tbuckley/cabot-search huggingface dataset:
Abstract 1043: TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition &amp; metastasis in liver cancer
Authors: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu
Journal: Cancer Research (2019)

Abstract Metastasis is the main cause of cancer mortality. However, the triggering mechanisms and regulation of epithelial–mesenchymal transition (EMT) factors in the commitment of metastasis have not been well characterized. Spermatogenic Zip 1 (SPZ1) acts as a proto-oncogene and an upstream regulator of EMT during tumorigenesis. Here we report that the HIV-1 Tat-interacting protein 60 kDa (Tip60) acetyltransferase mediates acetylation at lysine residues of SPZ1 at positions 369 and 374, and of TWIST1 at positions 73 and 76, which are required for SPZ1–TWIST1 complex formation and cancer cell migration in vitro and in vivo. Ectopic SPZ1 and TWIST1 expression, but not that of TWIST1 alone, enhanced vascular endothelial growth factor (VEGF) expression via the recruitment of bromodomain-containing protein 4 (BRD4), thus enhancing RNA-Pol II-dependent transcription and inducing metastasis. Neutralization of VEGF using humanized monoclonal antibodies such as Avastin, effectively abrogated the EMT and oncogenesis induced by the acetylated SPZ1–TWIST1 complex. Our findings highlight the importance of acetylation signaling in the SPZ1–TWIST1–BRD4 axis in the mediation of EMT and its regulation during tumor initiation and metastasis. Citation Format: Shen-Nien Wang, Li-Ting Wang, Shih-Hsien Hsu. TIP60-dependent acetylation of the SPZ1-TWIST complex promotes epithelial-mesenchymal transition &amp; metastasis in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1043.
Abstract 3006: A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration
Authors: Sengottuvelan Murugan, Vanisha Patel, Dipak K. Sarkar
Journal: Cancer Research (2019)

Abstract Breast cancer is the second most prevalent cancer after lung cancer among American women. The efficacy of current antitumor therapies is still quite limited. Endogenous opioid peptides, such as endorphin, which is involved in body stress controlling mechanisms, have been shown to enhance immune function and prevent cancer growth and progression in various animal models of cancers. Therefore, targeting the endogenous opioid peptides receptors in the regulation of cancer chemoprevention may offer new promise for the design of therapeutic strategies. Our previous studies have shown differential actions of mu-opioid receptor (MOR) and delta opioid receptor (DOR) on various cell types. In this study we tested the effects of a MOR antagonist naltrexone (NTX) and a DOR agonist (D-Ala2-,N-Me-Phe4,Gly-ol Enkephalin; DPDPE) on proliferation and invasion of human breast cancer cells of different molecular subtype such as T47D (Luminal A), MDA-MB-231 (triple negative, Claudin-Low) and MDA-MB- 468 (triple negative, basal A) in cultures. We used cytotoxicity, clonogenic, cell migration and cell invasion assays to identify effects of these drugs on cancer cells. We found that both NTX and DPDPE have significant cytotoxic effects on these breast cancer cells. Our work from clonogenic, cell migration and cell invasion assays showed that both NTX and DPDPE inhibit the formation of colony, migration and invasion of cancer cells in a concentration-dependent manner. These data suggest that naltrexone and DPDPE have anticancer efficacy in subtypes of human breast cancer cells. The anticancer effects varied depending on the concentration of the drugs and the subtype of breast cancer cells. (Supported by NIH grant R01 CA20863201). Citation Format: Sengottuvelan Murugan, Vanisha Patel, Dipak K. Sarkar. A novel strategy of targeting opioidergic receptors to potentially reduce human breast cancer cell proliferation, colony formation, invasion, and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3006.
Abstract LB-232: A novel approach for liquid biopsy by using nExo
Authors: Akira Yokoi, Alejandro Villar-Prados, Paul Allen Oliphint, Theresa J. O'Halloran, Jason Roszik, Anil K. Sood
Journal: Cancer Research (2019)

