tbuckley/cabot-search huggingface dataset:
Abstract 3711: R-Ras is required for T cell trafficking in high endothelial venues and implicated in anti-tumor immunity
Authors: Andrew M. Chan, Xiaocai Yan, Wai Nam Liu, Mingfei Yan
Journal: Cancer Research (2017)

Abstract R-Ras belongs the RAS superfamily of small GTP-binding proteins implicated in cell adhesion signaling. Unlike classical Ras proteins, R-Ras is not activated by growth factor receptors. Rather, its GTPase activity is modulated by molecules implicated in cell-cell adhesion including semaphorins and notch. Using an R-Ras knockout mouse strain, we have previously reported that R-Ras is required for murine Dendritic cell functions. Further characterization of this mouse strain revealed reduced cellularity of peripheral lymph nodes (PLNs) by 40% with T cell regions in the paracortex in which high endothelial venules (HEV) resided were less prominent when compared with wild-type (WT) mice. Consistently, immunohistological analysis for MECA-79, a marker of mature HEV, showed a 3- to 4-fold decrease in staining intensity. This is correlated with a 30-40% reduction in the number of CD62L+ CD4 and CD8 T cells in PLNs. Furthermore, R-Ras null T cells had reduced proliferative and homing capacity when compared with WT. More importantly, we demonstrated for the first time that the chemokine CCL21 was able to stimulate the GTP-loading of R-Ras within 15 seconds of addition. Indeed, R-Ras null T-cells displayed reduced binding to soluble ICAM-1 as well as to 2H-11 endothelial cells. To explore the role of R-Ras in anti-tumor immunity, B16/F10 melanoma cells were injected subcutaneously to WT and R-Ras null mice. In addition, a mouse breast tumor model was generated ineither WT or R-Ras-null genetic background. Tumor development and the number of infiltrating immune cells were analyzed to examine if R-Ras was involved in either anti- or pro-tumor immune responses. This work was supported by NIH CA78509 (AMC), MH59771 (AMC). MY was supported by Hong Kong PhD Fellowship Scheme (PF12-13584) and AMC was supported by the Lo Kwee-Seong Seed Fund, and a General Research Fund Grant, 14120915, from Hong Kong University Grants Committee. Note: This abstract was not presented at the meeting. Citation Format: Andrew M. Chan, Xiaocai Yan, Wai Nam Liu, Mingfei Yan. R-Ras is required for T cell trafficking in high endothelial venues and implicated in anti-tumor immunity [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 3711. doi:10.1158/1538-7445.AM2017-3711
Abstract 3791: Clinical significance of EpCAM-negative and CEA-positive circulating tumor cells in gastric carcinoma
Authors: Yuichiro Miki, Masakazu Yashiro, Tomohisa Okuno, Kishu Kitayama, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira
Journal: Cancer Research (2017)

