tbuckley/cabot-search huggingface dataset:
Abstract 1715: Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells
Authors: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange
Journal: Cancer Research (2016)

Abstract Growing evidence supports a subpopulation of cancer stem cells (CSCs) as both the drivers of tumor growth and the source of relapse following treatment. The identification of genes and pathways required for the survival of CSCs may therefore lead to better treatment outcomes. Here, as part of the OncoTrack* consortium, we report the use of 3D in vitro and xenograft models of patient-derived colon cancer for the identification of novel regulators of CSCs. Increased aldehyde dehydrogenase (ALDH) activity has been demonstrated to be a marker of normal intestinal stem cells and colon CSCs. We therefore isolated and functionally tested ALDH+ cells for CSC properties using 3D in vitro models and xenografts of patient derived colon cancer. These studies revealed ALDH+ cells to be highly enriched for CSCs. In addition, there was a positive correlation between CSC frequency in the models and tumor grade at time of surgical resection. ALDH+ CSCs were subjected to RNA sequencing for whole transcriptome analysis. These analyses demonstrated ALDH+ CSCs to be enriched for stem cell associated genes (ALDH1A1, BMI1, LGR5, CD44, CD166), signaling pathways (Wnt, Hedgehog) and developmental (embryonic, placental, tissue development, EMT) and metabolic processes (retinol metabolism, drug metabolism, hypoxia). Lentivirus mediated gene knockdown was carried out on a panel of genes that were differentially expressed in ALDH+ cells from 3D in vitro models and xenografts. These studies led to the identification of genes required for the self-renewal and survival of colon CSCs. Interestingly, these genes have been reported as important regulators of early embryonic and placental development but have not previously been reported in the regulation of cancer stem cells. *The research leading to these results has received funding from the European Union's Seventh Framework Program (FP7/2007-2013) for the Innovative Medicine Initiative under grant agreement n°115234. Citation Format: Joseph L. Regan, Stephanie Staudte, Dirk Schumacher, Ulrich Keilholz, Johannes Haybaeck, Hans Lehrach, Marie-Laure Yaspo, David Henderson, Andreas Steffen, Joern Toedling, Ralf Lesche, Reinhold Schaefer, Christian R. Regenbrecht, Dominik Mumberg, Martin Lange. Whole transcriptome analysis of patient-derived 3D in vitro and xenograft models of colon cancer identifies placental genes required for the survival of cancer stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1715.
Abstract 2184: The effects of specific heterocyclic compounds on angiogenesis and apoptosis factors in cancer cells
Authors: Funda Kosova, Özlem Temiz-Arpacı, İbrahim TUĞLU, Ercüment ÖLMEZ, Feyzan ÖZDAL KURT, Gorkem KISMALI, Zeki Ari, Mustafa ARISOY
Journal: Cancer Research (2016)

