tbuckley/cabot-search huggingface dataset:
Abstract 965: Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel
Authors: Charles Fermaintt, Susan Mooberry, April L. Risinger
Journal: Cancer Research (2020)

Abstract Microtubule targeted agents (MTAs) are a mainstay in the treatment of breast cancer and they are often used in combination with targeted agents, including immunotherapies. Although patients with triple-negative breast cancers (TNBCs) have historically had poorer clinical outcomes due in part to a lack of targeted therapeutic options, these cancers are often more immunogenic than other types of breast cancer. Recently, the combination of the PD-L1 inhibitor atezolizumab with the taxane nab-paclitaxel was found to prolong progression-free survival in patients with metastatic TNBC. Other combinations of MTAs and immune checkpoint inhibitors are actively being evaluated in clinical trials. There is a mechanistic rationale for this combination because paclitaxel is a direct TLR4 agonist that promotes activation of the innate immune system. To date, there has not been a comprehensive comparison of the immunomodulatory effects of different MTAs on immune cells or on or TNBC cells. We hypothesized that MTAs that differentially alter interphase microtubule structure and dynamics would have distinct effects on cell-intrinsic immunogenic pathways and that these effects could impact the efficacy of these drugs in combination with immunotherapies. The effects of 5 MTAs used for the treatment of TNBC, paclitaxel, docetaxel, ixabepilone, vinorelbine, and eribulin, on the expression of antitumor cytokines and other immunomodulatory genes in myeloid and TNBC cells was evaluated. Our results show that the TLR4-mediated induction of TNFα that occurs in response to paclitaxel was not observed with either eribulin or vinorelbine. Conversely, upregulation of type 1 interferons and interferon-stimulated genes (ISGs) was observed in monocytes and in bone-marrow derived macrophages within 6 h of treatment with eribulin or vinorelbine, but not with any of the microtubule stabilizers. Eribulin-mediated induction of type 1 interferons was also observed in a subset of eribulin-treated TNBC cells and was independent of its antimitotic effects. Importantly, type I interferon signaling has been shown to enhance the efficacy of immune checkpoint inhibitors, suggesting that microtubule destabilizers could have distinct advantages as compared to microtubule stabilizers in combination with these agents. Together, these results provide evidence that MTAs have different immune modulatory properties and suggest that the specific immune signatures initiated by different MTAs need to be considered for their optimal use with targeted agents, including checkpoint inhibitors. These studies were funded by Eisai. Citation Format: Charles Fermaintt, Susan Mooberry, April L. Risinger. Eribulin promotes a distinct immunogenic gene expression signature as compared with paclitaxel [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 965.
Abstract 5621: Humanized rat model
Authors: Bisoye Towobola Adedeji, Fallon K. Noto, Tseten Yeshi Jamling, Yash Argawal, Cole Jamison Beatty, Sara Grace Ho, Antu Das, Rajeev Kishore Salunke, Moses Turkle Bility
Journal: Cancer Research (2020)

