bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2956: Humanized IL17A/hIL17F mouse model provides a preclinical tool for the evaluation of therapeutic drugs targeting to IL-17 pathway
Authors: Li Chong , Zhao Lei , Zhu Tao , Chen Yichao , Kokabee Leila , Guo Chaoshe 
Published: July 2021

Abstract
Interleukin 17 (IL-17) is described as a pro-inflammatory cytokine produced by activated CD4 cells. Evidence shows that IL-17 is highly up-regulated at sites of inflammatory tissues of autoimmune diseases and amplifies the inflammation through synergy with other cytokines, such as TNF (tumor necrosis factor) α. Therefore, targeting IL-17/IL-17R, IL-17-producing pathways or IL-17-mediated signaling pathways can be considered for future therapy in autoimmune diseases. To evaluate the efficacy of IL17A and IL17F antibodies, we generated a double humanized B-hIL17A/hIL17F mouse in Biocytogen. In this model, the sequences encoding the extracellular domains of the mouse IL17A gene and the IL17F gene were replaced with the corresponding human sequences. IL17A and IL17F protein expression was detected in B-hIL17A/hIL17F mice by ELISA using a species-specific IL17A ELISA kit. In efficacy study of anti-human IL17A and IL17F antibody with psoriasis model induced in B-hIL17A/hIL17F mice, mice were treated with different dose of bimekizumab produced in house. Erythema and scaling score of the skin was significantly reduced compared with non-treatment group. The results suggest B-hIL17A/hIL17F mouse model is an effective tool for in vivo efficacy evaluation, which may represent a promising model for screening IL17 related drug candidates for the treatment of psoriasis disease.
Citation Format: Chong Li, Lei Zhao, Tao Zhu, Yichao Chen, Leila Kokabee, Chaoshe Guo. Humanized IL17A/hIL17F mouse model provides a preclinical tool for the evaluation of therapeutic drugs targeting to IL-17 pathway [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 2956.
Abstract 2966: Novel ex vivo model for ERα positive breast cancer
Authors: Munne Pauliina M. , Martikainen Lahja , Räty Iiris , Bertula Kia , Nonappa Nonappa , Peura Aino , Mutka Minna , Leidenius Marjut , Meretoja Tuomo , Kovanen Panu , Mattson Johanna , Heikkila Paivi , Joensuu Heikki , Ikkala Olli , Klefstrom Juha T. 
Published: July 2021

Abstract
Three-dimensional ex vivo cultures from patient-derived tumor tissue offer new opportunities for drug development and personalized treatment of cancer. However, one of the main challenges in establishing a tumor type faithful ex vivo tissue culture system is in optimization of biochemical and physical microenvironment to preserve desired phenotypic features. A collaboration with the Helsinki University Hospital enables us to receive live patient-derived breast cancer tissue samples from most breast cancer surgeries performed in the Southern Finland, typically samples arriving twice a week. Together with a group of materials scientists from Aalto Technical University we have explored seven different 3D culture matrices and defined their biomechanical properties and stiffness values with rheological measurements. Four investigated matrices preserved the luminal CK8+ cell phenotype of the luminal cancers they derived from, whereas rest of the matrices that included commonly used Matrigel and collagen scaffolds promoted a switch in the cell identity from luminal CK8+ to basal CK14+ phenotype. Furthermore, the genetic expression profiles examined with NGS corresponded to observed phenotypic switch. We noticed significant species-specific differences between mouse mammary and human breast samples in their morphology, phenotypic responses and ERα+ preservation to microenvironmental matrix stiffness. Furthermore, a combination of scaffold stiffness and composition of biochemical matrix constituency is required for long-term maintenance of ERα+ luminal tumour phenotype. Therefore, both physical properties and composition of the microenvironment need to be optimized for maintenance of breast tumor type specific phenotype and genetic profiles of ex vivo tumor explant cultures.