Abstract Exosomes are small extracellular vesicles secreted from all living cells; its contents are highly varied, including proteins, small RNAs and recently discovered, genomic DNA (gDNA). The presence of nuclear content in exosomes suggests that different cell compartments can contribute to exosome cargo; however, little is known about this sub population of nuclear derived exosomes (nExo). Here, we analyzed nExo isolated from ovarian cancer cells and characterized them to explore potential clinical relevance such as cancer detection and therapeutic response. Exosomes were isolated from ovarian cancer cell lines, normal human fallopian epithelial tube cells and bio-fluids from mouse and human samples. To determine the purity of exosomes, nanoparticle tracking system, immunoblotting assay and cryo-transmission electron microscopy were used. To analyze the content of exosomes, protein mass spectrometry and imaging flow cytometry analysis was performed. First, we determined that mass spectrometry analyses for ovarian cancer cell exosomes revealed that 12.5% of proteins are derived from the cell nucleus sub-population. Additionally, using a novel imaging flow cytometry technique which enables us to identify single exosome and to quantify them, we determined that 10% of exosomes carried gDNA. Conversely, normal cells secreted only 0.2% of nExo. Then we hypothesized that the prevalence of gDNA is affected by genotoxic drugs. Treating cells with either the PARP inhibitor olaparib or topoisomerase inhibitor topotecan increased the proportion of nExo secreted from ovarian cancer cells. In addition, PARP proteins exist in ovarian cancer cell exosomes and 80.4 % of the exosome co-localized with gDNA. Using in vivo preclinical models, serum from ovarian cancer bearing mice contained a higher number of nExo than non-tumor controls, and this population was increased in response to treatment of genotoxic drugs. Furthermore, plasma and ascites from ovarian cancer patients contain around 0.3 % of nExo, which include nuclear proteins and gDNA. We demonstrate that nExo are predominantly secreted from cancer cells and could serve as an important biomarker. Although the subpopulation is relatively rare, their presence in bio-fluids isolated from cancer patients holds the potential of serving as novel biomarkers for early detection and therapeutic response to genotoxic agents. Citation Format: Akira Yokoi, Alejandro Villar-Prados, Paul Allen Oliphint, Theresa J. O'Halloran, Jason Roszik, Anil K. Sood. A novel approach for liquid biopsy by using nExo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-232.
Allo-HCT from MUD/MRD for Paroxysmal Nocturnal Hemoglobinuria - 12 Years of Experience
Authors: Miroslaw Markiewicz, Malwina Rybicka-Ramos, Monika Dzierzak-Mietla, Anna Koclega, Krzysztof Bialas, Ewa Mendek-Czajkowska, Slawomira Kyrcz-Krzemien
Journal: Blood (2016)
Magnetic resonance elastography vs. transient elastography in detection of fibrosis and noninvasive measurement of steatosis in patients with biopsy-proven nonalcoholic fatty liver disease
Authors: C.C. Park, P. Nguyen, C. Hernandez, R. Bettencourt, K.S. Ramirez, L.E. Fortney, J. Hooker, E. Sy, M.H. Alquiraish, M.A. Valasek, E. Rizo, L. Richards, D. Brenner, C.B. Sirlin, R. Loomba
Journal: Journal of Hepatology (2017)
Abstract 16581: Dissociation Between S100A1 Protein Levels and Recovery of Muscle Function After LVAD
Authors: Mosi K Bennett, Wendy E Sweet, Matthew T Baumann, Maria Mountis, W.H. Wilson Tang, Randall C Starling, Christine S Moravec
Journal: Circulation (2012)

S100A1 is an important modulator of contractile reserve in the heart through its actions on intracellular calcium cycling and mitochondrial energy production. Studies in animal models and in human ...
The anti-tumor activity of the mTOR inhibitor RAD001 (everolimus) in nasopharyngeal carcinoma (NPC)
Authors: Brigette Ma, Vivian Lui, Cecilia Lau, Kakiu Ho, Daisy Yau, S. Hardikar, Anthony Chan
Journal: Cancer Research (2008)