Abstract &amp;lt;Background&amp;gt; It has been reported that the examination of circulating tumor cells (CTCs) is beneficial for predicting tumor stage or treatment response. The epitherial cell adhesion molecule (EpCAM) and cytokeratin has been used as epithelial markers for the identification of CTCs. Since the epithelial-mesenchymal transition is one of malignant phenotype of cancer cells, it is necessary to investigate other markers which might detect mesenchymal CTCs. &amp;lt;Aim&amp;gt; This study aims to clarify the clinical significance of EpCAM negative and CEA positive CTCs in patients with gastric cancer. &amp;lt;Methods&amp;gt; Forty patients who underwent operation for gastric cancer were enrolled in this study. A total of 10ml peripheral blood samples were obtained preoperatively. Informed consent to participate in this study was obtained from all of the patients before their surgery. This study was approved by the Human Ethics Review Committee of our University. After collection of mononuclear cell fraction, these cells were stained by PAPI, anti-CD45, anti-EpCAM, anti-cytokeratin, and anti-CEA (CD66e) antibody. We enumerated the number of cells which showed EpCAM, cytokeratin, and CEA positive expression among CD45 negative cells. ROC analyses were performed for investigating predictive value of these cell counts for distant metastasis. We examined association between these cell counts and clinicopathological features. &amp;lt;Results&amp;gt; ROC analyses revealed that the AUC for predicting distant metastasis using EpCAM, Cytokeratin, and CEA positive cell counts were 0.583, 0.638, and 0.769, respectively. The median number of EpCAM negative and CEA positive cells was 231 (range: 0-61897). The cell counts of EpCAM negative and CEA positive cells were significantly associated with Tumor depth (p=0.0084), lymph node metastasis (p=0.0107), and tumor size (p=0.023). &amp;lt;Conclusions&amp;gt; CEA might be useful marker for detecting high risk of recurrence in patients with gastric cancer. Citation Format: Yuichiro Miki, Masakazu Yashiro, Tomohisa Okuno, Kishu Kitayama, Tatsuro Tamura, Takahiro Toyokawa, Hiroaki Tanaka, Kazuya Muguruma, Kosei Hirakawa, Masaichi Ohira. Clinical significance of EpCAM-negative and CEA-positive circulating tumor cells in gastric carcinoma [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 3791. doi:10.1158/1538-7445.AM2017-3791
Enhanced prophylaxis with antiretroviral therapy for advanced HIV in Africa
Authors: James Hakim, Victor Musiime, Alex Szubert, Jane Mallewa, Abraham Siika, Clara Agutu, Simon Mark Walker, Sarah Pett, Mutsa Bwakura-Dangarembizi, Abbas Lugemwa, Symon Kaunda, Mercy Karoney, Godfrey Musoro, Sheila Kabahenda, Kusum Nathoo, Kathryn Maitland, Anna Griffiths, Margaret Thomason, Cissy Kityo, Peter Mugyenyi, Andrew Prendergast, Sarah Walker, Diana Gibb
Journal: New England Journal of Medicine (2017)
Abstract 618: Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells
Authors: Peng Li, Xin Du, Yun Xin, Jianyu Weng, Peilong Lai
Journal: Cancer Research (2017)

Abstract Chimeric antigen receptor (CAR) T cell immunotherapies have shown unprecedented success in treating leukemia but lack efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor (TIR) domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed enhanced effector function, expansion and persistency against CD19+ leukemic or mesothelin+ lung cancer cells in vitro and in vivo. In a patient with relapsed B cell acute lymphoblastic leukemia, a single dose of 5×104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling is a contributing component to CAR T cells for both leukemia and solid tumors and is capable of increasing the efficacy of CAR T cells and facilitating low dose clinical usage. Citation Format: Peng Li, Xin Du, Yun Xin, Jianyu Weng, Peilong Lai. Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T 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 618. doi:10.1158/1538-7445.AM2017-618
Overcoming the Roadblocks to Cardiac Cell Therapy Using Tissue Engineering
Authors: Mounica Yanamandala, Wuqiang Zhu, Daniel J. Garry, Timothy J. Kamp, Joshua M. Hare, Ho-wook Jun, Young-sup Yoon, Nenad Bursac, Sumanth D. Prabhu, Gerald W. Dorn, Roberto Bolli, Richard N. Kitsis, Jianyi Zhang
Journal: Journal of the American College of Cardiology (2017)

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart's contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality.
Abstract 3614: Antibody validation revises estrogen receptor beta research
Authors: Sandra Andersson, Mårten Sundberg, Nusa Pristovsek, Ahmed Ibrahim, Philip Jonsson, Borbala Katona, Carl-Magnus Clausson, Agata Zieba, Margareta Ramström, Ola Söderberg, Cecilia Williams, Anna Asplund
Journal: Cancer Research (2017)

