tbuckley/cabot-search huggingface dataset:
Abstract SY06-02: Optically activated nanomedicines: Photochemical activation as a priming and imaging tool in pancreatic cancer
Authors: Tayyaba Hasan
Journal: Cancer Research (2021)

Abstract Optical activation of materials leads to thermal, photochemical and radiative processes which can be captured for response-based therapeutic design. The ability to use light as a reagent to provide free radical and activated oxygen-mediated cytotoxicity, combined with a control of conventional drug release, allows for the fabrication of light-controllable intelligent multiagent nanoconstructs that attack multiple pathways making nanomedicines more effective against cancer. This optically activated approach allows for a mechanistically diverse and spatiotemporally controlled strategy to tumor destruction. The molecules used for light activation have, in addition to therapeutic capabilities, finite fluorescence, creating an imaging handle and providing a built-in Theranostic process. Strategies for syntheses and applications of these nanoagents in biology and medicine will be discussed. Citation Format: Tayyaba Hasan. Optically activated nanomedicines: Photochemical activation as a priming and imaging tool in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY06-02.
Abstract 1712: <i>Neospora caninum:</i> An immunotherapeutic protozoan against cancer
Authors: Louis Lantier, Agathe Poupée-Beaugé, Anne Di Tommaso, Céline Ducournau, Stéphanie Germon, Gordon S. Lee, Antoine Touze, Nathalie moiré, Isabelle Dimier-Poisson
Journal: Cancer Research (2021)

Abstract Background: Immunotherapy induces, provides, and/or reactivates anti-tumor immune responses. Some microorganisms also can initiate response that lyzes infected tumor and/or stimulates systemic immunity. Attenuated viruses or bacteria are well studied as oncotherapeutics, but no protozoa except Toxoplasma gondii. We assessed the effect on tumors of other protozoa that were naturally non-pathogenic to humans. Thus, we discovered the ability to use Neospora caninum (Nc) in a manner and form that demonstrated a synergistic array of pertinent immunotherapeutic characteristics against solid cancers. We report on the most recent data notably from Nc engineered to secrete human IL-15 within the tumor. Methods: In vitro, the immunostimulatory properties of Nc strains wildtype and engineered to secrete human IL-15 were studied. In vivo experiments of treatment with of Nc tachyzoites administered locally (intra and peri tumoral) or remotely (subcutaneous) in a murine thymoma EG7 tumor and in human Merkel cell carcinoma (MCC). Results: We demonstrated that the treatment of thymoma EG7 by Nc strongly inhibited tumor development. Analysis of immune responses and interactions between Nc and tumor cells showed that Nc had the ability to lyze infected cancer cells, reactivated immune competence within the tumor microenvironment (TME), and activated the systemic immune system by promoting the recruitment of immune cells to the site of tumor. We also established in a NOD/SCID mouse model that Nc was able to induce a strong regression of human MCC. Recently, to further enhance oncotherapeutic effect, we engineered an Nc strain to secrete human IL-15 (cross reactive with mouse cells), associated with alpha subunit of IL-15 receptor, increasing its stability. This strain induced proliferation of human PBMCs and their secretion of IFN-γ. In the EG7 model, human IL-15 secreting Nc showed greater protection against tumor development, confirming enhancement of immunotherapy by engineering Nc to deliver/secrete IL-15. Conclusion: These results highlight Neospora caninum as a potentially extremely efficient, and non-toxic anti-cancer agent, capable of being engineered to express at its surface or to secrete bio-drugs, like human IL-15 cytokine. Our work has identified the broad clinical possibilities of using N. caninum as an oncolytic protozoan in human medicine capable of vectoring molecular therapy, overcoming TME defenses. Citation Format: Louis Lantier, Agathe Poupée-Beaugé, Anne Di Tommaso, Céline Ducournau, Stéphanie Germon, Gordon S. Lee, Antoine Touze, Nathalie moiré, Isabelle Dimier-Poisson. Neospora caninum: An immunotherapeutic protozoan against cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1712.