1424   NPC is endemic in Southern China and platinum-based chemotherapy plays an important role in the treatment of advanced NPC. Akt signaling is frequently activated in NPC cell lines and has been implicated as a mediator of platinum-resistance in other cancers. RAD001 (everolimus) is a mTOR inhibitor that inhibits signaling of its downstream effectors: eukaryotic initiation factor (eIF) 4E binding proteins (4E-BP1) and 40S ribosomal S6 kinases (p70S6K). This study evaluated the effect of RAD001 on mTOR signaling and on cell growth when used alone or in combination with cisplatin in NPC cell lines. Five NPC cell lines (HK1, HONE-1, CNE-1, CNE-2, C666-1) were analyzed for the expression of total and phosphorylated (activated) level of mTOR and p70S6K1 (Thr/Ser) using Western Blot. HONE-1 and CNE-1 were found to express the highest basal levels of activated mTOR and p70S6K1 and were thus selected for testing with RAD001. When HONE -1 and CNE-1 cells were exposed to various concentrations of RAD001 for 48 hours, a dose-dependent inhibition of cell growth was detected with MTT assay, with maximal growth inhibition occurring at about 50% compared to control at 72 hours. The respective IC 50  values are: CNE-1 = 52 pM, HONE-1= 10 pM. Exposure of CNE-1 and HONE-1 cells to RAD001 at IC 50  concentration for 48 hours resulted in complete inhibition of p-p70S6K1 (Thr389) expression and significant inhibition of p-p70S6K1 (Thr421/Ser424) in both cell lines. The inhibition on p-mTOR (Ser 2448) expression was only partial. The combined effect of RAD001 and cisplatin on CNE-1 and HONE-1 cell growth was studied by exposing cells to cisplatin at IC 25  (0.2μg/ml) and IC 50  (0.3 μg/ml) concentrations, and RAD001 at IC 50  concentrations for 48 and 72 hours. An additive effect was seen at all concentrations and time points in both NPC cell lines. Our preliminary result suggests that RAD001 may be a promising agent against NPC and its effect on apoptosis and cell cycle should be evaluated.
Abstract 231: Optimizing lysosomal activation of antibody-drug conjugates (ADCs) by incorporation of novel cleavable dipeptide linkers
Authors: Paulin Salomon, Luke Harris, Emily E. Reid, Erin K. Maloney, Alan J. Wilhelm, Michael L. Miller, Ravi V. Chari, Thomas A. Keating, Rajeeva Singh
Journal: Cancer Research (2019)

Abstract Peptides constitute a major linker class in antibody-drug conjugates (ADCs), designed to connect antibodies to cytotoxic drug molecules. An optimal linker for an ADC should be stable in circulation and be cleaved efficiently in lysosomes upon binding and internalization of the ADC in target cells, releasing drug molecules that exit lysosomes and inhibit key cellular functions. Previous studies have focused on a limited selection of peptide linkers and specific biochemical tools, such as a cathepsin B cleavage assay, leading to the selection of a valine-citrulline dipeptide linker with a p-aminobenzyloxycarbonyl (PABC) spacer, which is now often used in candidate ADCs. In this study, we screened a panel of dipeptide linkers for efficient lysosomal proteolysis. Dipeptide linkers bearing different amino acids (typically both L, with D used as a control) were synthesized with a fluorogenic leaving group, 7-amino-4-methylcoumarin, which provided a convenient model system for screening of peptide cleavage using lysosomal extracts from cancer cells as well as several individual cathepsins. The linkers were also tested for stability in mouse, rat, cynomolgus, and human plasma. Based on these screens, we identified several novel, previously unreported peptide linker designs and incorporated them into ADCs bearing a DNA-alkylating indolinobenzodiazepine (IGN) payload. These ADCs with different peptide linkers were assayed for in vitro cytotoxicity in multiple cancer cell lines, in vivo efficacy in human tumor xenograft models in mice, and ex vivo plasma stability. In addition, we measured the impact of peptide linkers on the kinetics of proteolytic processing of ADCs in cancer cell lines. We observed that several dipeptide linker designs were superior in rates of lysosomal processing compared to a reference standard L-Ala-L-Ala dipeptide linker. Citation Format: Paulin Salomon, Luke Harris, Emily E. Reid, Erin K. Maloney, Alan J. Wilhelm, Michael L. Miller, Ravi V. Chari, Thomas A. Keating, Rajeeva Singh. Optimizing lysosomal activation of antibody-drug conjugates (ADCs) by incorporation of novel cleavable dipeptide linkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 231.
Abstract 1359: Detection of PD-L1 positive circulating tumor cells from patient with bladder cancer
Authors: Yongjoon Suh, Seong-Kun Kim, Hye Seon Lee, Yun-Gyu Jeong, Jeong-Mi Moon, Myoung Shin Kim, Byung Hee Jeon, U-Syn Ha
Journal: Cancer Research (2019)

