tbuckley/cabot-search huggingface dataset:
Abstract 2055: Therapeutic resistance to BET bromodomain inhibition in prostate cancer
Authors: Carl G. Engelke, Rohit Malik, Steven Kregel, Irfan A. Asangani, Kari Wilder-Romans, Xia Jiang, Xuhong Cao, Corey Speers, Arul M. Chinnaiyan
Journal: Cancer Research (2017)

Abstract Prostate cancer is the most common cancer among men and a leading cause of cancer-related death in North America. Current therapies include radical prostatectomy and radiotherapy for localized disease, and androgen deprivation therapy (i.e. surgical or medical castration) for metastatic disease. Recently, we described the use of inhibitors of bromodomain and extraterminal (BET) proteins for the treatment of castration-resistant prostate cancer (CRPC), which have since undergone investigation in clinical trials. In anticipation of patients refractory to treatment with BET inhibitors, we explored the development of resistance to a clinical-grade BET inhibitor in four cell line models—VCaP, LNCaP, LNCaP-AR, and 22Rv1—by serially passaging cells in increasing concentrations of drug with matched controls in DMSO. All resistance models displayed several-fold increased IC50 values relative to control in in vitro cell viability assays. Additionally, we have modeled resistance to BET inhibition in vivo by serially passaging cell line- and patient-derived xenografts in animals treated with BET inhibition. Interrogating these models through traditional molecular techniques and next-generation sequencing, we discovered several putative mechanisms of resistance to BET inhibition that we are currently validating in our laboratory. Note: This abstract was not presented at the meeting. Citation Format: Carl G. Engelke, Rohit Malik, Steven Kregel, Irfan A. Asangani, Kari Wilder-Romans, Xia Jiang, Xuhong Cao, Corey Speers, Arul M. Chinnaiyan. Therapeutic resistance to BET bromodomain inhibition in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2055. doi:10.1158/1538-7445.AM2017-2055
Abstract IA30: CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer
Authors: Raymond N. DuBois
Journal: Cancer Research (2017)

Abstract Emerging evidence suggests that once a primary tumor forms it can then influence the development of a supportive metastatic microenvironment, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A that stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruits CXCR2-positive myeloid-derived suppressor cells (MDSCs) to form a pre-metastatic niche that ultimately promotes liver metastases. Importantly, we found that pre-metastatic liver-infiltrating MDSCs induce tumor cell survival without involvement of the innate or adaptive immune responses. Our study provides the first evidence we know of showing that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1 that recruits CXCR2-positive MDSCs to form a pre-metastatic niche which promotes liver metastases. Our findings not only reveal a novel mechanism by which the interactions of malignant cells with their stromal counterparts in the primary tumor contribute to the formation of a pre-metastatic niche that favors tumor cell survival, but also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Citation Format: Raymond N. DuBois. CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA30.
Abstract 1473: miR-1207-3p regulates c-Myc in aggressive prostate cancer
Authors: Dibash K. Das, Olorunseun O. Ogunwobi
Journal: Cancer Research (2017)