Abstract The development of Novel cancer immunotherapies has relied on the use of immune humanized mice. The field of study can be enhanced using an immune humanized rat, which will provide several advantages over the currently available humanized mouse models. The SRG OncoRat®; A Rag2/Il2rg double-knockout rat supports the growth of larger tumors for serial fine needle biopsies to assess immune infiltration and serial blood draws for assessing human immune development and tumor biomarkers in real-time throughout an efficacy study. Using this rat, we developed a novel autologous human skin and immune cells-humanized rat model by co-engrafting full-thickness human-fetal skin and autologous fetal lymphoid organoids under the kidney capsule along with intravenous injection of autologous fetal-liver derived hematopoietic stem cells, thus termed, human skin-immune system humanized rat model (hSIS-humanized rat). We demonstrated the development of adult-like, full-thickness human skin and human lymphoid organoids along with human immune cells. Methicillin-resistant Staphylococcus aureus inoculation in the human skin results in infection and skin pathology, thus recapitulating clinical outcomes. This model will enable in vivo mechanistic studies for development and evaluation of novel therapeutics for skin infectious disease and may also provide a model for establishing skin grafts of patient-derived melanoma tumors to investigate melanoma metastasis and response to therapies. In addition, engrafting the rat with human lymphoid organs and human immune cells may provide a similar platform to the BLT mouse for immunotherapy studies. Furthermore, we demonstrated the presence of Human CD45+, CD3+, and CD20+ cells in peripheral blood, spleen, and bone marrow of the SRG OncoRat® engrafted with human PBMCs, hence humanizing the rat's immune system. These immune humanized rat models may be beneficial for evaluating immunotherapies in human cancer models, including assessment of immune cell infiltration through fine needle biopsies. Citation Format: Bisoye Towobola Adedeji, Fallon K. Noto, Tseten Yeshi Jamling, Yash Argawal, Cole Jamison Beatty, Sara Grace Ho, Antu Das, Rajeev Kishore Salunke, Moses Turkle Bility. Humanized rat model [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 5621.
Abstract 5423: Multimodal prediction of diagnosis for cancers of unknown primary
Authors: Jackson Michuda, Benjamin Leibowitz, Shlomit Amar-Farkash, Crystal Bevis, Alessandra Breschi, Joshuah Kapilivsky, Catherine Igartua, Joshua S. Bell, Kyle A. Beauchamp, Kevin White, Martin Stumpe, Nike Beaubier, Timothy Taxter
Journal: Cancer Research (2020)

Abstract Background: Tumors of unknown origin account for up to 5% of newly diagnosed cancers and the average survival time is 9 to 12 months from diagnosis. Establishing tumor type and subtype guides standard of care treatment for several NCCN targeted therapy guidelines. Methods: Targeted DNA sequencing for more than 500 cancer-associated genes and exome-capture RNA sequencing was carried out in more than 25,000 fresh frozen or paraffin embedded tumor samples, including both primary and metastatic tumors. Mutations, copy number variants, and viral sequences were detected from DNA sequencing while gene expression and fusion events were determined from RNA sequencing. We aimed to predict cancer type by utilizing multiple machine learning models trained on individual data types and harmonize predictions across multiple data types. Results: The transcriptome model predicts more than 60 unique diagnoses covering both solid and hematological cancers with &amp;gt;90% overall accuracy on a held-out test set. Of note, the model can accurately predict 10 subtypes of sarcoma and 6 subtypes of neuroendocrine tumors. Gene expression and splicing were the most informative data types, but a performant DNA-only model was also evaluated for application when only DNA data is available. Finally, we evaluated the model on an unlabeled cohort of poorly differentiated samples with inconclusive diagnosis. Conclusions: The incorporation of multiple modes of omics data can improve the interpretability and robustness of machine learning models to predict cancer diagnosis. Citation Format: Jackson Michuda, Benjamin Leibowitz, Shlomit Amar-Farkash, Crystal Bevis, Alessandra Breschi, Joshuah Kapilivsky, Catherine Igartua, Joshua S. Bell, Kyle A. Beauchamp, Kevin White, Martin Stumpe, Nike Beaubier, Timothy Taxter. Multimodal prediction of diagnosis for cancers of unknown primary [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 5423.
Potential urinary monitoring of the enhanced permeability and retention effect using MMP-2-responsive poly(ethylene glycol) derivatives
Authors: Xiaohang Sun, Takahiro Nomoto, Hiroyasu Takemoto, Makoto Matsui, Haochen Guo, Yudi Sun, Yutaka Miura, Nobuhiro Nishiyama
Journal: Journal of Controlled Release (2020)