Citation Format: Pauliina M. Munne, Lahja Martikainen, Iiris Räty, Kia Bertula, Nonappa Nonappa, Aino Peura, Minna Mutka, Marjut Leidenius, Tuomo Meretoja, Panu Kovanen, Johanna Mattson, Paivi Heikkila, Heikki Joensuu, Olli Ikkala, Juha T. Klefstrom. Novel ex vivo model for ERα positive breast 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 2966.
Abstract 297: Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy
Authors: Li Derun , Zhang Hongjun , Lyons Thomas W. , Martinot Theodore A. , Achab Abdelghani , lu Min , Nogle Lisa M. , McMinn Spencer , Mitcheltree Matthew J. , Childers Matthew , Pu Qinglin , Gathiaka Symon , Palani Anand , Chakravarthy Kalyan , DeCastro Amy D. , O'Neil Jennifer , Afshar Roshi , Walsh Nicole C. , Fan Peter W. , Cheng Mangeng , Miller Richard , Doty Amy , Palte Rachel , Kim Hai-Young , Saurí Josep , Beard Adam , Brynczka Christopher , Fischer Christian 
Published: July 2021

Abstract
Arginase overexpression has been associated with poor survival rates in advanced cancer patients treated with Keytruda. High levels of Arginase may lead to a depletion of arginine within the tumor microenvironment, inhibiting the immune response. Thus, arginase inhibition has the potential to greatly enhance immunotherapy treatment. Discovering novel arginase inhibitors was met with several challenges including analyzing/purifying extremely polar chemical matter without chromophores, synthetically challenging space, and poor bioavailability of compounds with ClogP less than minus two.
Cross-functional collaborations and innovations rapidly overcame these challenges. Structural chemistry and modeling guided the design of novel arginase inhibitors. Analytical and purification groups developed innovative analytical/purification methods. Novel technologies including ReatIR and Vapourtec flow system, provided key intermediates to enable chartering into synthetically challenging space. Through creative cyclization strategies and active transport strategy to improve bioavailability, the team ultimately delivered a diverse set of potent and extremely synthetically challenging arginase inhibitors to study the potential of arginase inhibition. Preliminary in vivo evaluation showed single agent efficacy in an EMT6 model. These arginase inhibitors have the potential to enhance immunotherapy.
Citation Format: Derun Li, Hongjun Zhang, Thomas W. Lyons, Theodore A. Martinot, Abdelghani Achab, Min lu, Lisa M. Nogle, Spencer McMinn, Matthew J. Mitcheltree, Matthew Childers, Qinglin Pu, Symon Gathiaka, Anand Palani, Kalyan Chakravarthy, Amy D. DeCastro, Jennifer O'Neil, Roshi Afshar, Nicole C. Walsh, Peter W. Fan, Mangeng Cheng, Richard Miller, Amy Doty, Rachel Palte, Hai-Young Kim, Josep Saurí, Adam Beard, Christopher Brynczka, Christian Fischer. Innovation in delivering synthetically challenging bicyclic arginase inhibitors to enhance immunotherapy [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 297.
Abstract 2987: Comparison of the anticancer effects of Mitomycin-C and 5-Fluorouracil on novel periocular sebaceous carcinoma cell lines
Authors: Lang Steven H. , Gallo Ryan A. , Zhang Michelle G. , Tse David T. , Pelaez Daniel , Rong Andrew J. 
Published: July 2021

Abstract
Background: Sebaceous carcinoma (SC) is a highly malignant and potentially lethal neoplasm that most commonly arises from the ocular adnexa. Surgical management is the current mainstay of treatment; however, globe sparing tumor control is often complicated by pagetoid (or intraepithelial) invasion. Topical mitomycin-c (MMC) or 5-fluorouracil (5-FU) have been used as adjunctive medical therapy on the basis of their success in treating other ocular neoplasms. Yet, little is known of their effects on SC tumorgenicity. Here, we characterized effects of MMC and 5-FU in SC in vitro.