Abstract Prostate cancer (PCa) is the most common non-skin cancer and the second leading cause of cancer-related death for men in the U.S. A major challenge is understanding the molecular mechanisms involved in the progression from the asymptomatic androgen-dependent PCa to the lethal castration resistant prostate cancer (CRPC). The chromosomal region 8q24 is associated with aggressive PCa and variants of this region have been identified to interact with the PVT1 non-coding gene in PCa. In previous work we demonstrated that microRNA-1207-3p (miR-1207-3p) has prognostic value in PCa, and directly binds to the 3’ UTR of Fibronectin type III domain containing 1 (FNDC1) to regulate a novel FNDC1/fibronectin (FN1)/androgen receptor (AR) pathway upregulated in metastatic PCa. miR-1207-3p is encoded at the PVT1 gene locus, which is located downstream of c-Myc on the 8q24 human chromosomal region. Studies have suggested amplification at the 8q24 human chromosomal region, which includes C-Myc, as a possible prognostic factor for CRPC. c-Myc is a well-established proto-oncogene that is commonly found to be amplified in up to 72% of CRPCs significant amplication of c-myc has been a consequence of antiandrogen treatment, and c-Myc is downstream of AR in some PCa. miRNAs have also been implicated in the regulation of c-Myc. Nevertheless, the mechanisms regulating c-Myc remain unclear in PCa. Using a panel of five PCa cell lines we discovered that c-Myc expression is higher in aggressive CRPC cell lines compared to non-aggressive CRPC and androgen-dependent prostate cancer cell lines. Furthermore, our data reveals that c-Myc expression is higher in the aggressive E006AA-hT PCa cell line when compared to the indolent E006AA PCa cell line. This suggests that c-Myc is associated with aggressive PCa. Moreover, overexpression of miR-1207-3p suppresses the expression of c-Myc in E006AA-hT PCa cells but not E006AA PCa cell line in which c-Myc is underexpressed compared to the normal prostate epithelial cell line, RWPE-1. Next, using a synthetic biotinylated miR-1207-3p duplex, we discovered that overexpression of miR-1207-3p more effictively inhibited migration, inhibited proliferation and increased apoptosis in the aggressive E006AA-hT PCa cell line with increased c-Myc expression when compared to the indolent E006AA PCa cell line with decreased c-Myc expression. These data demonstrate that the miR-1207-3p/FNDC1/FN1/AR pathway may regulate c-Myc in aggressive PCa. Citation Format: Dibash K. Das, Olorunseun O. Ogunwobi. miR-1207-3p regulates c-Myc in aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1473. doi:10.1158/1538-7445.AM2017-1473
Abstract 5233: Pancreatic cancer specific glycosylations survay by a panel of lectin staining; Tn antigen exposure as a result of o-glycan truncation
Authors: Yusuke Ozawa, Tatsuya Oda, Osamu Shimomura, Hiroaki Tateno, Jun Hirabayashi, Nobuhiro Ohkohchi
Journal: Cancer Research (2017)

Abstract The outermost coating of every cell type is predominantly composed of cell-specific glycans, and glycosylation changes in cancer has been used in clinical field as a tumor markers, such including AFP and CA19-9. We focused pancreatic cancer, the most intractable cancer with difficulty in early diagnosis, and insisted to glasp glycosylation patterns by using a panel of lectin histochemical stainings. Lectins are subgroup of proteins that specifically recognize and bind glycans, and thus helpful indication of glycosylation patterns. Lectin microarry is one of the advanced technologies which inables glycosylation patters of target materials at onece, however, obtained data with homogenized protein matelials applied lacks histological location and information. Instead, we used a panel of 20 types of lectins histochemical staining for cancer and normal tissues. The staining patterns were firstlly classified according to the ratio between cancer cells and stromal cells. a) Cancer high (cancer cell ++ and stromal cells -) b) equal (cancer cells ++ or + and stromal cells ++ or +) c) Cancer Low (cancer cells - or + and stromal cells ++ or +). Further more, the stainig in cancer cell were compaired with that of non cancerous pancreatic ductal epitherial cells. Among 20 lectins, CNL, Clitocybe nebularis Lectin binds motifs containing α/βGalNAc, Tn antigen, and blood group A, showed cancer cell staining higher than normal tissue in pancreatic cancer. Pancreatic cancer cell (31 of 58 patients,71%) were positive for CNL, but normal pancreatic duct cells (2 of 42 patients,4%) were positive in patients of pancreatic cancer. CNL is known to recognize Tn Antigen in O-glycosylation. Previously, it reported that during malignancy, glycosylation displays abnormal expression of shortened or truncated glycans, such as a Tn antigen, T antigen and their sialylated forms, ST, STn antigen. CNL staining pattern we showed in this report is considered to matching Tn staining. Our result indicated that speccific affinity of CNL lectin in pancreatic cancer and counterpart glycoprotein are STn antigen. We may insist that STn glycoprotein antigen could be used as a diagnostic marker of Pancreatic cancer and also it would be a target of new tumor-targetting strategies. Citation Format: Yusuke Ozawa, Tatsuya Oda, Osamu Shimomura, Hiroaki Tateno, Jun Hirabayashi, Nobuhiro Ohkohchi. Pancreatic cancer specific glycosylations survay by a panel of lectin staining; Tn antigen exposure as a result of o-glycan truncation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5233. doi:10.1158/1538-7445.AM2017-5233
Abstract 5327: Glioma derived cancer stem cells are hypersensitive to proteasomal inhibition
Authors: Dae-Hee Lee, Sang Cheul Oh, Yong Tae Kwon, Yong J. Lee, Young Dong Yoo
Journal: Cancer Research (2017)