The enhanced permeability and retention (EPR) effect is fundamental to tumor-targeted drug delivery using nanoparticles. However, recent studies reported heterogeneity of the EPR effect, and companion diagnostics are considered to be key to predicting and optimizing the benefits of the EPR effect. Here, as a new material to simply endow the function of companion diagnostics to nanoparticles, we designed a poly(ethylene glycol) (PEG) derivative conjugated with low molecular fluorescent dye through synthetic substrate linker that can be cleaved in response to MMP-2, which is overexpressed in tumor extracellular matrix. Upon tumor accumulation, the low molecular fluorescent dye is released from the PEG and quickly excreted to urine, thereby reporting its tumor accumulation level as a fluorescent signal in the urine. In this study, this urinary reporter was conjugated with albumin, and the functionalized albumin exhibited efficient accumulation in various tumors. Importantly, the functionalized albumin exhibited significantly higher excretion of the fluorescent dye in the urine in mice with tumors compared with those without tumors. The PEG derivatives proposed in this study may be a promising tool to predict the EPR effect in individual cancer patients.
Abstract 6560: Sann-Jhong-Kuey-Jian-Tang could inhibit glioblastoma cells through increasing TNF-α, Fas, Bax but decreasing Bcl-2, Mcl-1 expression
Authors: Chin Cheng Su
Journal: Cancer Research (2020)

Abstract Glioblastoma is a highly malignant brain tumor and poor response to current chemotherapeutic medicine (such as Temozolomide). Glioblastoma remains a challenging disease and there is a need to identify new treatments. Sann-Jhong-Kuey-Jian-Tang (SJKJT), a traditional Chinese medicine prescription, has been prescribed as complementary medicine for patients with solid tumors in Taiwan. However, the anticancer effects of SJKJT on human brain tumor have not yet been elucidated. The present study focused on the anticancer effects and molecular mechanisms of SJKJT in human Glioblastoma by using DBTRG cells. In the present study, we evaluated the cytotoxic effects of SJKJT on DBTRG cells by MTT assay. The protein expression levels of tumor necrosis factor-α (TNF-α), Fas, Fas-associated Death Domain (FADD), Caspase-8, Caspase-9, Caspase-3, Bcl-2-associated X protein (Bax), Bcl-2 and myeloid cell leukemia 1 protein (Mcl-1) in the DBTRG cells were measured by western blotting. The cell cycles were analyzed by fluorescence-activated cell sorting (FACS). The protein expression of caspase-3 in DBTRG cells was analyzed by immunocytochemical (ICC) method. The results revealed that SJKJT inhibit the proliferation of DBTRG cells in a time- and dose-dependent manner. The protein expression levels of TNF-α, Fas, FADD, Caspase-8, Caspase-9, Caspase-3, Bcl-2-associated X protein (Bax) increased in the DBTRG cells treated with SJKJT; however, the level of Bcl-2 and Mcl-1 were decreased. These results indicated that SJKJT can inhibit DBTRG cells through both extrinsic and intrinsic pathway. The use of traditional Chinese medicine prescription SJKJT may become a feasible therapy option. Further studies are warranted to elucidate its mechanisms of action. Citation Format: Chin Cheng Su. Sann-Jhong-Kuey-Jian-Tang could inhibit glioblastoma cells through increasing TNF-α, Fas, Bax but decreasing Bcl-2, Mcl-1 expression [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 6560.
Abstract 3566: Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia
Authors: Masakazu Yashiro, Hiroaki Kasashima, Yurie Yamamoto, Kenji Kuroda, Tomohiro Sera, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Tomohisa Okuno, Yuichiro Miki, Masaichi Ohira
Journal: Cancer Research (2020)

