tbuckley/cabot-search huggingface dataset:
Abstract 3228: An online tool to balance baseline covariates for mouse clinical trials
Authors: Binchen Mao, Davy Ouyang, Henry Li, Sheng Guo
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Randomization is a cornerstone of controlled studies such as mouse clinical trials (MCT). However, simple randomization schemes often lead to unbalanced group allocations, therefore reducing the statistical power of experimental studies. This issue becomes more relevant and critical in MCTs where it is usually necessary to allocate a large number of mice into multiple groups/arms, so that all groups have close tumor volumes (measured by average and variance) as well as other covariates such as body weight, while at the same time also using as few mice as possible. Possible allocations grow exponentially by mouse and group number, and it is computationally intractable to identify optimal allocation schemes; instead, heuristic methods are used to search for near-optimal solutions. Studylog® systems can balance tumor volume with at most one baseline covariate. Randmice, a newly developed tool by Stimunity, shows good performance in balancing bilateral tumors, but it cannot balance more than two baseline covariates. We have developed a fast, in-house, online tool to balance any number of baseline covariates and, in addition, users can assign different weights to each baseline covariate based on levels of importance. METHODS: We used a two-step method to balance designated baseline covariates for MCTs. First, we used a matched algorithm to find sub-matches from a population of mice, by grouping together mice with similar values of baseline covariates. Based on these sub-matches, we then used an optimization method to minimize the imbalance of baseline covariates guided by a weighted score function. Once the optimization was complete, a summary statistic table and a diagnostic plot for the top 10 group allocation solutions were displayed for picking the most suitable solution. RESULTS: We used our baseline covariate balancing tool for a benchmark set of mouse clinical trials with more than one baseline covariate to be balanced out, with the difference of key baseline covariates among groups well under control with close means. The tool completed the allocations in a few minutes by running on a single-CPU computer. CONCLUSIONS: We have developed a fast and powerful online tool to help preclinical researchers balance key baseline covariates in their studies, particularly in mouse clinical trials. Citation Format: Binchen Mao, Davy Ouyang, Henry Li, Sheng Guo. An online tool to balance baseline covariates for mouse clinical trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3228.
Abstract 3795: Investigate the mechanism of actions of flavonoid dimers in reversing doxorubicin resistance in breast cancer stem cells
Authors: Gege Sun, Iris L. Wong, Jiahua Cui, Zhen Liu, Bill T. Chan, Larry M. Chow
Journal: Cancer Research (2020)

Abstract Drug resistance, radioresistance and metastasis are the biggest hurdle in effective cancer treatment. Recent studies suggest that these problems might be caused by the presence of cancer stem cells (CSCs). CSCs are a small group of cells which can self-renew, remain undifferentiated, resist to cancer drugs and radiotherapy. It can be predicted that selective killing of CSCs may lead to tutor regression and may be a new therapeutic solution. Naturally occurring flavonoids are weakly active in inhibiting ABC transporter leading to drug accumulation in cancer cells. We have been working on the design, synthesis and characterisation of novel flavonoid dimers that can be used to reverse drug resistance in cancer cells. We recently discovered that a new class of triazole-linked flavonoid dimers 13_9 and 15_2 were effective in reversing drug resistance in CD44+CD24-/low MCF7 breast cancer stem cells at an effective concentration of less than 32 nM. Our studies suggested that a novel mechanism was involved which is independent of ABC transporters. To determine the mechanism behind, we have designed and synthesised a photoactivatable derivative of 13_9 (13_9X2) to identify the protein target(s). 13_9X2 contains a photoactivating functional group which can capture the target protein by forming a covalent bond under UV irradiation and a clickable functional group which can be used for pull-down and further identification using mass spectrometry. One candidate target is peroxiredoxin 1 (PRDX-1) which is a reactive oxygen species (ROS) scavenger. We hypothesise that CSCs are resistant to doxorubicin-induced ROS damage by overexpressing PRDX-1. By binding and disrupting PRDX-1, 13_9 and 15_2 reduce ROS scavenging ability of PRDX-1, resulting in the reversal of drug resistance in CSCs. This work provides new insights into the mechanisms of cell signalling regulation of cancer cell resistance in breast CSCs and provides a better understanding of how flavonoid dimers reverse drug resistance in CSCs. Additionally, this work contributes to the development of new anticancer drugs which can sensitize CSCs to current chemotherapy. Citation Format: Gege Sun, Iris L. Wong, Jiahua Cui, Zhen Liu, Bill T. Chan, Larry M. Chow. Investigate the mechanism of actions of flavonoid dimers in reversing doxorubicin resistance in breast cancer stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3795.
Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial
Authors: Ephraim J. Fuchs, Paul V. O’Donnell, Mary Eapen, Brent Logan, Joseph H. Antin, Peter Dawson, Steven Devine, Mary M. Horowitz, Mitchell E. Horwitz, Chatchada Karanes, Eric Leifer, John M. Magenau, Joseph P. McGuirk, Lawrence E. Morris, Andrew R. Rezvani, Richard J. Jones, Claudio G. Brunstein
Journal: Blood (2020)
Abstract 949: Anti-cancer activity by photoimmunotherapy is driven by adaptive immune responses and vaccinates the host against the tumor
Authors: C. Daniel De Magalhaes Filho, Michelle A. Hsu, Stephanie M. Okamura, Dany Gitnick, Estela Solis, Jerry J. Fong, Miguel Garcia-Guzman
Journal: Cancer Research (2020)

Abstract INTRODUCTION: Photoimmunotherapy (PIT) is an investigational anti-cancer treatment platform utilizing cell-targeted antibodies conjugated to the IR700 (IRDye 700DX®) light-excitable dye. Upon illumination with non-thermal red light, target cells bound with antibody-conjugates undergo rapid necrosis. Previous work demonstrated that PIT induces features of immunogenic cell death of tumor cells and ignites an immune response against the tumor. In these preclinical studies, we investigated the extent to which the immune response contributes to the in vivo anti-cancer activity using syngeneic cancer models. METHODS: PIT treatment was applied to a panel of mouse and human cancer cell lines targeted by their respective antigen-binding conjugate in vitro, and the release of damage-associated molecular patterns (DAMPs) was measured from the cell supernatant. To determine the contribution of the immune response to PIT anti-cancer activity, PIT treatment was applied to immunocompetent animals with antibody-mediated CD8 T cell depletion, or blockade of CD40-CD40L axis concurrent with tumor implant or PIT treatment. To determine whether the immunogenic properties of PIT treatment induce vaccinal effects, immunocompetent animals were inoculated with in vitro PIT-treated cancer cells, and then challenged with live tumor cells in the contralateral flank one week later. RESULTS: Cancer cells treated with PIT released significant amounts of immunogenic cell death markers including DAMPs such as ATP and Annexin A1. The anti-cancer activity of PIT treatment in immunocompetent animals was inhibited when 1) pre-existing immunity was abrogated by blockade of the CD40-CD40L interaction at time of tumor implant, and 2) CD8 T cells were depleted from the animals. Applying CD40-CD40L blockade concurrent with PIT treatment partially abrogated anti-cancer activity. When animals were inoculated with cancer cells treated by PIT ex vivo, tumor rejection was achieved in 8 out of 9 animals when challenged with live tumor cells on the contralateral flank. CONCLUSIONS: Cancer treatment by PIT induces necrotic and immunogenic cell death resulting in local and systemic immune response. These preclinical data indicate that adaptive immune responses induced by PIT treatment drive the anti-cancer effects and can also provide vaccinal effects due to the release of DAMPs and cancer antigens. Citation Format: C. Daniel De Magalhaes Filho, Michelle A. Hsu, Stephanie M. Okamura, Dany Gitnick, Estela Solis, Jerry J. Fong, Miguel Garcia-Guzman. Anti-cancer activity by photoimmunotherapy is driven by adaptive immune responses and vaccinates the host against the tumor [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 949.