Methods: Periocular SC tissue samples were collected from two patients with histologically confirmed disease. This study was approved by the University of Miami Institutional Review Board and was conducted in a Health Insurance Portability and Accountability Act of 1996—compliant manner. Molecular characterization of the SC cells was done by immunocytochemistry and whole exome sequencing. SC cells were treated with MMC and 5-FU. The cytotoxic effects were evaluated using a viability assay and the kinetics of these effects were investigated by measuring cell proliferation over time. Migration capability of SC cells after drug treatment was examined by wound healing assays.
Results: Two SC cell lines, called Bascom Palmer 50 and 52 (BP50 and BP52), were established. Both cell lines retain the immunophenotypic and molecular features of SC. MMC reduced cell viability in both cell lines in a dose-dependent manner. MMC decreased SC cell proliferation and reduced overall cell number significantly compared to the untreated controls in a dose-dependent manner. MMC also inhibited SC migration capacity significantly. Conversely, 5-FU treatment did not affect cell viability or migration capacity in a dose-dependent fashion. While treatment with high-dose 5-FU inhibited SC proliferation, it did not reduce cell number below baseline.
Conclusions: We successfully generated SC cell lines and characterized the effects of MMC and 5-FU on these lines. Clinical medical management of periocular SC has been based of empirical data. Our findings suggest that MMC possess superior cytotoxic and cytostatic activity against SC compared to 5-FU in vitro. Taken together, these preliminary findings indicate that MMC may be more efficacious than 5-FU in the treatment of periocular SC. Currently, investigations are underway to identify novel therapeutic targets and test their efficacy in our cell lines.
Citation Format: Steven H. Lang, Ryan A. Gallo, Michelle G. Zhang, David T. Tse, Daniel Pelaez, Andrew J. Rong. Comparison of the anticancer effects of Mitomycin-C and 5-Fluorouracil on novel periocular sebaceous carcinoma cell lines [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 2987.
Abstract 2988: Characterization of 3D models of human breast, prostate and colorectal cancer
Authors: Hudson Katie , Cross Neil , Jordan-Mahy Nicola , Leyland Rebecca 
Published: July 2021

Abstract
Tumorigenic expression of programmed death-ligand 1 (PD-L1) and its receptor PD-1 is found in many cancers, though the intrinsic roles of these proteins and how immunotherapy treatment may affect these pathways needs to be fully explored across human cancers. One platform to assess the expression and regulation of these proteins is 3D cell culture, which is thought to more closely mimic the architecture of solid tumors and more closely recapitulate in vivo human tumors in terms of cell heterogeneity, immunological and tumorigenic marker expression and treatment response, to investigate PD-L1/PD-1 signaling in cancer cells. Human breast (MDA-MB-231 and MCF-7), prostate (LNCaP and PC3) and colorectal (SW480 and SW620) cancer cell lines were cultured in both scaffold-free and scaffold-based 3D cell culture models to facilitate the formation of spheroids that display cell heterogeneity. 3D cancer models were analyzed by microscopy, qPCR and flow cytometry to assess the viability of spheroids, and measure any alterations in immunological and tumorigenic markers at mRNA and protein level, respectively, compared to their 2D monolayer counterparts. Breast, prostate and colorectal cancer cells cultured in 3D were highly viable over time and displayed significantly altered levels of immunological and tumorigenic marker expression at mRNA and/or protein level compared to their 2D monolayer counterparts. Importantly, PD-L1 expression changed in a 3D environment which may be linked to the increased cell-cell and cell-ECM interactions; increased expression of PD-L1 regulatory genes/proteins; or hypoxic regions that establish in 3D spheroids. The significantly altered expression levels of immunological and tumorigenic markers in a 3D cell culture environment is more likely to mimic that of an in vivo human tumor than standard 2D cell culture; allowing for optimized in vitro evaluation of the role of tumorigenic PD-L1/PD-1 and how immunotherapy treatment may affect these pathways.