Abstract Introduction: Benzoxazole have received considerable attention during last few decades as they are endowed with variety of biological activities and have wide range of therapeutic properties. The present study aimed to evaluate cytotoxic and antiapoptotic activities of new synthesize benzoxazole derivative in breast cancer cell lines. Material and Method: In this study, the breast cancer cell lines MDA-MB and MCF-7 were used. Cytotoxic activities of novel benzoxazole-derived compound were analyzed with MTT assay. Additionally, the level of its effects on NF-κB and apoptosis-related proteins were examined by the western blot. Immunohistochemical stainings were done for VEGF, eNOS proteins and Tunnel assay was performed to show DNA damage. Results: The structure of the compound synthesized in our study 5-amino-2-(p-bromophenyl)-benzoxazole was proved by elemental analysis, IR, 1H NMR and mass spectroscopy analysis methods. Novel benzoxazole analogue detected cytotoxic on breast cancer cells dose dependent manner, MCF-7 cells were found more sensitive by MTT assay. When the protein was examined in immunohistochemistry with regard to VEGF, eNOS and TUNEL, it was observed that it caused a reduction in VEGF and an increase in eNOS and TUNEL. We observed that it wasn't between groups in Apaf-1 and BCL-2 levels, but down regulation was observed in caspase 3 and Nfkβ levels compared to control group. Novel benzoxazole compound increased Cytochrome C level in treated cells compared to the control group in MDA-MB cells but not in the MCF-7 cells. Conclusion: In summary, It is felt that this newly synthesized heterocyclic compound increases apoptozis by reducing the activation of Nfkβ, and in this way has shown an effect of inhibiting tumor growth in cancer treatment. Key Words: Heterocyclic Compounds, NF-κB, APAF-1, Cytochrome C, Caspase-3, bcl-2 Citation Format: Funda Kosova, Özlem Temiz-Arpacı, İbrahim TUĞLU, Ercüment ÖLMEZ, Feyzan ÖZDAL KURT, Gorkem KISMALI, Zeki Ari, Mustafa ARISOY. The effects of specific heterocyclic compounds on angiogenesis and apoptosis factors in cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2184.
Extended phase I study of AS1411 in renal and non-small cell lung cancers
Authors: D. A. Laber, B. S. Taft, G. H. Kloecker, P. J. Bates, J. O. Trent, D. M. Miller
Journal: Journal of Clinical Oncology (2006)

13098 Background: AS1411 is an oligonucleotide aptamer that binds to nucleolin, a protein expressed on the surface of tumor cells. A dose-escalating phase I trial in patients with various advanced cancers revealed no serious toxicities and consequently did not reach an MTD. There was evidence of activity, especially in renal cell carcinoma (RCC). This study has been reopened for further dose escalation to reach an optimal biological dose (OBD; unless an MTD is reached) in patients with RCC and non-small cell lung cancer (NSCLC). Methods: Patients had advanced RCC or NSCLC refractory to standard treatment. AS1411 was administered as a single continuous 7-day iv infusion, with the option of a second cycle. Patients were enrolled in cohorts of 3. If no serious toxicity was observed within 28 days, the dose was escalated to the next level. Toxicity was graded using the NCI CTCAE v3.0. The study plan was to enroll additional patients at the OBD such that a total of 12 RCC and 12 NSCLC patients received a 7-day infusion. Blood and urine samples were taken for pharmacokinetic analysis. Tumor responses were assessed every 28 days using the RECIST guidelines. Results: No serious adverse events have been observed up to a dose of 22mg/kg/day, which was associated with a mean peak plasma concentration of 1.5 μM. Response findings to date are as follows: of 5 RCC patients, 1 maintains a near-complete response 18 months after treatment, 3 have ongoing stable disease (SD; 1 at 3 months, 2 at 2 months) and a fourth had progressive disease (PD) at 2 months post-treatment; of 3 NSCLC patients, 1 has an ongoing SD and 2 had PDs at 1 month post-treatment. Recruitment and follow up continues. Conclusions: A 7-day infusion of AS1411 at 22mg/kg/day was not associated with any serious adverse events and achieved peak plasma concentrations in the range at which killing of various cancer cell lines is observed in vitro. A single further escalation is planned to reach a dose of 40mg/kg/day. Observation of additional cases of stable disease in RCC supports the previous observations of anti-cancer effects in this disease. [Table: see text]
BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1
Authors: Rinske Drost, Kiranjit K. Dhillon, Hanneke van der Gulden, Ingrid van der Heijden, Inger Brandsma, Cristina Cruz, Dafni Chondronasiou, Marta Castroviejo-Bermejo, Ute Boon, Eva Schut, Eline van der Burg, Ellen Wientjens, Mark Pieterse, Christiaan Klijn, Sjoerd Klarenbeek, Fabricio Loayza-Puch, Ran Elkon, Liesbeth van Deemter, Sven Rottenberg, Marieke van de Ven, Dick H.W. Dekkers, Jeroen A.A. Demmers, Dik C. van Gent, Reuven Agami, Judith Balmaña, Violeta Serra, Toshiyasu Taniguchi, Peter Bouwman, Jos Jonkers
Journal: Journal of Clinical Investigation (2016)

Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.
Abstract 3531: Autophagy facilitates leukemogenesis in a murine model of MLL-AF9-driven AML
Authors: Qiang Liu, Longgui Chen, Hong-Gang Wang
Journal: Cancer Research (2016)

Abstract Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by the clonal expansion of immature myeloid cells. There is an urgent and unmet need for the development of novel therapeutics against AML. Autophagy is a lysosomal catabolic process that has been implicated in leukemia cell survival and chemotherapy response. However, the biological role of autophagy in AML leukemogenesis remains poorly defined. In this study, we genetically ablated ATG5, a gene that is essential for autophagy, in AML cells during leukemogenesis in a murine model of MLL-AF9-driven AML. The homozygous deletion of ATG5 in AML cells significantly delayed MLL-AF9-induced leukemogenesis and progression in vivo. Likewise, the in vitro deletion of ATG5 in MLL-AF9 driven AML cells demonstrated decreased growth as well as reduced colony forming units. Interestingly, ATG5 deficiency demonstrated an altered differentiation hierarchy of MLL-AF9-induced AML cells in vivo that could be linked to decreased proliferation and suppressed leukemogenesis. Overall, this study provides insight at how autophagy can facilitate AML progression. A more comprehensive understanding on autophagy in AML is needed prior to the deployment of autophagy modulators for the treatment of AML. Citation Format: Qiang Liu, Longgui Chen, Hong-Gang Wang. Autophagy facilitates leukemogenesis in a murine model of MLL-AF9-driven AML. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3531.
Abstract 1718: Characteristics of carbonic anhydrase 9-expressing cells in the human intestinal crypt base
Authors: Yozo Suzuki, Hidekazu Takahashi, Masahiro Tanemura, Junichi Nishimura, Naotsugu Haraguchi, Masahisa Ohtsuka, Susumu Miyazaki, Mamoru Uemura, Taishi Hata, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori
Journal: Cancer Research (2016)

Abstract Background/Aims: In many tissues, stem cells are sequestered in hypoxic microenvironments. However, little is known about the relationship between hypoxia and the intestinal crypt base, the presumed location of intestinal stem cells. This study investigated the expression of carbonic anhydrase 9 (CA9), a hypoxia-inducible membrane-tethered protein, in normal intestinal crypt base cells and in adenoma and early colorectal cancer. Methods: Using surgically resected human colorectal cancer specimens, we investigated the expression pattern and functional associations of CA9 in human adult normal intestinal epithelia and in adenoma and early colorectal cancer using immunofluorescence, immunohistochemical staining, flow cytometry, and quantitative real-time polymerase chain reaction. Results: Almost all slender cells in the crypt base in the ileum were CA9+. In the right and left colon, 25% and 40% of all cells, respectively, were CA9+. Notably, CA9+ cells had eosinophilic structures in their basal cytoplasm. Adenomas and T1 colorectal cancer showed broad CA9 expression. Flow cytometry analysis indicated that CA9+ cells had increased mRNA levels of AXIN2, a Wnt signaling factor. Conclusion: These observations indicate that CA9 expression in normal crypt base cells is associated with intestinal epithelial stemness. CA9 expression may be involved in the carcinogenesis of colorectal cancer. Citation Format: Yozo Suzuki, Hidekazu Takahashi, Masahiro Tanemura, Junichi Nishimura, Naotsugu Haraguchi, Masahisa Ohtsuka, Susumu Miyazaki, Mamoru Uemura, Taishi Hata, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Characteristics of carbonic anhydrase 9-expressing cells in the human intestinal crypt base. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1718.
An Ethical Debate: Transplantation and interventional ventilation on the intensive therapy unit
Authors: S. M Willatts
Journal: BMJ (1995)