Abstract LB-360: Foreign body responses create a highly active anti-tumor environment to recruit and eradicate metastatic cells
Authors: Jing Wang, Matthew Hall, Grace Bushnell, Joseph Decker, Sophia Orbach, Ravi Raghani, Yining Zhang, Aaron Morris, Jeffery Ma, Pridvi Kandagatla, Jacqueline Jeruss, Lonnie Shea
Journal: Cancer Research (2020)

Abstract Immune signaling within a metastatic niche drives recruitment and colonization, and the subsequent tumor cell fate within the niche. We employed a biomaterial scaffold as a synthetic metastatic niche to dissect the signals driving the responses within the niche relative to the native metastatic niche, which was the lung in these models. For both the natural and the synthetic niche, Gr-1+ cells secreting S100A8/A9 were the major factors contributing to tumor cell recruitment. Interestingly, upon recruitment, tumor cells in the synthetic niche were observed to undergo senescence and were cleared whereas cells within the native niche accumulated and ultimately proliferated to form macrometastases. The synthetic niche has underlying inflammation due to the foreign body responses (FBR) consisting of N1-polarized Gr1+ myeloid cells, M1-polarizedmacrophage, mature dendritic cells and highly cytotoxic CTLs and NK cells, which were not observed in the lung. Furthermore, we found two proteins (osteopontin and decorin) that are associated with developing FBR greatly improve the cytotoxicity of CTLs and NK cells in the lung from stage 3 breast cancers by increasing their production of Perforin/Granzyme, Fas/TRAIL and IFNr/TNFa. Our results highlight the potential of FBR-associated biomolecules to be used as immune-editing anticancer drugs and also inspire the development of therapeutic implants to actively catch and eradicate metastatic cells. Citation Format: Jing Wang, Matthew Hall, Grace Bushnell, Joseph Decker, Sophia Orbach, Ravi Raghani, Yining Zhang, Aaron Morris, Jeffery Ma, Pridvi Kandagatla, Jacqueline Jeruss, Lonnie Shea. Foreign body responses create a highly active anti-tumor environment to recruit and eradicate metastatic cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-360.
Abstract 1426: A PI3K/AKT scaffolding protein, IQ motif-containing GTPase associating protein 1 (IQGAP1), promotes head and neck carcinogenesis
Authors: Tao Wei, Suyong Choi, Darya Buehler, Richard A. Anderson, Paul F. Lambert
Journal: Cancer Research (2020)

Abstract Purpose: Head and neck cancer (HNC) is the sixth most common cancer worldwide with a 5-year survival rate of less than 50%. The PI3K/AKT/mTOR signaling pathway is frequently implicated in HNC. Recently, IQ motif-containing GTPase activating protein 1 (IQGAP1) was discovered to scaffold the PI3K/AKT signaling pathway. IQGAP1 gene expression is increased in HNC, raising the hypothesis that IQGAP1 contributes to HNC. Experimental Design: We performed a combination of in vitro studies using human cancer cell lines treated with a cell permeable peptide that interferes with IQGAP1's ability to bind to PI3K, and in vivo studies utilizing mice genetically knocked out for the Iqgap1 (Iqgap1-/-). In vivo EGF-stimulation assays were used to evaluate PI3K signaling. To study the role of IQGAP1 in HNC, we used a well-validated mouse model that drives HNC via a synthetic oral carcinogen, 4-nitroquinoline 1-oxide (4NQO). Results: IQGAP1 is necessary for efficient PI3K signaling in vitro and in vivo. Disruption of IQGAP1-scaffolded PI3K/AKT signaling reduced HNC cell survival. Iqgap1-/- mice had significantly lower cancer incidences, lesser disease severity and fewer cancer foci. IQGAP1 protein levels were increased in HNC arising in Iqgap1+/+ mice. The level of PI3K signaling in 4NQO-induced HNC arising in Iqgap1-/- mice was significantly reduced, consistent with the hypothesis that IQGAP1 contributes to HNC at least partly through PI3K signaling. High IQGAP1 expression correlated with reduced survival, and high pS6 levels correlated with high IQGAP1 levels in HNC patients. Conclusions: These data demonstrate that IQGAP1 contributes to head and neck carcinogenesis. Citation Format: Tao Wei, Suyong Choi, Darya Buehler, Richard A. Anderson, Paul F. Lambert. A PI3K/AKT scaffolding protein, IQ motif-containing GTPase associating protein 1 (IQGAP1), promotes head and neck carcinogenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1426.