Abstract Immunotherapy with PD-L1 inhibitors greatly enhanced the clinical outcomes of patients with late stage metastatic bladder cancer. However, a concern has been raised in the front-line clinical use of PD-L1 inhibitors (permbrolizumab and atezolizumab) as a single treatment to PD-L1-low patients, due to a poorer overall survival compared with patients treated with plantinum-based chemotherapy. In accordance, reliable evaluation of PD-L1 expression is required for selecting patients relevant for treatment with PD-L1 inhibitors. However, due to the regional heterogeneity in primary tumor, evaluation of PD-L1 levels in tissue biopsy might be less reliable than the levels in circulating tumor cells (CTCs). Here, we developed the evaluating system of PD-L1 levels in CTCs isolated from the blood of patients with bladder cancer. Initially, CTCs were enriched by Smart Biopsy Cell Isolator (CytoGen), which utilizes the size-based gravity filtration for CTC isolation. The isolated CTCs were then validated with the expression of EpCAM, Vimentin and CK as well as a negative selection with CD45, and were analyzed for PD-L1 expression status by immunocytochemical staining. Using the evaluating system, we show that PD-L1 (+) cancer cell was efficiently recovered from the healthy human blood samples in a spike and recovery experiment. Furthermore, we evaluated PD-L1 expression status in CTCs isolated from ~25 patients with bladder cancer. Collectively, this study implicates the possibility that PD-L1 expression status could be analyzed at the levels of CTCs instead of the matching primary tumor tissue biopsy, probably with a better clinical diagnostic option. Citation Format: Yongjoon Suh, Seong-Kun Kim, Hye Seon Lee, Yun-Gyu Jeong, Jeong-Mi Moon, Myoung Shin Kim, Byung Hee Jeon, U-Syn Ha. Detection of PD-L1 positive circulating tumor cells from patient with bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1359.
Abstract 2098: IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90
Authors: Vijaya Kumar Pidugu, Meei-Maan wu, Hima Bindu Pidugu, Te-Chang Lee
Journal: Cancer Research (2019)