Abstract Although proteasome inhibitors (PIs) are used as anticancer drugs to treat various cancers, their relative therapeutic efficacy on stem cells vs. bulk cancers remains unknown. Here, we show that stem cells derived from gliomas, GSCs, are up to 1,000-fold more sensitive to PIs (IC50, 27-70 nM) compared with their differentiated controls (IC50, 47-&amp;gt;&amp;gt;100 µM). The stemness of GSCs correlates to increased ubiquitination, whose misregulation readily triggers apoptosis. PI-induced apoptosis of GSCs is independent of NFκB but involves the phosphorylation of JNK as well as the transcriptional activation of endoplasmic reticulum (ER) stress-associated proapoptotic mediators. In contrast to the general notion that ER stress-associated apoptosis is signaled by prolonged unfolded protein response (UPR), GSC-selective apoptosis is instead counteracted by the UPR. ATF3 is a key mediator in GSC-selective apoptosis. Pharmaceutical uncoupling of the UPR from its downstream apoptosis sensitizes GSCs to PIs in vitro and during tumorigenesis in mice. Thus, a combinational treatment of a PI with an inhibitor of UPR-coupled apoptosis may enhance targeting of stem cells in gliomas. Key words: glioma; glioma stem cells; proteasome inhibitors; ubiquitin proteasome system; apoptosis; c-Jun N-terminal kinase (JNK) Citation Format: Dae-Hee Lee, Sang Cheul Oh, Yong Tae Kwon, Yong J. Lee, Young Dong Yoo. Glioma derived cancer stem cells are hypersensitive to proteasomal inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5327. doi:10.1158/1538-7445.AM2017-5327
Thyroid stimulating hormone exhibits the impact on LDLR/LDL-c via up-regulating hepatic PCSK9 expression
Authors: Yingyun Gong, Yizhe Ma, Zhengqin Ye, Zhenzhen Fu, Panpan Yang, Beibei Gao, Wen Guo, Dandan Hu, Jingya Ye, Shuai Ma, Fan Zhang, Li Zhou, Xinyu Xu, Zhong Li, Tao Yang, Hongwen Zhou
Journal: Metabolism (2017)
Abstract 5122: Utilizing zebrafish to study the effect strigolactone on breast cancer cells
Authors: Kira Lin, Christopher Grivas, Elema Boru, Yaron Dayani, Eric Berens, Anna T. Riegel, Eric Glasgow, Ronit I. Yarden
Journal: Cancer Research (2017)

Abstract Strigolactones (SLs) are a novel class of phytohormones that regulates shoot branching patterns and above-ground plant architecture by inhibiting the outgrowth of axillary lateral buds or meristems. The SL analogues (SLAs) inhibit the growth and survival of a wide array of cancer-derived cell lines including: prostate, colon, lung, melanoma, osteosarcoma and leukemic cell lines, while minimally affecting normal cultured cells. Interestingly, cancer cells with high metastatic potential are more sensitive to the inhibitory effect of SLAs than less aggressive cells. Treatment of cancer cells with SLAs leads to the activation of stress-related signaling including p38MAPKs and JNK1/2, and disrupt the microtubule network. Furthermore, a reduction in acetylated-alpha-tubulin was observed in SLA-treated MDA-MB-231 cells. Microtubules dynamics has been proposed as one of the mechanisms that regulate cell migration by acting on lamellipodia formation. The ECIS invasion assay data suggests that even at low concentration of SLA and as soon as 6 hours, SLAs suppress MDA-MB-231 cells’ ability to invade the HUVEC monolayer. To further examine the effect of SLAs on the invasive and metastatic behaviors of cancer cells in vivo, fluorescently labeled MDA-MB-231 cells were used as xenograft models in zebrafish. Embryos injected with MDA-MB-231 cells showed 66.6% metastasis in vehicle treated control fishes, as compared to 22.85% in SLAs treated fishes. This suggests that SLAs are potent inhibitors of cancer dissemination and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Kira Lin, Christopher Grivas, Elema Boru, Yaron Dayani, Eric Berens, Anna T. Riegel, Eric Glasgow, Ronit I. Yarden. Utilizing zebrafish to study the effect strigolactone on breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5122. doi:10.1158/1538-7445.AM2017-5122
Abstract 3439: MicroRNA-34a epigenetically silences epithelial-mesenchymal transitions (EMT)-TFs in metastatic breast cancer cells
Authors: Saber Imani, Chunli Wei, Jingliang Cheng, Junjiang Fu
Journal: Cancer Research (2017)