Abstract B66: Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454
Authors: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra
Journal: Clinical Cancer Research (2020)

Abstract Metastasis causes poor prognosis and yet remains the least understood aspect of cancer. To identify key regulators of ovarian cancer metastasis that drive early colonization and are also essential for advanced metastasis, we have applied a novel, comprehensive approach of combining the analysis of an organotypic 3D culture model of early metastasis with ovarian cancer patient tumors. Using matched primary and metastatic tumors from 42 OC patients, we have compared the fully formed metastatic tumors with the primary tumor of the same patient. Since this is an end-point analysis and reveals little about the intermediated regulatory steps, we have also studied the changes occurring during early metastatic colonization as a result of the interactions with the metastatic microenvironment by using an organotypic 3D culture model of omental metastasis. By combining these two approaches, we have identified key master regulators of metastasis that are essential for early metastatic colonization and remain important in the fully formed metastatic tumor. We specifically focused on microRNAs because of their pleotropic effects through translational inhibition of multiple targets, and also our previous studies have demonstrated their important role in metastasis. Using this approach, we identified a novel microRNA miR-4454, downregulated in the metastasizing ovarian cancer cells through their specific paracrine interactions with fibroblasts in the metastatic microenvironment. The downregulation of miR-4454 promoted high-grade serous ovarian cancer cell migration, invasion, proliferation, and clonogenic growth as well as metastasis in xenografts. The targets of miR-4454 were identified by RNA-seq in high-grade serous ovarian cancer cells overexpressing the microRNA. SPARC and BAG5 were found to be the functional effectors of miR-4454. SPARC activated FAK signaling and promoted metastasis, while BAG5 inhibited apoptosis and helped the metastasizing cancer cells tide over adverse conditions in the microenvironment. Since miR-4454 is essential for early metastatic colonization as well as in advanced metastasis, targeting it is a promising approach to treat metastatic ovarian cancer. Citation Format: Subramanyam Dasari, Taruni Pandhiri, Tommaso Grassi, Daniel W. Visscher, Francesco Multinu, Komal Agarwal, Andrea Mariani, Viji Shridhar, Anirban K. Mitra. Paracrine interactions with microenvironmental fibroblasts promote ovarian cancer metastasis through downregulation of miR-4454 [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B66.
Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent In Situ Hybridization, and Next-Generation Sequencing
Authors: Yu-Cheng Lee, Jui-Yu Chen, Chun-Jui Huang, Harn-Shen Chen, An-Hang Yang, Jen-Fan Hang
Journal: Endocrine Pathology (2020)
Me6TREN targets β-catenin signaling to stimulate intestinal stem cell regeneration after radiation
Authors: Sihan Wang, Yi Han, Jing Zhang, Shu Yang, Zeng Fan, Feiling Song, Lijuan He, Wen Yue, Yanhua Li, Xuetao Pei
Journal: Theranostics (2020)

Background: Acute gastrointestinal syndrome (AGS) is one of the most severe clinical manifestations after exposure to high doses of radiation, and is life-threatening in radiological emergency scenarios. However, an unmet challenge is lacking of an FDA-approved drug that can ameliorate the damage of radiation-exposed intestinal tissues and accelerate the regeneration of injured epithelia. In this study, we investigated whether the small molecule Me6TREN (Me6) can regulate intestinal stem cell (ISC) proliferation and promote crypt regeneration after irradiation. Methods: Lethally irradiated mice were administered with Me6 or PBS to study the survival rate, and sections of their small intestine were subjected to immunostaining to evaluate epithelial regeneration. An intestinal organoid culture system was employed to detect the role of Me6 in organoid growth and ISC proliferation. We further investigated the key signaling pathways associated with Me6 using microarray, western blotting, and RNA interference techniques. Results: We identified the small molecule Me6 as a potent intestinal radiation countermeasure. Systemic administration of Me6 significantly improved ISC and crypt cell regeneration and enhanced the survival of mice after high doses of radiation. Using an in vitro intestinal organoid culture system, we found that Me6 not only induced ISC proliferation but also increased the budding rate of intestinal organoids under unirradiated and irradiated conditions. Me6 remarkably activated the expression of ISC-associated and proliferation-promoting genes, such as Ascl2, Lgr5, Myc, and CyclinD1. Mechanistically, Me6 strongly stimulated the phosphorylation of β-catenin at the S552 site and increased the transcriptional activity of β-catenin, a key signaling pathway for ISC self-renewal and proliferation. This is further evidenced by the fact that knockdown of β-catenin abolished the effect of Me6 on intestinal organoid growth in vitro and crypt regeneration in irradiated mice. Conclusion: The small molecule Me6TREN induced ISC proliferation, enhanced intestinal organoid growth in vitro, and promoted intestinal tissue regeneration after radiation injury by activating β-catenin signaling.