Citation Format: Katie Hudson, Neil Cross, Nicola Jordan-Mahy, Rebecca Leyland. Characterization of 3D models of human breast, prostate and colorectal 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 2988.
Abstract 299: Self-assembling peptide hydrogel for delivery and conversion of temozolomide in glioblastoma treatment
Authors: Pitz Megan , Nukovic Alexandra , Elpers Margaret , Wilde Sarah , Alexander-Bryant Angela 
Published: July 2021

Abstract
Traditional treatment methods for glioblastoma multiforme (GBM) including resection, radiation, and chemotherapy have been largely unsuccessful, with a current 5-year survival rate of 5.6%. In this project we examine the potential of nanosized self-assembling peptide hydrogels to locally deliver and convert temozolomide (TMZ), an FDA-approved pH-sensitive prodrug, for GBM treatment. The peptide hydrogel is designed to load TMZ into the hydrophobic regions of the hydrogels, and during hydrogel degradation in vivo, convert TMZ into its active form. Hydrogel characterization, drug loading and conversion, and cellular uptake and viability are examined to determine the in vitro efficacy of this delivery method. A combination of dynamic light scattering (DLS), scanning electron microscopy (SEM), and circular dichroism (CD) are used to characterize size and structure of the hydrogels. Loading and conversion of TMZ are quantified using UV-Vis spectroscopy. Fluorescent imaging and cell viability assays are used to determine uptake and anti-cancer effects of the drug-loaded hydrogels on glioblastoma cells. Our results show high uptake in drug-resistant T98G and non-resistant LN-18 glioblastoma cell lines using several of our tunable peptide formulations. CD has shown that all peptide formulations form mostly beta-sheet and random structures during self-assembly. SEM and DLS show that peptide hydrogels formed in a water solvent are more polydisperse than hydrogels in a PBS solvent. Using a pH-meter, we have shown that as the peptides in PBS degrade, there is an increase in local pH. Additionally, TMZ conversion is observed to occur more quickly in drug-loaded hydrogels than TMZ alone. Preliminary cell viability studies have shown that unassembled peptides are not cytotoxic; some of the assembled peptide hydrogels are cytotoxic while others maintain greater than 80% viability when compared to untreated cells. Future studies for the project will include cell viability assays with the most promising peptide formulations loaded with TMZ to determine efficacy of the delivery and conversion system. Finally, this project will culminate in an in vivo study to confirm the overall anti-cancer effect of the drug-loaded peptide hydrogels in a tumor model of GBM. Acknowledgements: This research was supported in part by the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740, the National Institute of Health Award # P30GM131959, and National Science Foundation's Graduate Research Fellowship Program.
Citation Format: Megan Pitz, Alexandra Nukovic, Margaret Elpers, Sarah Wilde, Angela Alexander-Bryant. Self-assembling peptide hydrogel for delivery and conversion of temozolomide in glioblastoma treatment [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 299.