Abstract Purpose: Hypoxic environments are randomly scattered throughout carcinomas. Although hypoxia is cytotoxic to both cancer cells and normal cells, some types of cancer cells acquire characteristics that allow them to survive and progress in a hypoxic environment. Hypoxia is considered to be associated with aggressive tumor phenotypes of gastric carcinomas, including the ability to metastasize. Hypoxia is clinically associated with metastasis and poor patient outcome, however the underlying processes remain unclear. It has been reported that lysyl oxidase (LOX) is a hypoxia-responsive factor and is associated with the malignant progression of carcinoma. The aim of this study was to clarify the relationship between the epithelial–mesenchymal transition (EMT) and LOX in gastric cancer cells under hypoxia. Methods: Two gastric cancer cell lines, OCUM-2MD3 and OCUM-12, were used in an in vitro study. The effect of siLOX on the EMT and motility of gastric cancer cells under hypoxic condition was analyzed by RT-PCR, western blot, wound-healing assay, and invasion assay. Correlations between LOX expression and the clinicopathological features of 544 patients with gastric carcinoma were examined immunohistochemically. Results: Hypoxic conditions increased the number of polygonal or spindle-shaped cells of EMT in gastric cancer cells. The EMT of cancer cells induced by hypoxia was inhibited by treatment with LOX siRNA. Taken together, the number of migrating and invading gastric cancer cells in hypoxia was significantly decreased by LOX knockdown. LOX siRNA significantly increased the E-cadherin level and decreased the vimentin level of gastric cancer cells. LOX expression was significantly associated with invasion depth, tumor differentiation, lymph node metastasis, lymphatic invasion, venous invasion, and peritoneal metastasis. Multivariable analysis revealed that LOX was an independent parameter for overall survival. Conclusion: HIF-1α might increase the expression of LOX, which affects the EMT of gastric cancer cells in hypoxic conditions via down-regulation of E-cadherin level and up-regulation of vimentin level. LOX expression may be a useful prognostic factor for patients with gastric cancer. Citation Format: Masakazu Yashiro, Hiroaki Kasashima, Yurie Yamamoto, Kenji Kuroda, Tomohiro Sera, Atsushi Sugimoto, Shuhei Kushiyama, Shingo Togano, Tomohisa Okuno, Yuichiro Miki, Masaichi Ohira. Lysyl oxidase is associated with the epithelial–mesenchymal transition of gastric cancer cells in hypoxia [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 3566.
Islet transplantation in the subcutaneous space achieves long-term euglycaemia in preclinical models of type 1 diabetes
Authors: Ming Yu, Divyansh Agarwal, Laxminarayana Korutla, Catherine L. May, Wei Wang, Negin Noorchashm Griffith, Bernhard J. Hering, Klaus H. Kaestner, Omaida C. Velazquez, James F. Markmann, Prashanth Vallabhajosyula, Chengyang Liu, Ali Naji
Journal: Nature Metabolism (2020)
Coordinated and sustained immune memory responses after mild COVID-19
Authors: Aljawharah Alrubayyi
Journal: Nature reviews. Immunology (2020)

Rodda, L. B. et al. Functional SARS-CoV-2-specific immune memory persists after mild COVID-19. Preprint at medRxiv https://doi.org/10.1101/2020.08.11.20171843 (2020) Article PubMed PubMed Central Google Scholar Download references OxImmuno Literature Initiative, University of Oxford, Oxford, UK Aljawharah Alrubayyi You can also search for this author in PubMed Google Scholar Correspondence to Aljawharah Alrubayyi. The author declares no competing interests. Reprints and Permissions Alrubayyi, A. Coordinated and sustained immune memory responses after mild COVID-19. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-00450-6 Download citation Published: 07 September 2020 DOI: https://doi.org/10.1038/s41577-020-00450-6
Abstract 1854: Oridonin inhibits cell growth of esophageal carcinoma cells via induction of apoptosis
Authors: Xiaojun Zhang, Mengtao Xing, Yangcheng Ma, Xiao Wang, Jianying Zhang
Journal: Cancer Research (2020)