Author Correction: Altered proximal tubular cell glucose metabolism during acute kidney injury is associated with mortality
Authors: David Legouis, Sven-Erick Ricksten, Anna Faivre, Thomas Verissimo, Karim Gariani, Charles Verney, Pierre Galichon, Lena Berchtold, Eric Feraille, Marylise Fernandez, Sandrine Placier, Kari Koppitch, Alexandre Hertig, Pierre-Yves Martin, Maarten Naesens, Jérôme Pugin, Andrew P. McMahon, Pietro E. Cippà, Sophie de Seigneux
Journal: Nature Metabolism (2020)
Abstract 5059: Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies
Authors: Annika Wulf-Goldenberg, Verena Kiver, Maria Stecklum, Bernadette Brzezicha, Philipp Jurmeister, Caroline Schweiger, Jens-Uwe Blohmer, Ulrich Keilholz, Jens Hoffmann
Journal: Cancer Research (2020)

Abstract Breast cancer is a highly heterogeneous disease, with a heterogeneous prognosis. Patient-derived xenograft models (PDX) can reflect this heterogeneity and can be used to support the development of novel therapeutic strategies against breast cancer. Preclinical experiments with larger cohorts of breast cancer PDX can be used to model a clinical phase II study with new drugs or drug combinations. The predictive value of these preclinical trials is currently evaluated in co-clinical trials, where treatment effects are compared between patients and their corresponding PDX. We present results from our translational pre- and co-clinical studies in breast cancer immune therapy. As part of the EFRE-POP Project, we established PDX by collecting breast cancer tissue samples from surgery and engrafting them on immunodeficient mice. The tissues were obtained from patients with disease progression after chemotherapy with three to four drugs. PDXs have been successfully engrafted, phenotypically characterized and drug-screened. The PDXs were tested for response to the standard of care therapies. The staining for estrogen/progesterone/androgen/Her2 receptors, Ki-67, and CK5/6 of the original tumor and the PDX were comparable. The patient tumors and the breast cancer PDX models were further analyzed for the expression of PD-L1. We identified four patients that had received PD-1 or PD-L1 antibodies after a sample (used to establish a corresponding PDX) was obtained. To evaluate the response of our preclinical PDX models to immune checkpoint inhibitors, we engrafted mice with a human immune system either by transplanting allogeneic hematopoietic stem cells (HSC) or allogenic PBMC's from healthy donors. Besides, we were able to obtain PBMC's from the patients to set up an autologous model. The patient-derived tumors were transplanted to these humanized mice and after successful engraftment treated with the PD-1 or PD-L1 antibodies corresponding with the clinical treatment of the patient. In summary, humanized PDX of refractory tumors have been established and the first pre-clinical evaluation of response to immune therapy provides evidence that xenografts respond in a qualitatively similar manner as the patient. This suggests a translational relevance of the described pre-clinical models. Citation Format: Annika Wulf-Goldenberg, Verena Kiver, Maria Stecklum, Bernadette Brzezicha, Philipp Jurmeister, Caroline Schweiger, Jens-Uwe Blohmer, Ulrich Keilholz, Jens Hoffmann. Breast cancer patient-derived xenograft models for pre- and co-clinical investigation of immune based therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5059.