Abstract 2990: In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) patient samples
Authors: Vishwakarma Bandana Ajay , Wesa Amy 
Published: July 2021

Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. It is characterized by proliferation and accumulation of monoclonal, small, mature CD5+ B-cells in peripheral blood, bone marrow and secondary lymphoid organs. The current treatment regimens have improved overall survival but CLL patients will eventually experience relapse. The disease is still incurable making it a necessity to discover and screen for new drugs. Patient derived CLL specimens undergo spontaneous apoptosis when grown in culture and is a major limitation to screening for new therapeutic drugs. We have established an in vitro culture conditions which supports growth and proliferation of patient derived primary CLL cells. Champions has a bank of primary CLL patient samples across different Rai stage, genetic mutations and relapsed and refractory cases. We tested nine CLL samples (models) for proliferation. All nine models proliferated 1.5 to 9.6-fold in the optimized media in 6 days, as measured using CellTiter-Glo. Flow cytometric analysis showed that the CLL cells mostly retained the primary phenotypic characteristic CD5+CD10-Cd19+CD20+ even after being in the culture for 6 days. Next, we screened for sensitivity of primary CLL patient samples (N=9) against known standard of care (SOC) drugs venetoclax, ibrutinib, idelalisib, chlorambucil and cytarabine. Primary PBMC patient samples were seeded in 96 well plates in the enriched media and treated with respective drugs over a concentration range over 5 logs. Drug sensitivity was assessed using CellTiter-Glo® luminescent cell viability assay on day 6. Our in vitro assay indicated varied sensitivity of patient samples to approved standard of care drugs. A relapsed bendamustine pre-treated patient sample was sensitive to all the SOC drugs tested. In addition to drug response, whole exome sequencing and RNAseq are being conducted on these samples, to compare mutational analyses with drug responsiveness. With clinically annotated patient-derived CLL samples, WES and RNAseq plus drug response to standard of care provides a comprehensive ex vivo platform for the preclinical testing of drug candidates, which may not only provide information on agent efficacy, but that can permit potential biomarker mining and exploration of patient selection criteria for investigational new agents in CLL.
Citation Format: Bandana Ajay Vishwakarma, Amy Wesa. In vitro drug sensitivity screening platform for primary chronic lymphocytic leukemia (CLL) 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 2990.
Abstract 3001: Multicellular structures of serous ovarian cancer nature isolated from pleural effusions are sufficient to recreate peritoneal carcinomatosis in immunosuppressed mice
Authors: Goyeneche Alicia A. , Sunassee Ashwyna , Ritch Sabrina J. , Koch Michael , Bell Maria , Gao Zu-hua , Telleria Carlos M. 
Published: July 2021

Abstract
High-grade serous ovarian cancer (HGSOC) is a lethal disease often diagnosed in grade III International Federation of Gynecology and Obstetrics (FIGO) upon colonization of the peritoneal cavity, or in grade IV FIGO when it colonizes the pleural cavity. When in the pleural cavity, the disease often manifests with accumulation of pleural effusions containing multicellular structures (MCS). In this work, we studied whether MCS isolated from a pleural effusion of a patient that did not respond to chemotherapy are sufficient to cause peritoneal carcinomatosis in immunosuppressed mice when implanted orthotopically. Nude mice were injected intraperitoneally with MCS isolated from the pleural effusions of a heavily treated patient. We determined the time taken for the disease to develop, the tissues targeted, presence or absence of ascites, the macroscopic and microscopic disease appearance, and the expression of standard biomarkers of HGSOC. We contrasted the histopathology of the tumors recreated in mice against that of the original tumor taken during diagnostic surgery. MCS from pleural effusions were sufficient to recreate disease in the mice, which reached their humane-endpoint seven months following MCS injection (n=3). The animals developed abundant cellular peritoneal ascites. In addition, macro and microscopic discrete disease was observed in the fat surrounding the ovaries, the omental-pancreatic area, the peritoneal wall, a lymph node, the diaphragm, and the lung. The histopathology of the disease showed infiltrating papillary architecture, areas with cells arranged in a solid pattern, and tumor nests with slit-like lumens that stained positive for mutant p53, p16, and WT1. Our results provide proof of principle that MCS isolated from pleural effusions of a HGSOC patient are sufficient to recreate peritoneal carcinomatosis in nude mice, depicting most morphological features found at postoperative diagnosis.
Citation Format: Alicia A. Goyeneche, Ashwyna Sunassee, Sabrina J. Ritch, Michael Koch, Maria Bell, Zu-hua Gao, Carlos M. Telleria. Multicellular structures of serous ovarian cancer nature isolated from pleural effusions are sufficient to recreate peritoneal carcinomatosis in immunosuppressed mice [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 3001.