Abstract 222: Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics
Authors: Chengyue Wu, David A. Hormuth, Federico Pineda, Gregory S. Karczmar, Thomas E. Yankeelov
Journal: Cancer Research (2021)

Abstract Introduction: Standard-of-care neoadjuvant therapeutic regimens are based on clinical trials designed to identify treatment protocols at the population level, which cannot capture the unique characteristics of individual patients. Moreover, it is impossible for clinical trials to experimentally evaluate all the possible treatment combinations and dosing strategies. Mechanism-based, mathematical modeling can potentially address this critical barrier to achieving truly personalized treatment. In this contribution, we present preliminary results using a fluid dynamics model personalized with a patient's imaging data to optimize a drug injection protocol in breast cancer. Methods: Nine breast cancer patients are included in this study. MRI data are acquired, processed, and used to estimate hemodynamics and imported to our drug delivery model. By varying the dosing schedule, the model predicts varying dynamics of drug distribution throughout the breast. We define an objective function, MSTD, balancing the treatment efficacy and toxicity, and use it to optimize the injection protocol for each patient. The injection schedules tested include: (a) single injection on day 1 of each 3-week cycle; double injections of half the total dose each at (b) day 1 and 2, (c) day 1 and 3, (d) day 1 and 5, and (e) day 1 and 8 within each 3-week cycle. The doses tested vary from 0 to 100 μg/ml of maximal plasma concentration. Improvement ratio of the optimal protocol to a standard protocol, 10 μg/ml via schedule (a), is measured. Results: The optimal protocol and improvement are reported for each patient in Table 1. Conclusion: Our modeling system can efficiently solve the personalization of drug injection protocol as an optimal control problem. Different patients have different optimal treatment protocols, each of which is predicted to outperform the standard protocol. Table 1.Optimal injection protocol for individual patientsPatientOptimal scheduleOptimal dose (μg/ml)Improvement ratio1(e)8.891.492(e)6.071.823(e)5.882.124(e)7.362.415(e)5.193.266(e)5.203.377(e)5.703.598(e)4.103.079(e)4.593.49NCI U01CA142565, U01CA174706, R01CA218700, R01CA172801, U24CA226110, P30CA014599. CPRIT RR160005. Citation Format: Chengyue Wu, David A. Hormuth, Federico Pineda, Gregory S. Karczmar, Thomas E. Yankeelov. Towards patient-specific optimization of neoadjuvant treatment protocols for breast cancer based on image-based fluid dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 222.
Abstract 460: Novel breast cancer biomarker in liquid biopsies and its immune regulatory role
Authors: Safaa A. Ibrahim, Valerie Riehl, Kenneth D. Beaman
Journal: Cancer Research (2021)

Abstract The discovery of a feasible and specific biomarkers is required for early detection of breast cancer. Breast cancer secretes microvesicles (MV) in large quantities to blood circulation to communicate with distant cells such as immune cells to support tumor growth and prepare the metastatic niche. Our recent studies detected a specific peptide from the a2 isoform vacuolar ATPase (a2NTD) as a component of the MV of breast cancer cells and not from MV of normal mammary epithelial cells. a2NTD expression positively correlates with the invasiveness of breast cancer cells, modulates immune cells, and promotes tumor growth, and metastasis. Detection of a2NTD in liquid biopsies and determination of its regulatory role will offer a feasible and specific biomarker for breast cancer. We revealed that a2NTD were highly expressed in exosomes isolated from plasma of breast cancer patients (BC-Ex) in comparison to isolated exosomes from normal donors (N-Ex). BC-Ex induces the gene expression and the secretion of cancer promoting factors from PBMCs such as IL-8, MCP-1, TNF-α and MMP-9 relative to vehicle control or N-Ex. Angiogenesis assay showed that secreted factors from BC-Ex treated PBMCs promote tube formation in HUVEC cell line. In addition, treatment of whole blood from healthy volunteers with MDA MB-231 MV or recombinant a2NTD drives the neutrophil transition from high density neutrophils (HDN) to Low density neutrophils (LDN). Flow cytometrical analysis showed that LDN possess the PMN-MDSCs markers CD11b+ CD15+ CD14- CD33- HLA-DR-. In addition, a2NTD treatment was associated with decreased internal staining of Arg-1 in neutrophils and the release of Arg-1 suggesting that a2NTD reprograms neutrophils to have immunosuppressive phenotype. Together, this data shows that a2NTD can be a potential predictor of the growth and metastasis of breast cancer. Citation Format: Safaa A. Ibrahim, Valerie Riehl, Kenneth D. Beaman. Novel breast cancer biomarker in liquid biopsies and its immune regulatory role [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 460.