Abstract Interferon-induced protein with tetratricopeptide repeats (IFITs) family, well-known interferon-stimulated genes, have multiple tetratricopeptide repeats with helix-turn-helix structural motifs that mediate a variety of protein-protein interactions. Four IFIT genes have been identified in humans: IFIT1, IFIT2, IFIT3, and IFIT5. While the importance of IFIT1 and IFIT3 in the prognosis of cancer has been reported, the molecular basis of IFIT1 and IFIT3 in cancer progression remains unexplored. We have previously shown that high IFIT1 and IFIT3 expression associated with advanced T-stage, lymph node metastasis, perineural invasion, lymphovascular invasion, extranodal extension, and poor overall survival rate in oral squamous cell carcinoma (OSCC) patients. Also, we have demonstrated that high IFIT1 or IFIT3 expression promoted OSCC invasion and metastasis by EGFR signaling via enhancing EGFR endocytic recycling. Intriguingly, our recent studies have revealed the involvement of IFIT1 and IFIT3 in the resistance to chemotherapeutic agents in OSCC cells. The failure of chemotherapy or targeted therapy was often associated with the intrinsic or acquired drug resistance in cancer cells. In the present study, we intended to explore the biological role of IFIT1 and IFIT3 on drug resistance in OSCC cells. Our results showed that ectopic expression of IFIT1 or IFIT3 proteins in OSCC cells significantly increased the resistance to various therapeutic drugs such as cisplatin, carboplatin, 5-FU, and doxorubicin. Whereas, silencing of IFIT1 and IFIT3 by shRNA enhanced the sensitivity to these drugs. We further demonstrated that enhanced expression of IFIT1 and IFIT3 significantly increased the levels of C-terminal phosphorylation of Hsp90 and activation of its client proteins, such as EGFR, AKT, p38, and SAPK/JNK. Using mass spectrophotometric, immunoprecipitation and immunofluorescence analyses, we identified the interactions of IFIT1 and IFIT3 with Hsp90. Suppression of Hsp90 by a specific inhibitor resulted in decreased activation of its downstream targets in IFIT1- or IFIT3-overexpressing cells. These results suggested a novel mechanism of IFIT1 and IFIT3 in activating Hsp90 and several downstream signaling regulators which are crucial for OSCC tumor progression and drug resistance. Thus, IFIT1 and IFIT3 may act as co-chaperones and serve as potentially important prognostic biomarkers for OSCC progression. Citation Format: Vijaya Kumar Pidugu, Meei-Maan wu, Hima Bindu Pidugu, Te-Chang Lee. IFIT1 and IFIT3 modulate the drug response in human oral squamous cell carcinoma through interaction and activation of Hsp90 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2098.
Abstract 5285: The role of HIV-1 TAT interactive protein 2 in modulating tumor response to hypoxia
Authors: Qingyu Stephanie Zhou, Xiaofang Guo, Minghua Li, Hua Pan
Journal: Cancer Research (2019)

Abstract While there is ample evidence that HIV-1 TAT interactive protein 2 (HTATIP2) is a tumor suppressor exerting its pro-apoptotic and anti-metastatic activities by regulating the expression of a subset of pro-apoptotic and anti-apoptotic genes and metastasis suppressor genes, it remains unclear if HTATIP2 has a role in tumor response to hypoxia. The objective of this study was to define the role of HTATIP2 in mediating certain molecular and cellular changes in response to hypoxia in tumors. We employed a series of isogenic A549 human lung adenocarcinoma sublines that were genetically deficient for HTATIP2 and/or HIF-1α to examine the potential modulatory effect of HTATIP2 on oncogenic signaling pathways mediated by HIF-1α and HIF-2α, and established the HTATIP2-deficient A549 xenograft model to explore the impact of deletion of HTATIP2 on tumor response to hypoxia. Results from the human HIF-regulated cDNA plate array study revealed that under hypoxic condition (0.5% O2), several genes promoting tumor metastasis and resistance to apoptosis and anticancer treatment, including HIF1α, CYSD, MMP1, MXI1, NDRG2, PAI1 and NDRG1, were upregulated to a greater extent in HTATIP2 knockdown A549 cells than in the control A549 cells. In contrast, genes involved in angiogenesis, glucose metabolism and protection of apoptosis under hypoxia, such as PDGF, PDK1, CA9, and SAG, were upregulated to a greater extent in control A549 cells than in HTATIP2-knockdown A549 cells. Results from the in vivo study demonstrated that the mean growth rate of HTATIP2-deficient A549 xenograft tumors was significantly increased as compared with that of parental A549 xenograft tumors irrespective of the presence or absence of sorafenib treatment. Moreover, the data of photoacoustic imaging (PAI) of tumor hypoxia revealed that the parental A549 tumors were better oxygenated than the counterpart HTATIP2-deficient A549 tumors. After the 10-day sorafenib treatment, the oxygenated regions in sorafenib-treated parental A549 tumors were significantly reduced as compared with the vehicle-treated parental A549 tumors, whereas no significant change in the oxygenated regions was found between vehicle- and sorafenib-treated HTATIP2-deficient A549 tumors. The overall finding of our study suggests that downregulation of HTATIP2 affords growth advantage to tumor cells by fine-tuning tumor adaptation to hypoxia, leading to tumor progression and aggression. Citation Format: Qingyu Stephanie Zhou, Xiaofang Guo, Minghua Li, Hua Pan. The role of HIV-1 TAT interactive protein 2 in modulating tumor response to hypoxia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5285.