles found altered in cancer genomes and used advances in synthetic gene synthesis to prospectively interrogate all possible alleles of known cancer genes. In parallel, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. Integrating these studies with genome characterization of human tumors and protein-protein interaction databases facilitates the identification of genes and pathways required for the survival of specific cancer subtypes. These studies allow us to define a global cancer dependencies map, which will help further operationalize precision cancer medicine. Citation Format: William C. Hahn. Systematic interrogation of cancer dependencies and synthetic lethal interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY42-03.
Abstract 3471: Mutual regulation of MDM4 and TOP2A in cancer cell proliferation
Authors: Tao Liu, Hailong Zhang, Sha Yi, Lubing Gu, Muxiang Zhou
Journal: Cancer Research (2019)

Abstract MDM4 and topoisomerase IIα (TOP2A) are important cancer-related factors. MDM4 acts as an oncoprotein promoting cancer progression by inhibiting tumor suppressor p53. As a DNA replication- and cell division-regulating enzyme, TOP2A is the main target of many anticancer therapy regimens, even though the exact role of TOP2A in cancer remains elusive. Herein we report that MDM4 and TOP2A bind to each other and are mutually upregulated at the post-translational level, leading to enhanced TOP2A catalytic activity, inhibition of p53, and increased tumor-cell proliferation. We demonstrate that the C-terminal region (CTR) of TOP2A binds to a unique sequence (residues 188-238) of MDM4, which contains an auto-inhibitory segment regulating MDM4-p53 interaction. TOP2A binding in turn activates MDM4 for p53 binding, resulting in enhanced inhibition of p53 and cancer cell proliferation. Conversely, binding of the MDM4 sequence to the CTR of TOP2A upregulates TOP2A protein expression. This in turn interferes with TOP2A DNA-decatenating activity. These results reveal novel functions of MDM4 and TOP2A as well as their interactions in oncogenesis, suggesting that inhibition of the MDM4-TOP2A interaction may represent a novel strategy in specifically and simultaneously targeting TOP2A and MDM4 for cancer treatment. Citation Format: Tao Liu, Hailong Zhang, Sha Yi, Lubing Gu, Muxiang Zhou. Mutual regulation of MDM4 and TOP2A in cancer cell proliferation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3471.
Poly (ADP) Ribose Glycohydrolase Can Be Effectively Targeted in Pancreatic Cancer
Authors: Aditi Jain, Lebaron C. Agostini, Grace A. McCarthy, Saswati N. Chand, AnnJosette Ramirez, Avinoam Nevler, Joseph Cozzitorto, Christopher W. Schultz, Cinthya Yabar Lowder, Kate M. Smith, Ian D. Waddell, Maria Raitses-Gurevich, Chani Stossel, Yulia Glick Gorman, Dikla Atias, Charles J. Yeo, Jordan M. Winter, Kenneth P. Olive, Talia Golan, Michael J. Pishvaian, Donald Ogilvie, Dominic I. James, Allan M. Jordan, Jonathan R. Brody
Journal: Cancer Research (2019)

Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR (