bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3977: Stromal BMP signaling imbalance mediated by GREM1 and ISLR regulates colorectal cancer progression
Authors: Kobayashi Hiroki , Gieniec Krystyna A. , Wang Tongtong , Wright Josephine A. , Suzuki Nobumi , Lannagan Tamsin RM , Hayakawa Yoku , Leedham Simon J. , Arpaia Nicholas , Mukherjee Siddhartha , Wang Timothy C. , Enomoto Atsushi , Takahashi Masahide , Worthley Daniel L. , Woods Susan L. 
Published: September 2020

Abstract
Introduction
Cancer-associated fibroblasts (CAFs), a heterogeneous component of the tumor microenvironment, substantially influence tumor progression. Bone morphogenetic proteins (BMP) play a critical part in defining the intestinal epithelial niche and either promote or retard cancer progression in a context-dependent manner. However, the role of BMP signaling in the colorectal cancer (CRC) stroma remains to be fully elucidated. This study investigated the significance of mesenchymal BMP signaling as a potential therapeutic target in CRC progression.
Design
Using CRC expression array data, we identified two CAF-specific factors involved in BMP signaling, then verified their upregulation in the human CRC stroma by in-situ hybridization (ISH). We took advantage of a preclinical mouse model of CRC hepatic metastasis to test approaches targeting the BMP signaling pathway.
Results
CRC microarray data identified GREM1 and ISLR as CAF-specific genes involved in BMP signaling. In colonic myofibroblasts, Grem1-overexpression inhibited BMP signaling whereas BMP7 signaling was augmented by Islr overexpression, suggesting opposing roles for GREM1 and ISLR in the regulation of BMP signaling. ISH using human rectal cancer samples revealed that GREM1 and ISLR were expressed in distinct CAF subpopulations and that GREM1 and ISLR expression predicted poor and favorable survival, respectively. Notably, Grem1 and Islr expression was differentially regulated by Foxl1, an intestinal mesenchyme-lineage transcription factor, and TGF-b, indicating a mechanism for generating fibroblast heterogeneity. Finally, adeno-associated virus 8-mediated in-vivo overexpression of Islr in hepatocytes retarded growth and generated more differentiated histology in CRC hepatic metastases.
Conclusion
These data suggest that increased stromal BMP signaling may ameliorate CRC progression and provide a rationale for targeting stromal BMP signaling to inhibit CRC progression and metastasis.
Citation Format: Hiroki Kobayashi, Krystyna A. Gieniec, Tongtong Wang, Josephine A. Wright, Nobumi Suzuki, Tamsin RM Lannagan, Yoku Hayakawa, Simon J. Leedham, Nicholas Arpaia, Siddhartha Mukherjee, Timothy C. Wang, Atsushi Enomoto, Masahide Takahashi, Daniel L. Worthley, Susan L. Woods. Stromal BMP signaling imbalance mediated by GREM1 and ISLR regulates colorectal cancer progression [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 3977.
Abstract 4002: Adipose tissue supernatant of overweight ER positive breast cancer patients promotes migration of MCF-7 breast cancer cells
Authors: Ma Jie , Timmer-Bosscha Hetty , Werker Paul M. , Schröder Carolina P. , Arjaans Marlous 
Published: September 2020

Abstract
Introduction: Adipose tissue is a major component of the breast cancer microenvironment, and preclinical studies have suggested that adipose tissue might play a pivotal role in breast cancer progression. In this study we investigated the effect of adipose tissue from patients with ER positive breast cancer on migration of ER positive MCF-7 breast cancer cells.
Materials and Methods: Adipose tissue samples were collected from patients with ER positive breast cancer undergoing a mastectomy. In total, adipose tissue samples from 3 normal weight (BMI: 18.5-24.9) and 7 overweight breast cancer patients (BMI: 25-29.9) were collected. Samples from the mastectomy specimens were minced in small pieces, incubated in RPMI-1640 and after 48 hours (h) the supernatant was harvested. The effect of adipose tissue supernatant on the migration of MCF-7 cells was monitored in real-time for 48 h with the xCELLigence cell invasion and migration plates expressed in delta cell index (DCI). In addition, effect of adipose tissue supernatant on migration was assessed by quantification of F-actin positive lamellipodia of MCF-7 cells in a scratch assay after 24 h. In all experiments, RPMI-1640 with 1% or 20% FCS was used as a negative or positive control respectively.
Results: Supernatant of overweight patients significantly induced MCF-7 migration compared to supernatant of normal weight patients after 24 h (xCELLigence DCI: 1.22 ± 0.15 vs. 0.95 ± 0.19 (P=0.038)), 36 h (DCI 1.40 ± 0.21 vs. 0.91 ± 0.31 (P=0.019)) and 48 h (DCI 1.72 ± 0.23 vs. 0.98 ± 0.43 (P=0.007)). In addition, there was a significant difference between the overweight group and negative control at 36 h, and 48 h (DCI 1.40 ± 0.21 vs. 1.06 ± 0.12, P=0.038 and DCI 1.72 ± 0.23 vs. 1.11 ± 0.21, P=0.004 respectively). No significant difference between normal weight group and negative control was found at any of the time points. After 24 h MCF-7 cells incubated with supernatant of overweight patients developed significantly more F-actin positive lamellipodia compared to MCF-7 cells incubated with supernatant of normal weight patients (44.26 ± 3.26% vs. 25.47 ± 1.88% P&lt;0.001).
Conclusion: In this study, we showed that adipose tissue supernatant of patients with ER positive breast cancer can promote migration of MCF-7 breast cancer cells in a weight dependent manner. Whether this is the case in other breast cancer subtypes as well, and the potential clinical implication, is of interest for future studies.
Citation Format: Jie Ma, Hetty Timmer-Bosscha, Paul M. Werker, Carolina P. Schröder, Marlous Arjaans. Adipose tissue supernatant of overweight ER positive breast cancer patients promotes migration of MCF-7 breast cancer 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 4002.
Abstract 4014: Measuring direct binding to epigenetic targets using SPR
Authors: Eells Rebecca , Baker Lynn K. , Bray Christopher , Ma Haiching 
Published: September 2020

Abstract
Epigenetic modifications are dynamic and reversible processes that regulate gene expression without altering the underlying sequence of the DNA. Gene expression is instead controlled by chromatin modifications, such a DNA methylation, histone modification, and chromatin remodeling. Proteins involved in epigenetic modifications are categorized as writers, which modify the chromatin; readers, that recognize the modifications; and erasers which remove the modifications. While essential for cellular function, abnormal expression or alteration of the proteins involved in epigenetic regulation leads to diseases, such as cancer. Due to their role in disease, epigenetic modifiers are attractive targets for the discovery and development of novel therapeutics. Research in the field has shown many epigenetic proteins are druggable and several FDA-approved drugs have already been developed (Ref. 1). At Reaction Biology we offer a suite of services for epigenetic drug discovery, including the largest panel for epigenetic screening and profiling in the industry with over 30 Methyltransferases, 100+ Reader Domain Proteins, HATs, HDACs, Demethylases, DUBs, PARPs, and more. In order to directly probe the strength of the binding interaction between the epigenetic target and potential therapeutics we offer biophysical assays, such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and microscale thermophoresis (MST). Here we present SPR binding data for three epigenetic targets: NSD2 (writer), PRMT5 (writer), and Bromodomain-4 (reader). Through the use of commercially available controls, we developed SPR assays for these targets that can be used to screen compound or fragment libraries, determine kinetics/affinity, and profile binding specificity. (Ref 1.) V. Prachayasittikul et al (2017) Exploring the epigenetic drug discovery landscape. Expert Opin. Drug Discov. 12(4): 345-362.
Citation Format: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma. Measuring direct binding to epigenetic targets using SPR [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 4014.
Abstract 4037: In vitro cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax
Authors: Gupta Aparna , Humphreys Robin , Hanson Derek , Wang Qi 
Published: September 2020

Abstract
Introduction: Current treatment options for AML patients who are older or unfit for intensive chemotherapy are limited and associated with less than ideal outcomes, even with newly approved regimens of venetoclax plus low-dose cytarabine or DNA hypomethylating agents. CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, was approved by the US FDA in 2017 and EMA in 2018 for treatment of adults with newly diagnosed therapy-related AML and AML with myelodysplasia-related changes. The objective of this study was to assess the cytotoxic effects of CPX-351 plus venetoclax versus combinations of venetoclax plus cytarabine, decitabine, or azacitidine.
Methods: Three AML and three ALL cell lines were treated with single-agent CPX-351, venetoclax, cytarabine, decitabine, or azacitidine, or with combinations of CPX-351 plus venetoclax, venetoclax plus cytarabine, venetoclax plus decitabine, or venetoclax plus azacitidine. The cells were plated 24 hours prior to treatment and incubated with the test agents for 72 hours. Cytotoxicity was measured with a luminescent Cell Viability Assay.
Results: As a single agent, all tested drugs demonstrated cytotoxicity to all cell lines, but with different potencies. CPX-351 plus venetoclax showed synergistic or additive effects in all AML and ALL cell lines tested (Table). Combinations of venetoclax with cytarabine, decitabine, or azacitidine showed variable responses (synergistic, additive, and antagonistic effects). In addition, data suggest the highest combination doses with CPX-351 may attain greater cell killing versus the other drug combinations tested.
TableCICell lineCell originCPX-351 + venetoclaxCytarabine + venetoclaxAzacitidine + venetoclaxDecitabine + venetoclaxHL-60AML0.701.010.711.66SKM-1AML0.911.931.291.14KG-1AML0.530.950.590.77CCRF-CEMALL0.700.990.861.99MOLT-3ALL0.740.680.630.73Jurkat E6-1ALL0.791.331.141.40CI was calculated using the Chou and Talalay method, where CI of &lt;1 = synergistic, 1 = additive, and &gt;1 = antagonistic.
Conclusions: These data demonstrated that the combination of CPX-351 and venetoclax is synergistic or additive in all cell lines tested. Future studies confirming these findings in in vivo hematologic malignancy models can help to design a novel dose-regimen, which may provide the best benefit with good tolerability.
Citation Format: Aparna Gupta, Robin Humphreys, Derek Hanson, Qi Wang. In vitro cytotoxicity of CPX-351 plus venetoclax compared with hypomethylating agents or cytarabine plus venetoclax [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 4037.
Abstract 4051: Anlotinib inhibits the progress of colorectal cancer cells by antagonizing glycolysis & JAK2-STAT3 signaling
Authors: Jia Zhenxian , Zhang Zhi , Li Ze , Li Ang , Xie Yuning , Wu Hongjiao , Yang Zhenbang , Zhang Hongmei , Zhang Xuemei 
Published: September 2020

Abstract
Background: Anlotinib is a novel multi-target tyrosine kinase receptor inhibitor (TKI) that has been proved to treat advanced NSCLC as a third-line regime in China. This study designed to investigate the effectiveness & possible mechanism of anlotinib colorectal cancer (CRC) therapy.
Methods: CCK-8 assay & CyQUANT NF assay were used to detect the sensitivity of CRC cells to DDP & anlotinib. Real time quantitative polymerase chain reaction was used to detect the mRNA level of hub genes. The protein expression of pVEGFR2, cleaved PARP, cleaved caspase 3, JAK2, pJAK2, STAT3 & PSTAT3 were determined by western blot. The roles of DDP & anlotinib in the progression, invasion & metastasis of CRC cells were evaluated by colony formation, wound healing & trans-well assay. Lactate release & glucose consumption were measured to investigate glucose metabolism. Cell apoptosis was analyzed by Hoechst33342 fluorescence staining & flow cytometer.
Results: We found that anlotinib may improve the treatment of CRC by blocking the effects of VEGFA. Subsequently, in vitro assays demonstrated that anlotinib &/or DDP inhibited cell proliferation, migration & invasion & also activated apoptosis in human colorectal cancer cells. Additionally, glucose metabolism in CRC HCT-116 & LOVO cells was suppressed by anlotinib &/or DDP. In other hand, anlotinib &/or DDP may improve the treatment of CRC by inhibiting JAK2-STAT3 signaling pathway.