Abstract MicroRNA-34a (miR-34a) as key regulator of tumor suppression gene potentially plays a profound role in the tumorigenesis and progression of several cancers including breast cancer. In the present study, we invstigated the expression, targets and functional effects of miR-34a and its correlation with tumour characteristics and clinical outcome in the epithelial to mesenchymal transitions (EMT) stage of metastatic breast cancer (MBC). We focused to analyze EMT-inducing transcription factors (EMT-TFs)/miR-34a feedback loop, like TWIST1, SLUG, ZEB1/2, NOTCH1, on promotes MBC migration, invasion and metastasis. We found that miR-34a potently inhibits NOTCH1, ZEB1 protein expression activity in breast cancer cells. Importantly, the miR-34a do not have any inhibitory effects upon the SLUG and ZEB2. Using quantitative reverse transcription-PCR and western blot analysis, we showed that average pre-miR-34a expression is down regulated in human metastatic breast tissues as compared to normal human breast and negatively correlates with clinicopathological features of MBC patients. Ectopic expression of miR-34a in metastatic breast cancer cell-line BT-549 significantly inhibited cell proliferation, migrations, survival and cell invasion, but no clear effect on cancer cell growth. We provide indication that these regulatory pathways may stabilize epithelial and mesenchymal states, individually. We have consequently revealed that miR-34a is downregulated in MBC tissues and that it suppresses tumor growth by affecting several malignancy endpoints via downregulation of multiple EMT-TFs. Mutational or epigenetic inactivation of the EMT-TFs/miR-34a pathway probably alterations the equilibrium of these regulations toward EMT and the mesenchymal state and thereby contributes to metastasis. The results also suggest that miR-34a could serve as a potential therapeutic agent for MBC. Funding support: This work was supported by the NSFC (81172049, 81672887), Corresponding author email:fujunjiang@hotmail.com;fujunjiang@swmu.edu.cn Citation Format: Saber Imani, Chunli Wei, Jingliang Cheng, Junjiang Fu. MicroRNA-34a epigenetically silences epithelial-mesenchymal transitions (EMT)-TFs in metastatic breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3439. doi:10.1158/1538-7445.AM2017-3439
Abstract 1482: Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene <i>in vivo</i> and <i>in vitro</i>
Authors: Chunming Jiang, Xiang Fang, Xuepeng Wang, Maoqiang Li, Wu Jiang, Liulong Zhu, Zhenyu Bian
Journal: Cancer Research (2017)

Abstract Objective: We aimed to study the effect of triptolide on OS and the related molecular mechanism. Methods: The cell viability, apoptosis portion, tumor size, tumor weight and invasion of OS cells were determined. The relative level of miR-181 in OS tissues and the adjacent tissues was determined by qRT-PCR. The target gene of miR-181a was determined and verified by luciferase report assay. At last, OS cells were treated with triptolide and triptolide + miR-181a mimics to verify the relationship between triptolide and miRN-181a. Results: Triptolide inhibited the cell viability, promoted the apoptosis, decreased the tumor size and weight, and reduced the invasion of OS cells. The level of miR-181a in OS cells decreased significantly after treating with triptolide, and the relative level of miR-181a in OS tissues was markedly higher than that in the adjacent tissues. PTEN was reported and verified the direct target gene of miR-181a. The overexpression of miR-181a decreased the inhibition of triptolide on OS proliferation and promotion on OS apoptosis. Conclusion: Triptolide inhibited the proliferation of OS by regulating miR-181a via targeting PTEN gene in vivo and vitro. Note: This abstract was not presented at the meeting. Citation Format: Chunming Jiang, Xiang Fang, Xuepeng Wang, Maoqiang Li, Wu Jiang, Liulong Zhu, Zhenyu Bian. Triptolide inhibits the growth of osteosarcoma by regulating microRNA-181a via targeting PTEN gene in vivo and in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1482. doi:10.1158/1538-7445.AM2017-1482
End-of-Life Decisions in the Netherlands over 25 Years
Authors: Agnes van der Heide, Johannes J M van Delden, Bregje D Onwuteaka-Philipsen
Journal: New England Journal of Medicine (2017)

Data from physicians in the Netherlands show that the percentage of patients in whom an end-of-life decision preceded death increased from 39% in 1990 to 58% in 2015. Continuous deep sedation was provided in 18.3% of all deaths in 2015.
Abstract 3892: Delineating the role of ZEB1 loss in the chemo and radioresistance of glioma stem cells
Authors: Mecca Madany, Lincoln Edwards, John S. Yu
Journal: Cancer Research (2017)

Abstract The most prevalent brain cancer, Glioblastoma Multiforme (GBM) has an average survival of less than 2 years. Despite advances in therapy there is still an overall poor response to treatment which has been attributed to glioma stem cells (GSC’s), a subset of tumor cells that are able to self-renew, inhibit differentiation and are often chemo and radioresistant. The genetics and mechanisms underlying how glioma stem cells are able to repopulate tumors and affect patient survival desperately need to be defined. We are interested in delineating the role that ZEB1 (zinc finger e-box binding homeobox-1) loss has on GSC’s and what role this loss plays in the chemo and radioresistance of GSC’s. Most insights into ZEB1 regard it as tumorigenic and an initiator of EMT (epithelial mesenchymal transition). Surprisingly, in this study, we have shown that in TCGA datasets ZEB1 deletion frequently occurs and this loss actually results in poorer glioma patient survival. Copy number analysis as well as immunohistochemistry on patient samples shows that ZEB1 loss occurs both at the gene and protein level. Stable ZEB1 knockdown in our patient derived glioma stem cell lines results in increased proliferation and a resistance to differentiation. Following chemotherapy as well as radiotherapy, knockdown cell lines show increased cell viability as well as higher levels of secondary neurosphere formation. Decreased apoptosis and changes in cell cycle as well as the DNA damage response pathway were also observed in the knockdown lines following chemo and radiotherapy. Overall, this data indicates that loss of ZEB1 in GSC’s results in enhanced resistance to standard therapy. With these results, we have reason to believe that ZEB1 may be used as a novel therapeutic target to combat the chemo and radioresistance of glioma stem cells. Citation Format: Mecca Madany, Lincoln Edwards, John S. Yu. Delineating the role of ZEB1 loss in the chemo and radioresistance of glioma stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3892. doi:10.1158/1538-7445.AM2017-3892
Differential Recognition of<i>Mycobacterium tuberculosis</i>–Specific Epitopes as a Function of Tuberculosis Disease History
Authors: Thomas J. Scriba, Chelsea Carpenter, Sebastian Carrasco Pro, John Sidney, Munyaradzi Musvosvi, Virginie Rozot, Grégory Seumois, Sandy L. Rosales, Pandurangan Vijayanand, Delia Goletti, Edward Makgotlho, Willem Hanekom, Mark Hatherill, Bjoern Peters, Alessandro Sette, Cecilia S. Lindestam Arlehamn
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Individuals with a history of tuberculosis (TB) disease are at elevated risk of disease recurrence. The underlying cause is not known, but one explanation is that previous disease results in less-effective immunity against Mycobacterium tuberculosis (Mtb).Objectives: We hypothesized that the repertoire of Mtb-derived epitopes recognized by T cells from individuals with latent Mtb infection differs as a function of previous diagnosis of active TB disease.Methods: T-cell responses to peptide pools in samples collected from an adult screening and an adolescent validation cohort were measured by IFN-γ enzyme-linked immunospot assay or intracellular cytokine staining.Measurements and Main Results: We identified a set of “type 2” T-cell epitopes that were recognized at 10-fold–lower levels in Mtb-infected individuals with a history of TB disease less than 6 years ago than in those without previous TB. By contrast, “type 1” epitopes were recognized equally well in individuals with or without previous TB. The differential epitope recognition was not due to differences in HLA class II binding, memory phenotypes, or gene expression in the responding T cells. Instead, “TB disease history–sensitive” type 2 epitopes were significantly (P < 0.0001) more homologous to sequences from bacteria found in the human microbiome than type 1 epitopes.Conclusions: Preferential loss of T-cell reactivity to Mtb epitopes that are homologous to bacteria in the microbiome in persons with previous TB disease may reflect long-term effects of antibiotic TB treatment on the microbiome.