tbuckley/cabot-search huggingface dataset:
Abstract SY08-02: Normal and neoplastic stem cells
Authors: Irving L. Weissman
Journal: Cancer Research (2016)

Abstract The transition from single cell species to multicellular organisms led to organ and tissue development. The development and maintenance of organs/tissues in multicellular organisms has resulted in the emergence of specialized cells that self-renew as well as differentiate; these rare cells are stem cells. Following embryonic development, most of our tissues and organs are continuously regenerated from tissue/organ specific stem cells. The principal property that distinguishes such stem cells from their daughter cells is self-renewal; when stem cells divide they give rise to stem cells (by self-renewal) and progenitors (by differentiation). In most tissues only the primitive stem cells self-renew. Even within a particular tissue, stem cells may be diverse, and subject to stem cell competition for their niche. We have documented both germline stem cell and somatic stem cell competition in species as diverse as colonial protochordates and humans. Stem cell isolation and transplantation is the basis for regenerative medicine. Self-renewal is dangerous, and therefore strictly regulated. Poorly regulated self-renewal can lead to the genesis of cancer stem cells, the only self-renewing cells in the cancerous tumor. The Weissman lab has followed the progression from hematopoietic stem cells (HSCs) to myelogenous leukemias. They have found that the developing cancer clones progress at the stage of HSCs, until they become fully malignant. At this point, the “leukemia” stem cell is at a stage of a downstream oligolineage or multilineage progenitor that has evaded programmed cell death and programmed cell removal, while acquiring or keeping self-renewal. In the case of chronic myeloid leukemia, bcr-abl+ HSC clones outcompete normal HSCs in the chronic phase. The transition from the chronic phase to myeloid blast crisis results in the leukemia stem cells appearing in the granulocyte-macrophage progenitor (GMP) stage. While there are many ways to defeat programmed cell death and senescence, there appears to be one dominant method to avoid programmed cell removal—the expression of the cell surface “don't eat me” protein CD47, the ligand for macrophage SIRPα. All cancers tested express CD47 to overcome expression of “eat me” signals such as calreticulin. Antibodies that block the CD47-SIRPα interaction enable phagocytosis and killing of the tumor cells in vitro and in vivo. All tested human solid tumors and lymphomas/leukemias/myelomas express CD47 and are susceptible to phagocytosis in the presence of anti-CD47 blocking antibodies. Citation Format: Irving L. Weissman. Normal and neoplastic 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 SY08-02.
Abstract 1982: BRD4-FOXO axis maintains differentiated mammary epithelial phenotype by regulating p63 and GRHL3 expression
Authors: Sankari Nagarajan, Upasana Bedi, Anusha Budida, Wanhua Xie, Feda Hisham Moh’d Hamdan, Vivek Kumar Mishra, Zeynab Najafova, Malik Alawi, Daniela Indenbirken, Stephan Knapp, Cheng-Ming Chiang, Adam Grundhoff, Christina H. Scheel, Vijayalakshmi Kari, Florian Wegwitz, Steven A. Johnsen
Journal: Cancer Research (2016)