Transplantation is a successful, cost effective treatment for terminal organ failure limited by a shortfall of donor organs to meet the need. This is currently estimated at over 5700 organs for the United Kingdom and Republic of Ireland.1 2

A confidential audit of all deaths in intensive therapy units has shown that even if all patients diagnosed as brainstem dead became donors the need could not be met.3 This led to the Exeter protocol for interventional ventilation of patients with rapidly progressive intracranial pathology which was expected to be fatal.4 Worldwide estimates suggest about 40 potential candidates for interventional ventilation per million population, which would greatly improve the outlook for those awaiting a transplant.5 The age of donor organs acquired in this way is greater but the proportion …
Evaluation of expression of ERCC1 in hepatocellular cancer.
Authors: E. Bas, N. S. Turhal, O. Er, M. Aliustaoglu, S. Seber, F. Dane, T. Korkmaz, I. Soyuer, S. Ozkara, C. Celikel
Journal: Journal of Clinical Oncology (2010)

e14685 Background: Hepatocellular cancer (HCC) is a common cancer, especially in Asia. The pathogenesis of this disease is multifactorial and includes many pathways. Excisional repair cross complementation1 (ERCC1) is a DNA repair enzyme and existence of it is implicated in worsening prognosis in cisplatin treated lung cancer patients. The expression rate of ERCC1 in HCC is not known. Herein we studied this to find out whether a subset of HCC patients can be identified to benefit from cisplatin. Methods: Sixty one patients with HCC who had enough tissue to do immunohistochemistry are identified in three institutions. There were no exclusion criteria other than unavailability of tissue blocks. Since this study's only intention was to identify the presence or absence of the ERCC1, no data on patient characteristics is compiled. Immunohistochemical staining was performed manually using the standard streptavidin-biotin-peroxidase method. Monoclonal anti- ERCC 1 (D-10) from Santa Cruz Biotechnology ( Santa Cruz, CA) is used. Results: Out of 61 patients (< 2%) had ERCC1 expression. Conclusions: ERCC1 expression in HCC is very low. Although around 10% of HCC patients respond to cisplatin, this is unlikely to be due to ERCC1 negativity. Pathways other than ERCC1 should be searched to find ways to help these patients' treatment strategies. No significant financial relationships to disclose.
RelA: a tale of a stitch in time
Authors: Murray Korc
Journal: Journal of Clinical Investigation (2016)

Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer in which NF-κB pathways promote biological aggressiveness. In this issue of the JCI, Lesina et al. investigated the role of RelA, the p65 partner of p50 that together form the most common NF-κB complex, in the early stages of pancreatic malignant transformation and in established PDAC. By deleting Rela in the context of an oncogenic Kras-driven autochthonous model of PDAC, the authors demonstrated that RelA is a mediator of oncogene-induced senescence (OIS) and the senescence-associated secretory phenotype (SASP) that attenuates acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN) formation, and PanIN progression to PDAC. Loss of the tumor-suppressor function of RelA in the early stages of Kras-driven pancreatic neoplastic transformation was associated with decreased OIS and SASP and a protumorigenic tumor microenvironment that harbored more M2 macrophages and myeloid-derived suppressor cells. The beneficial effects of RelA were mediated by increased expression of CXCL1 and its activation of CXCR2. By contrast, in advanced stages of Kras-driven murine PDAC, loss of p53 or p16 was associated with senescence bypass, and RelA deficiency in this context attenuated cancer cell proliferation and prolonged mouse survival, indicating that RelA enhances tumor progression in established PDAC.
Abstract 4644: Inhibition of the androgen receptor at two drug-targetable sites on the DNA-binding domain protein surface
Authors: Kush Dalal, Aishwariya Sharma, Mani Roshan-Moniri, Hendrik Borgmann, Nada Lallous, Shannon Awrey, Huifang Li, Fuqiang Ban, Eric LeBlanc, Artem Cherkasov, Paul S. Rennie
Journal: Cancer Research (2016)