Abstract The discovery of estrogen receptor β (ERβ/ESR2) in 1996 was a landmark discovery. Its homology with breast cancer pharmacological target and predictive biomarker estrogen receptor α (ERα /ESR1) raised hopes for improved endocrine therapies. However, after twenty years of intense research the therapeutic promises have not materialized. We here perform a rigorous validation of 13 anti-ERβ antibodies, and demonstrate that the vast majority are unspecific. Using well-characterized controls and a panel of validation methods, we conclude that only the rarely used monoclonal antibody PPZ0506 targets ERβ in a specific manner in immunohistochemistry. We applied this antibody for protein expression profiling in 44 normal and 21 malignant human tissues, and found that detection of ERβ protein is limited to testis, ovary, placenta, lymphoid cells, granulosa cell tumors, and a subset of malignant melanoma and thyroid cancers. This expression pattern aligns well with RNA-seq data, but contradicts a multitude of studies. We did not find evidence that normal or cancerous human breast express ERβ protein. Our study highlights how inadequately validated antibodies can lead an exciting and promising field astray. Citation Format: Sandra Andersson, Mårten Sundberg, Nusa Pristovsek, Ahmed Ibrahim, Philip Jonsson, Borbala Katona, Carl-Magnus Clausson, Agata Zieba, Margareta Ramström, Ola Söderberg, Cecilia Williams, Anna Asplund. Antibody validation revises estrogen receptor beta research [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 3614. doi:10.1158/1538-7445.AM2017-3614
Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies
Authors: Marco Mina, Franck Raynaud, Daniele Tavernari, Elena Battistello, Stephanie Sungalee, Sadegh Saghafinia, Titouan Laessle, Francisco Sanchez-Vega, Nikolaus Schultz, Elisa Oricchio, Giovanni Ciriello
Journal: Cancer Cell (2017)
Abstract 895: Fucosylation inhibits invadopodia formation and melanoma invasion
Authors: Tyler S. Keeley, Eric Lau, Shengyu Yang
Journal: Cancer Research (2017)

Abstract Background: Melanoma is the most deadly skin cancer and metastasis is essentially responsible for all melanoma related death. Recently, fucose treatment has been shown to inhibit melanoma cell migration and invasion in vitro, and melanoma metastasis in a mouse model, suggesting that protein fucosylation could be exploited to prevent or suppress melanoma metastasis. Invadopodia are proteolytic actin-rich protrusions used by metastatic melanoma cells to degrade extracellular matrix and to promote invasion and metastasis. In this study, we investigated the mechanisms by which fucosylation regulate melanoma invasion and invadopodia formation Method: The melanoma cells were treated with L-fucose-supplemented medium or infected with fucokinase-expressing lentivirus to increase protein fucosylation. shRNAs were also employed to knockdown fucokinase and to inhibit fucosylation in melanoma cells. The effects of fucosylation on invadopodia formation and extracellular matrix degradation were determined by phalloidin staining and degradation of fluorescently labeled gelatin thin film. Results: Here, we show that the addition of L-fucose to complete media inhibits the ability of melanoma cells to form invadopodia in a dose-dependent manner. The overexpression of hFUK in WM793 cells showed a similar result as L-fucose treatment, where invadopodia formation was significantly reduced. In addition, we observed a significant decrease in the percentage of cells that have invadopodia during L-fucose supplementation or hFUK overexpression. In an invadopodia precursor assay, the hFUK-overexpressing cell line exhibited delayed FBS-stimulated invadopodia formation. Conclusions: Our data suggest that fucose or the overexpression of hFUK reduces melanoma invasion by inhibiting invadopodia formation. Given that invadopodia formation was hindered within an hour after stimulation, we believe that invadopodia initiation is affected by increased fucosylation, resulting in fewer invadopodia and slower extracellular matrix degradation. Citation Format: Tyler S. Keeley, Eric Lau, Shengyu Yang. Fucosylation inhibits invadopodia formation and melanoma invasion [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 895. doi:10.1158/1538-7445.AM2017-895
Abstract 3822: Expression of androgen receptor and CD24 correlates with improved 5-year survival in Pakistani patients with invasive breast cancer
Authors: Nazia Riaz, Romana Idress, Sadia Habib, Azhar Hussain, El-Nasir Lalani
Journal: Cancer Research (2017)

Abstract Introduction: Androgen receptor (AR) expression has been shown to correlate with improved survival in luminal A, B and triple negative (TN) breast cancer (BCa). Cancer stem cells (CSC) with CD44+/CD24- and ALDH1+ phenotype is associated with pro-invasive gene signature in BCa. Aim of our study was to evaluate prognostic significance of AR expression in relation to CD44, CD24 and ALDH1 in invasive BCa. Methodology: Immunohistochemical expression of AR, CD44, CD24 and ALDH1 was evaluated in 180 FFPE blocks of BCa cases from one institution. Clinico-pathological details and follow-up data were collected from medical charts. Data was analyzed on SPSS 19. Five-year survival was estimated by Kaplan Meier. Results: Median age of patients was 55 years (range: 28-87). Fifteen percent of patients were diagnosed with stage I, 52.2% with stage II, 25% with stage III and 7.8% with stage IV disease. Mean duration of follow-up was 4.5 years (SD+ 2.7) and 29% mortalities were attributed to BCa. AR was expressed in 63.9%, ER in 61%, PR in 51% &amp; HER-2/neu in 30% of tumors. CD44, CD24 and ALDH1 were expressed in 60%, 43.3% &amp; 28.3% of tumors respectively. AR expression was associated (p-value&amp;lt;0.001) with grade II tumors expressing ER, PR and CD24 but lacking ALDH1. Multivariable analysis confirmed AR (adjusted HR 0.43, 95% CI 0.19-0.95) and PR (adjusted HR: 0.20, 95% CI: 0.07-0.60) to be independently associated with better outcome. Five year survival of patients with AR+ versus AR- expressing tumors, showed that patients with AR+ tumors had significantly better outcome (p-value=0.03) with survival advantage of 39.6 months. Survival advantage decreased by 9.6 months in tumors expressing CD44+/CD24-/AR- (p-value=0.01) phenotype and by 12 months in patients whose tumors were phenotypically ALDHI+ /AR- (p-value=0.12). We stratified TN tumors into 2 groups: A. TN/CD24+/AR+; B. TN/CD24-/AR- and found that group A tumors had a trend towards better 5 survival (p-value=0.09). Conclusions: Three individual markers (CD44, CD24, AR) may afford prognostic information. Combinations of CD44, CD24 and AR permitted patient stratification into 3 risk categories: poor risk CD24-/AR-; intermediate risk CD44+/CD24-/AR- and good risk CD24+/AR+. Stratification of TN group showed that loss of AR and CD24 was associated with poorest outcome. These results underscore the relevance and importance of AR and CD24 as prognostic markers in invasive BCa. Citation Format: Nazia Riaz, Romana Idress, Sadia Habib, Azhar Hussain, El-Nasir Lalani. Expression of androgen receptor and CD24 correlates with improved 5-year survival in Pakistani patients with invasive breast 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 3822. doi:10.1158/1538-7445.AM2017-3822
Abstract 192: Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma
Authors: John Alton Copland, Laura A. Marlow, Ilah Bok, James L. Miller, Matsuda Akiko, Yan W. Asmann, Vivekananda Sarangi, Steven R. Alberts, Kabir Mody, Lewis R. Roberts, Mark J. Truty, Tushar C. Patel
Journal: Cancer Research (2017)