Abstract Esophageal Cancer estimated leading deaths are more than 400,000 every year in worldwide, while 80% due to esophageal squamous cell carcinoma. In worldwide, esophageal cancer leading death ranks in sixth among cancer leading causes of death, while the 5-year survival rate of esophageal cancer is 19%. Oridonin, a tetracyclic diterpenes compound, has been indicated the anti-tumor activity for digestive system tumors. To assess the anticancer activity of oridonin on esophageal cancer, we performed cell proliferation experiment of oridonin on esophageal squamous cell carcinoma cell line TE-8 using SRB assay. We found that IC50 of oridonin on TE-8 treated for 72h is 3.0μM, which is better than positive control Gemcitabine treatment on TE-8 for 72h (5.7 μM), as well as TE-8 cells shrunk and floated with increasing concentration on oridonin. At the same time, oridonin induced a dose-dependent inhibition of cell colony formation of esophageal cancer cell line. Colony numbers of TE-8 cell line treated with 1μM and 2μM oridonin are 111 and 54, respectively, which are significantly different (p&amp;lt;0.05). Accompanying with marked morphological changes, flow cytometer results showed that oridonin triggered sub-G0/G1 cell cycle arrest in a dose-dependent manner. After treatment by 10μM and 20μM oridonin for 24h, percentage of sub-G0/G1 cells were 25.5 and 55.3%, respectively, which are significantly different (p&amp;lt;0.05). The apoptosis results showed that oridonin treatment led to the accumulation of cells in early-(Annexin V+/PI-) and late-stage (Annexin V+/PI+) apoptosis in a dose-dependent manner. Citation Format: Xiaojun Zhang, Mengtao Xing, Yangcheng Ma, Xiao Wang, Jianying Zhang. Oridonin inhibits cell growth of esophageal carcinoma cells via induction of apoptosis [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 1854.
Abstract 1088: Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling
Authors: Kali J. Dale, Martin McMahon
Journal: Cancer Research (2020)

Abstract RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers. Citation Format: Kali J. Dale, Martin McMahon. Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling [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 1088.
Abstract 5977: Maf1 suppresses hepatocarcinogenesis in mice through inhibition of Akt-mTOR signaling
Authors: Di Cao, Xiaoxing Li, Yang Yang, Yu-Feng Zhou, Mei-Yin Zhang, Shan-Shan Zhang, Qian-Nan Ren, Hui-Zhong Zhang, Yao-Jun Zhang, Shi-Juan Mai, Hui-Yun Wang
Journal: Cancer Research (2020)

Abstract Maf1 is a transcriptional repressor downstream of mTORC1by inhibiting transcription of lipogenic genes by RNA Pol II and ribosomal/transfer RNA genes by RNA Pol III. We recently showed that Maf1 suppresses the growth of cultured liver cancer cells and xenograft tumors by blocking Akt-mTOR signaling through the tumor suppressor PTEN. However, whether Maf1 has tumor suppressor activity has never been demonstrated in physiologically relevant tumor models. Here, we investigated the role of Maf1 in hepatocarcinogenesis in NRas/Akt- and c-Myc-driven mouse liver cancer models generated by hydrodynamic transfection (HDT). We found that Maf1 or Maf1-4A, a non-phosphorylatable and active form of Maf1, significantly attenuated the development of NRas/Akt-driven liver tumors. On the other hand, while knockdown of Maf1 alone did not cause any discernible abnormality in the mouse liver, down-regulation of Maf1 markedly accelerated c-Myc-induced liver tumor development. At the molecular level, Maf1 strongly suppressed phosphorylation of Akt-mTOR pathway components, including Akt and S6. Conclusions: Maf1 suppresses hepatocarcinogenesis through restraining Akt/mTOR signaling. These new findings provide first in vivo evidence that Maf1 is a liver tumor suppressor. Citation Format: Di Cao, Xiaoxing Li, Yang Yang, Yu-Feng Zhou, Mei-Yin Zhang, Shan-Shan Zhang, Qian-Nan Ren, Hui-Zhong Zhang, Yao-Jun Zhang, Shi-Juan Mai, Hui-Yun Wang. Maf1 suppresses hepatocarcinogenesis in mice through inhibition of Akt-mTOR signaling [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 5977.