Conclusions: Our preclinical studies showed that anlotinib inhibited cell proliferation, invasion, migration & activated apoptosis by antagonizing glycolysis & JAK2-STAT3 signaling. Combination chemotherapy of anlotinib with cisplatin is more sensitive to CRC.
Citation Format: Zhenxian Jia, Zhi Zhang, Ze Li, Ang Li, Yuning Xie, Hongjiao Wu, Zhenbang Yang, Hongmei Zhang, Xuemei Zhang. Anlotinib inhibits the progress of colorectal cancer cells by antagonizing glycolysis & JAK2-STAT3 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 4051.
Abstract 4053: Mucin 5ac as a potential therapeutic target for KRAS-driven lung adenocarcinoma
Authors: Velasco Torrez Walter V. , Deng Shanshan , Ramos-Castaneda Marco A. , Del Aguila-Soto Segundo W. , Moghaddam Seyed 
Published: September 2020

Abstract
Lung cancer continues to be the leading cause of cancer death in the United States, with more than 140,000 deaths per year. One of the main types of lung cancer is non-small cell lung cancer with lung adenocarcinoma (LUAD) being the most prominent subtype and is mainly due to oncogenic mutations like KRAS, which offers limited and unsuccessful treatments. The mucus barrier produced by mucins, particularly Mucin 5ac (Muc5ac) which is mainly expressed by lung epithelial cells, is essential for airway homeostasis. However, its overproduction can promote respiratory diseases such as chronic obstructive pulmonary disease (COPD), which is known to increase the risk of lung cancer by 3-10 fold. We have previously shown that Muc5ac is commonly expressed in patients with KRAS-driven LUAD and is associated with poor prognosis. Additionally, we found that lack of Muc5ac (genetic deletion) in mice with LUAD either induced chemically by urethane or genetically engineered with mutant KRAS presented with significantly reduced tumor burden. Therefore, we sought a translational approach by inhibiting Muc5ac in our KRAS-driven lung cancer mutant mouse model using an antisense oligonucleotide (ASO) against Muc5ac and hypothesized that the administration of this drug would result in decreased Muc5ac mRNA expression and reduced tumor burden. This was tested by intrapharyngeal administration of either ASO (5mg/kg) or vehicle (saline) twice a week to a cohort of six-week-old KRASG12D mutant mice for a total duration of eight weeks. Our results showed a 5-fold decrease in Muc5ac mRNA expression and a 42% reduction in overall tumor burden when compared to age and sex matched control mice. Additionally, analysis of bronchoalveolar lavage fluid showed a predominance of macrophages with significant downregulation of the protumorigenic M2 type macrophage polarization markers Fizz1 and Arg1 as well as significant upregulation of TNF-a, which suggests a mechanism mediated by direct tumor cytotoxic activity or apoptosis associated with a reduction in macrophage mediated immunosuppressive tumor microenvironment. In conclusion, our study suggests that administration of Muc5ac ASO effectively inhibits mucin production and ameliorates tumor progression, which ultimately could provide insight in both treatments and prevention against KRAS-driven LUAD.
Citation Format: Walter V. Velasco Torrez, Shanshan Deng, Marco A. Ramos-Castaneda, Segundo W. Del Aguila-Soto, Seyed Moghaddam. Mucin 5ac as a potential therapeutic target for KRAS-driven lung adenocarcinoma [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 4053.
Abstract 4087: ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer cells
Authors: Ramachandran Ilangovan , Ramadoss Sivakumar , Karuppaiyah Selvendiran , Nathan Lauren , Kumaran R. Ileng , Chaudhuri Gautam 
Published: September 2020

Abstract
Introduction: Ovarian cancer is one of the most common malignancies among women that causes severe mortality in USA and globally. Despite advances in cancer treatments in the last few decades, there is no substantial improvement in the survival rates of patients with advanced ovarian cancers. This is mainly attributed to drug resistance and tumor recurrence. Most patients develop resistance to platinum compounds, which are often used as the first-line therapy. Several studies have shown that aldehyde dehydrogenase (ALDH1A1) plays an important role in cancer stemness and confers resistance to cell death induced by platinum compounds used to treat ovarian cancers. Therefore, in this study, we determined the effect of a small-molecule inhibitor of ALDH1A1 (A37) in cisplatin-resistant ovarian cancer cells and assessed it's molecular mechanism of action.