Abstract 1544: Generation of ALK CAR-T cells for neuroblastoma therapy
Authors: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Ineês Mota, Diego Alvarado, Elisa Landoni, Jasna Metovic, Manuel Nüesch, Rafael Blasco-Patiño, Mauro Papotti, Gianpietro Dotti, Roberto Chiarle
Journal: Cancer Research (2021)

Abstract Neuroblastoma (NB) is the most deadly cancer in children with dismal survival in high-risk patients. The majority of NB express the full length anaplastic lymphoma kinase (ALK) receptor, that typically acts as driver oncogene together with MYCN. In contrast to ALK-driven lung cancer or lymphoma, targeted therapies with ALK tyrosine kinase inhibitors (TKIs), despite encouraging, induce only partial responses in NB. Therefore, additional tools to improve NB treatment are strongly needed. To specifically target NB cells, we developed a series of ALK chimeric antigen receptor (CAR) T constructs from antibodies that recognize both human and mouse ALK. Murine ALK CAR-T cells are able to control the growth of ALK+ leukemia and NB in syngeneic tumor models without detectable toxicity. From the leading candidate, we generated fully humanized ALK CAR-T cells that showed potent in vitro killing activity against a large panel of human NB lines, with activity comparable to GD2 CAR-T cells that are currently in clinical trials for NB patients. Remarkably, ALK CAR-T treatment synergized in vivo with the ALK inhibitor lorlatinib. Mechanistically, lorlatinib not only reduced tumor growth, but enhanced ALK expression on the surface of tumor cells, thereby facilitating ALK CAR-T targeting. Combination of ALK CAR-T cells with lorlatinib resulted in enhanced killing of NB cells and cure or markedly increased survival in mouse models of human metastatic NB even with low ALK expression. These findings support the clinical development of ALK CAR-T cells for NB therapy. Citation Format: Elisa Bergaggio, Wei-Tien Tai, Andrea Aroldi, Ineês Mota, Diego Alvarado, Elisa Landoni, Jasna Metovic, Manuel Nüesch, Rafael Blasco-Patiño, Mauro Papotti, Gianpietro Dotti, Roberto Chiarle. Generation of ALK CAR-T cells for neuroblastoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1544.
Abstract 2656: Muscle wasting in head and neck carcinomas: Investigations on the underlying transcriptional reprogrammation
Authors: Héla Hachicha, Iryna Pirozhkova, Aurore Gelin, François Bidault, Valérie Rouffiac, Thibault Dayris, Thierry Ragot, Ingrid Breuskin, Caroline Even, Philippe Gorphe, Pierre Busson
Journal: Cancer Research (2021)

Abstract Introduction: Cancer cachexia is a multifactorial syndrome associated with a skeletal muscle atrophy that affects at least 55% of patients bearing Head and Neck Squamous Cell Carcinomas (HNSCCs). To our knowledge, molecular mechanisms of muscle alterations have never been investigated on clinical muscle specimens from HNSCC patients. The aim of this study was to perform transcriptome profiling by bulk RNAseq on muscle fragments from HNSCC patients with and without cachexia and from nude mice bearing human HNSCC xenografts. Methods: Our study was made in three parts: 1) In Vitro investigations on human myoblasts co-cultivated with HNSCC cells. 2) In Situ investigations on muscles collected from nude mice xenografted with HNSSCs cells (FADU). 3) Exploration of clinical muscle samples collected from HNSCC patients. RNA sequencing was used to assess gene expression changes and gene function enrichment related to cachexia, in myoblasts co-cultivated with malignant cells as well as skeletal muscle samples collected from mice xenografted with HNSCC cells (FADU) or HNSCC patients. Results: In vitro experimentations showed significant impact of malignant cells on myoblast proliferation and differentiation. In nude mice, FADU xenografts resulted in distant loss of muscle mass at various anatomic locations. RNA sequencing of muscle samples from cachectic patients showed significant differences in gene expression compared with control muscles samples from tumor-free donors. Commonly modified pathways included immune and inflammatory response, mitochondrial metabolism and striated muscle differentiation. The most