Abstract Background: The paucity of effective therapeutic agents for hepatocellular cancer (HCC) underscores the critical need for more effective therapeutic strategies. Recent studies indicate lipid biosynthesis and desaturation is required for HCC survival. Targeting these may prove beneficial because such changes contribute to therapeutic resistance. Stearoyl CoA desaturase (SCD1), a key mediator of fatty acid (FA) biosynthesis and rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids (MUFAs), is upregulated in HCC and many other cancers. As such, we therapeutically targeted a novel lipogenic tumor survival mechanism mediated by SCD1 as a means to combat the chemoresistance associated with HCC. In so doing, we evaluated a novel lead SCD1 inhibitor in HCC. Methods: Paraffin embedded patient HCC tissues were examined for SCD1 expression. Using combined computational and synthetic chemistry approaches, we synthesized four novel specific SCD1 inhibitors with SSI-4 being the lead SCD1 inhibitor. HCC cell lines were examined using proliferation assays for response to SSI-4. IC50 concentrations for blocking SCD1 enzyme activity was determined. Blood half-life and bioavailability of single dose SSI-4 was determined. Mechanisms of action of SCD1 were examined that included Endoplasmic reticulum (ER) stress. In vivo, antitumor activity was determined using HCC patient derived xenograft (PDX) mouse models. Results: We identified elevated SCD1 mRNA and protein in HCCs tissues. SSI-4 dose-dependently inhibits cell proliferation in HCC cell lines with specificity demonstrated by oleic acid (MUFA) co-culture. Single dose oral gavage SSI-4 demonstrated a half-life of ~4 hours and excellent oral bioavailability. SSI-4 was well tolerated with long-term daily dosing. SSI-4 treatment of HCC cells and tumors led to endoplasmic reticulum (ER) stress followed by apoptotic cell death. Single agent SSI-4 demonstrated antitumor activity in HCC PDX mouse models with suppression of ER stress regulated proteins. Conclusions: Targeting a novel lipid metabolic pathway in HCC may provide effective therapy for aggressive HCC. Citation Format: John Alton Copland, Laura A. Marlow, Ilah Bok, James L. Miller, Matsuda Akiko, Yan W. Asmann, Vivekananda Sarangi, Steven R. Alberts, Kabir Mody, Lewis R. Roberts, Mark J. Truty, Tushar C. Patel. Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma [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 192. doi:10.1158/1538-7445.AM2017-192
Abstract 4784: Regulation of ovarian cancer stem cell population by DDB2
Authors: Tiantian Cui, Amit Kumar Srivastava, Chunhua Han, Zhiqin Gao, Xiaoli Zhang, Altaf A. Wani, Qi-En Wang
Journal: Cancer Research (2017)

Abstract Cancer stem cells (CSCs), representing the root of many solid tumors including ovarian cancer, have been implicated in disease recurrence, metastasis, and therapeutic resistance. Our previous study has demonstrated that DNA damage-binding protein 2 (DDB2) is able to reduce the abundance of CSCs in the bulk ovarian cancer cells, providing a novel mechanism to explain the DDB2-mediated suppression of tumorigenicity and metastasis, and also suggesting that low expression of DDB2 is required for the maintenance of CSCs. However, the underlying mechanisms still remain unclear. By using the Tet-On DDB2 modulation system, we have confirmed our previous finding that downregulation of DDB2 expands the CSC population in the 2008 ovarian cancer cell line. We also found that DDB2 is able to suppress non-CSC-to-CSC conversions in this cancer cell line. DDB2 has been recognized as a transcriptional regulator. Our microarray analysis has identified ALDH1A1 to be targeted and regulated by DDB2. The downregulation of ALDH1A1 expression by DDB2 at both mRNA and protein levels has been validated in various ovarian cancer cell lines. The mechanistic investigation demonstrated that DDB2 can bind to the promoter region of the ALDH1A1 gene, facilitating the enrichment of histone H3K27me3 by recruiting EZH2 to the promoter region, eventually inhibiting the promoter activity of the ALDH1A1 gene. In addition, we also found that DDB2 competes with transcription factor C/EBPβ for binding to the ALDH1A1 promoter, indirectly inhibiting the ALDH1A1 promoter activity. Finally, we knocked down the expression of DDB2 and ALDH1A1 individually or simultaneously in the 2008 ovarian cancer cell line, and analyzed their tumorigenicity. We found that downregulation of ALDH1A1 is able to block DDB2 silencing-induced expansion of the CSC population, indicating that ALDH1A1 plays a critical role in DDB2-mediated suppression of the CSC population in ovarian cancer cells. In summary, our data demonstrated that DDB2, functioning as a transcription repressor, is able to abrogate ovarian CSC properties by downregulating ALDH1A1 expression. This study provides a novel mechanism underlying the regulation of the CSC population, and would facilitate the development of efficient strategies for eliminating CSCs to prevent tumor relapse and metastasis in ovarian cancers. (Supported by NIH R01CA151248) Citation Format: Tiantian Cui, Amit Kumar Srivastava, Chunhua Han, Zhiqin Gao, Xiaoli Zhang, Altaf A. Wani, Qi-En Wang. Regulation of ovarian cancer stem cell population by DDB2 [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 4784. doi:10.1158/1538-7445.AM2017-4784