Experimental methods: The cisplatin-resistant ovarian cancer cells (A2780-CR) were exposed to various concentrations of ALDH1A1 inhibitor (A37) and then the cell proliferation by water-soluble tetrazolium salt (WST-1) assay, cell cycle analysis by flow cytometry and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer) were performed. Furthermore, the protein expression of critical signaling molecules that modulate the proliferation of ovarian cancer cells was assessed by western blot analysis.
Results: A37 treatment drastically decreased the proliferation of A2780-CR cells at 24 and 48 h. In addition, cell cycle analysis revealed a significant increase in G1 phase and dramatic decrease in S phase of the cell cycle upon A37 treatment. Interestingly, A37 suppressed the basal OCR, an indicator of mitochondrial respiration. Furthermore, A37 reduced the protein expression of mammalian target of rapamycin (mTOR), which plays a critical role in cancer cell cycle and proliferation.
Conclusions: Our findings indicate that the ALDH1A1 inhibitor (A37) induces cell cycle arrest and suppresses the cell proliferation of cisplatin-resistant ovarian cancer cells, possibly through downregulation of mTOR signaling. Most importantly, A37 affects the cancer cell metabolism by reducing the mitochondrial respiration. Taken together, our study highlights the importance of potential therapeutic implication of ALDH1A1 inhibitor towards the treatment of chemoresistant-ovarian cancers.
Citation Format: Ilangovan Ramachandran, Sivakumar Ramadoss, Selvendiran Karuppaiyah, Lauren Nathan, R. Ileng Kumaran, Gautam Chaudhuri. ALDH1A1 inhibitor induces cell cycle arrest and reduces cell proliferation of cisplatin-resistant ovarian cancer 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 4087.
Abstract 4107: The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptosis
Authors: Abdin Shifaa M. , Tolba Mai F. , Zaher Dana M. , Omar Hany A. 
Published: September 2020

Abstract
Aim: The emergence of breast cancer resistance to chemotherapy represents a major obstacle in cancer therapy. Multiple cellular signalling pathways augment such resistance including the nuclear factor (NF)-κB. In the presented work, we investigated the impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced apoptotic cell death via Annexin V/PI flow cytometry and other molecular biology-based assays.
Methods: Doxorubicin (DOX)-resistant MCF-7 and MDA-MB-231 breast cancer cell lines were developed and utilized for the current study. Cytotoxicity assays were performed to evaluate the median inhibitory concentration (IC50) of different NF-κB pharmacological inhibitors. Chemotherapy-induced apoptosis in parental and resistant breast cancer cells was assessed in the presence or absence of different NF-κB pharmacologic inhibitors such as pentoxifylline (PTX) and bortezomib (BTZ).
Results: Treatment of MDA-MB-231 cell line with a sub-cytotoxic concentration of PTX significantly enhanced DOX-induced apoptosis by 6-fold (p&lt;0.001) in wild type cells, and by 8-fold (p&lt;0.01) in the resistant subclones. Similarly, BTZ significantly boosted the percentage of apoptotic cells by 6-fold (p&lt;0.001) in parental cells co-treated with DOX. However, the same treatment boosted the percentage of apoptotic cells by 11-fold (p&lt;0.01) in DOX-resistant MDA-MB-231 cells. It is noteworthy that the increased sensitivity to DOX-induced apoptosis that was mediated via NF-κB inhibition was more prominent in the resistant clones.
Conclusion: The data generated from this study support the potential merit of NF-κB inhibitors as adjuvants to improve breast cancer sensitivity to chemotherapy. Further mechanistic investigations are currently in progress in our laboratories to characterize the relationship between NF-κB inhibition and key signaling pathways for breast cancer chemoresistance.
Funding: This work was supported by grant # 1801110326-P from the Research Funding Department, University of Sharjah, UAE, and grant #AJF2018050 from Al Jalila Foundation, UAE.
Citation Format: Shifaa M. Abdin, Mai F. Tolba, Dana M. Zaher, Hany A. Omar. The impact of NF-κB inhibition on the sensitivity of breast cancer cells to chemotherapy-induced 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 4107.