Abstract The androgen receptor (AR) is a hormone inducible transcription factor that continues to be an important drug-target to prevent or slow the progression of prostate cancer. Current small molecule inhibitors, such as Enzalutamide (anti-androgens), compete with naturally occurring steroids that bind to the hormone binding pocket of the AR ligand binding domain (LBD). In advanced or castration resistant prostate cancer (CRPC), mutations in the LBD confer drug-resistance by converting anti-androgens into agonists, prompting research to develop small molecule inhibitors that target different sites on the AR protein surface. Recently, we characterized a set of small molecules that could interact with the DNA binding domain (DBD) of the AR and block its transcriptional activity. Here, we extend the pioneering observations by clarifying the mechanism of two classes of compounds that either block AR-chromatin interactions or reduce AR-dimerization in the cell nucleus. Compound efficacy is demonstrated across multiple prostate cancer cells lines, including enzalutamide resistant forms, with respect to AR transactivation, cell viability and expression of downstream genes. We also characterize the pharmacological properties of the lead compound and its effects on tumour xenografts in mice. Collectively, these results lay the foundation for the development of alternative prostate cancer drugs that interfere with the biochemical function of the activated, nuclear localized AR. Citation Format: Kush Dalal, Aishwariya Sharma, Mani Roshan-Moniri, Hendrik Borgmann, Nada Lallous, Shannon Awrey, Huifang Li, Fuqiang Ban, Eric LeBlanc, Artem Cherkasov, Paul S. Rennie. Inhibition of the androgen receptor at two drug-targetable sites on the DNA-binding domain protein surface. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4644.
Abstract 4653: Combination Azacitidine and histone deacetylase inhibition induces a multi factorial synergistic anti-tumor response in non-small cell lung cancer (NSCLC)
Authors: Michael Topper, Christin Hanigan, Michelle Vaz, Katherine Chiappinelli, Julin Justin, Lauren Murphy, Cynthia Zahnow, Stephen Baylin
Journal: Cancer Research (2016)

Abstract Epigenetic therapy holds much promise as an emerging paradigm for the treatment of many disparate types of human cancer. However, the data in solid malignancies, particularly, would suggest further optimization is required to extract the true potential of these therapies. In our current study, we have deployed at low, clinically achievable doses, chronic combinatorial administration of the DNA methyltransferase inhibitor Azacitidine in conjunction with both benzamide and hydroxyamic acid based histone deacetylase inhibitors (HDACi) in NSCLC. We have developed our paradigms by sequentially employing chronic HDACi administration after Azacitidine. This strategy achieves durable alteration of the cell transcriptome with corresponding induction of both cell cycle arrest and apoptosis. These events appear driven by alterations, both transcriptionally and post transcriptionally of Myc and Myc regulatory proteins. Epigenetic treatment induced perturbation of Myc is facilitated by Wnt pathway inhibition through induction of Wnt antagonists, namely DKK proteins. Importantly, as part of this scenario of altering a Myc regulatory axis, there is a synergistic cytotoxic response mediated at least in part through downregulation of a critical effector, the Skp2 oncogene. Additionally, we observe significant induction of an interferon responsive viral defense gene signature as the result of epigenetic treatment. This gene signature has been shown to correlate with response to immune checkpoint blockade in the setting of metastatic melanoma. We propose that this combination of viral defense gene signature augmentation in conjunction with potent direct epithelial cancer cytotoxicity holds promise to be a more complete therapeutic paradigm for the treatment of NSCLC. Citation Format: Michael Topper, Christin Hanigan, Michelle Vaz, Katherine Chiappinelli, Julin Justin, Lauren Murphy, Cynthia Zahnow, Stephen Baylin. Combination Azacitidine and histone deacetylase inhibition induces a multi factorial synergistic anti-tumor response in non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4653.