remarkable finding was the up-regulation of the BIRC3 transcript which encodes the anti-apoptotic protein c-IAP2. This alteration was observed both in human cachectic muscles and murine muscle fragments from tumor-bearing mice. Conclusions: Although the mechanism of BIRC3 up-regulation in cachectic muscle cells is not well understood, this finding is likely to be important for patient management in a context of promising therapeutic results obtained using Smac mimetics. Because these compounds are inhibitors of the c-IAP protein family, it will be important in the future to monitor their positive or negative effects on muscle alterations in cachectic HNSCC patients. Citation Format: Héla Hachicha, Iryna Pirozhkova, Aurore Gelin, François Bidault, Valérie Rouffiac, Thibault Dayris, Thierry Ragot, Ingrid Breuskin, Caroline Even, Philippe Gorphe, Pierre Busson. Muscle wasting in head and neck carcinomas: Investigations on the underlying transcriptional reprogrammation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2656.
Late Potentials and Pace-Mapping as Guides for Ablation of Ventricular Tachycardia in Patients with Nonischemic cardiomyopathy
Authors: Nakahara Shiro, Toratani Noritaka, Kamijima Tohru, Okano Akiko, Kobayashi Sayuki, Sakai Yoshihiko, Takayanagi Kan, Shivkumar Kalyanam
Journal: Circulation (2013)
Abstract 2036: Plasticity and vulnerability associated with extrachromosomal and intrachromosomal BRAF amplifications
Authors: Kai Song, Jenna Minami, Trevor Ridgley, Arthur Huang, Rachana Jayaraman, William Crosson, Jesus Salazar, Eli Pazol, Senaratne Niroshi, Rao Nagesh, Kim Paraiso, Thomas Graeber
Journal: Cancer Research (2021)

Abstract Cancer cells display two modes of focal amplifications (FA): extrachromosomal double minutes (DMs/ecDNAs) and intrachromosomal homogenously staining regions (HSRs). Understanding the plasticity of these two modes is critical for preventing targeted therapy resistance. We developed a combined BRAF plus MEK inhibitor resistance melanoma model that bears high BRAF amplifications through both ecDNA and HSR modes, and investigated FA dynamics in the context of drug resistance plasticity. Cells harboring FAs displayed mode switching between ecDNAs and HSRs, from both de novo genetic changes and selection of pre-existing subpopulations. We found that copy number plasticity is not exclusive to ecDNAs. Single cell-derived clones with HSRs also exhibit BRAF copy number and corresponding HSR length plasticity that allows them to respond to dose reduction and recover from drug addiction. In addition, upon kinase inhibitor escalation, we observed reproducible selection for cells with BRAF kinase domain duplications residing on ecDNAs. Whole genome sequencing of sublines with different FA formats allowed fine reconstructions of BRAF amplicon and revealed conserved structures during the transitions due to drug dose manipulations. The amplification boundaries in our cell line model were found consistent with those in clinically observed cases of combined BRAF/MAPK inhibitor resistance. RNA-seq and CRISPR screening performed on parental, ecDNA and HSR sublines revealed distinct biology and vulnerabilities associated with each kind of FA. Vulnerabilities for genes involved in ecDNA maintenance in DNA repair pathways identified in our model are consistent with previous reports, such as a role for DNA-dependent protein kinase (DNA-PK/PRKDC). Our screen reveals many new targets. In sum, the karyotypic plasticity of FAs allows cancer cells to respond to drug dose challenges through a myriad of mechanisms, including increases or decreases in DMs, shortening of HSRs, and acquisition of secondary resistance mechanisms. The cellular vulnerabilities identified in our study provide roadmaps for therapeutically targeting each kind of FA mode. Citation Format: Kai Song, Jenna Minami, Trevor Ridgley, Arthur Huang, Rachana Jayaraman, William Crosson, Jesus Salazar, Eli Pazol, Senaratne Niroshi, Rao Nagesh, Kim Paraiso, Thomas Graeber. Plasticity and vulnerability associated with extrachromosomal and intrachromosomal BRAF amplifications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2036.
Abstract LB202: Biphosphorylated Src at Y416/527 is active in triple-negative breast cancer cell lines and a subset of patient samples
Authors: Olga V. Razorenova, Luke Nelson, Heather Wright, Nguyen Dinh, Kevin Nguyen, Scott Heinemann
Journal: Cancer Research (2021)

Abstract Targeted therapeutics are needed for triple-negative breast cancer (TNBC). In this study, we investigated the activation of Src family of cytoplasmic tyrosine kinases (SFKs) and two SFK substrates: CUB-domain containing protein 1 (CDCP1) and protein kinase C delta (PKCd) in 56 formalin-fixed, paraffin-embedded (FFPE) TNBCs. Expression of SFK phosphorylated at Y416 (SFK_pY416+) in tumor cells was strongly associated with phosphorylation of CDCP1 and PKCd (CDCP1_ pY743+ and PKCd_pY311+), as assessed by immunohistochemistry, indicating increased SFK activity in situ. To enable biochemical analysis, protein extraction from FFPE tissue was optimized. Cleaved CDCP1 isoform (70 kDa) was expressed to a varying degree in all samples but only phosphorylated in TNBC tumor cells that expressed SFK_pY416. Interestingly, active SFK was found to be biphosphorylated (SFK_pY416+/pY527+). Biphosphorylated active SFK was observed more frequently in forkhead box protein A1 (FOXA1)-TNBCs. In addition, in SFK_pY416-samples, FOXA1+ TNBC tended to be SFK_pY527+ (classic inactive SFK), and FOXA1- TNBC tended to be SFK_pY527-(SFK poised for activation). Strong SFK_pY416 staining was also observed in tumor-infiltrating lymphocytes in a subset of TNBCs with high tumor-infiltrating lymphocyte content. This report will facilitate protein biochemical analysis of FFPE tumor samples and justifies the development of therapies targeting the SFK/CDCP1/PKCd pathway for TNBC treatment. Citation Format: Olga V. Razorenova, Luke Nelson, Heather Wright, Nguyen Dinh, Kevin Nguyen, Scott Heinemann. Biphosphorylated Src at Y416/527 is active in triple-negative breast cancer cell lines and a subset of patient samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB202.
Perioperative and mid-term oncological and functional outcomes after partial nephrectomy for entirely endophytic renal tumors: A prospective multicenter observational study (the RECORD2 Project)
Authors: A. Mari, F. Di Maida, A. Antonelli, M. Barale, P. Bove, E. Brunocilla, R. Campi, U. Capitanio, C. Fiori, A. Gallioli, A.A. Grosso, P. Gontero, N. Longo, F. Montorsi, F. Porpiglia, A. Porreca, B. Rocco, R. Schiavina, V. Li Marzi, R. Tellini, C. Trombetta, V. Ficarra, M. Carini, A. Minervini
Journal: European Urology (2021)
Concordance of biopsy and pathologic ISUP grading in salvage radical prostatectomy patients for recurrent prostate cancer
Authors: F. Preisser, R.M. Pose, A. Heinze, T. Steuber, U. Michl, G. Salomon, P. Mandel, M. Graefen, D. Tilki
Journal: European Urology (2021)
Prognostic Value of Urinary and Plasma C-Type Natriuretic Peptide in Acute Decompensated Heart Failure
Authors: Xiao Ma, Yang Chen, Shawn H. Reginauld, Christopher G. Scott, Seethalakshmi R. Iyer, Jacob J. Schaefer, Tomoko Ichiki, Horng H. Chen, Andrew D. Rule, John C. Burnett, S. Jeson Sangaralingham
Journal: JACC Heart Failure (2021)