Abstract Bromodomain-containing protein 4 (BRD4) is an important epigenetic reader which promotes gene transcription to modulate cell-specific functions and is under intensive investigation for its potential as an anti-tumor therapeutic target. However, the role of BRD4 in non-transformed cells remains unclear. Using RNA sequencing and chromatin immunoprecipitation-sequencing analyses in normal basal-like breast epithelial cells, we demonstrate that BRD4 is required for the expression of epithelial-specific genes and suppression of stem cell-like properties by binding to the distal regions of epithelial-related genes. Moreover, BRD4 occupancy correlates with enhancer activity and enhancer RNA (eRNA) transcription of these genes. Interestingly, we show that BRD4 perturbation regulates the expression of p63 and Grainy Head-like transcription factor-3, GRHL3, whose depletion partially mimics BRD4 inhibition and impairs a differentiated phenotype. By binding to the distal regions of p63 and GRHL3, BRD4 promotes RNA polymerase-II occupancy and thus affects eRNA transcription. Motif analyses on cell-specific BRD4 binding sites predict the involvement of FOXO transcription factors. Consistently, inhibition of EGFR-AKT signalling activates FOXO1 function and promotes the expression of p63 and GRHL3. Activation of Src kinase signaling decreases RNA polymerase-II occupancy on BRD4 target genes and enhancers. Altogether, these findings provide evidence that BRD4 promotes a differentiated epithelial phenotype in non-transformed mammary cells at least in part through the activation of p63 and GRHL3 expression by associating with FOXO factors. Citation Format: Sankari Nagarajan, Upasana Bedi, Anusha Budida, Wanhua Xie, Feda Hisham Moh’d Hamdan, Vivek Kumar Mishra, Zeynab Najafova, Malik Alawi, Daniela Indenbirken, Stephan Knapp, Cheng-Ming Chiang, Adam Grundhoff, Christina H. Scheel, Vijayalakshmi Kari, Florian Wegwitz, Steven A. Johnsen. BRD4-FOXO axis maintains differentiated mammary epithelial phenotype by regulating p63 and GRHL3 expression. [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 1982.
Evaluation of serum protein mass spectrometry technology to identify NSCLC patients with tumor response to gefitinib.
Authors: Y. Pei, S. Wei, B. Yao, X. Ma, Y. Yang, L. Yuan, Q. Li, P. Ji, S. Hu, L. Ji
Journal: Journal of Clinical Oncology (2010)

3107 Background: To evaluate SELDI as a potential technique for predicting response to gefitinib in NSCLC patients. Methods: 36 serum samples of NSCLC patients (13 men and 23 women)who had received SELDI-TOF-MS (surface-enhanced laser desorption/ionization time-of-flight mass spectrometry) inspection before gefitinib (250 mg/day) treatment were evaluated. Patients had measureable disease and received gefitinib for >1 month. Patients were categorized into 3 groupsaccording to tumor response RECIST (Response Evaluation Criteria In Solid Tumors) to gefitinib: efficacy group (CR+PR), stable group (SD), and inefficacy group (PD). The mass spectrums were analyzed by Biomarker Wizard 3.1 Software and Protein Chi p 3.2.0 Software. The work proceeded in 3 stages. In the first stage, 9 patients were categorized into 3 groups after gefitinib treatment and the differences between their protein fingerprint were analyzed. In the second stage, patients were divided into gefitinib suitable or not suitable groups and the imprecise effect group based on the protein fingerprintsidentified in the first stage, so as to verify the coincidence between standardized fingerprints and clinical response. The third stage provided further confirmation of the relationship between fingerprint curve shape and its dynamic change and the response to gefitinib based on the findings from the first stage. Results: 6 valuable fingerprints were screened out and analyzed by software. Four peaks showed obvious differences among the 3 response groups. An extremely obvious cluster of peaks appeared in PD group, which was attenuated in SD group, but hardly recognized in CR+PR group. The coincidence of response and marked fingerprints were:a) inpatients were suitable to receive gefitinib (advantage group) 76.2% in patients with CR+PR, 100% in patients with control (CR+PR+SD) and 0% in PD;b) in the unfavorable medication groups,the proportion of CR+PR was 0%, CR+PR+SD was 14.3%,and PD was 85.7%. Conclusions: The coincidence of response and marked fingerprint in the group identified as advantage patients was 76.2% for those withCR/PR, 100% for patients with control, and 0% for patients with PD. No significant financial relationships to disclose.
Abstract 4580: A blueprint of androgen receptor splice variant transactivation
Authors: Subing Cao, Duo Xu, Yanfeng Qi, Yang Zhan, Oliver Sartor, Yan Dong
Journal: Cancer Research (2016)

Abstract Constitutively active androgen receptor splice variants (AR-Vs) have been implicated as one driver of castration-resistant progression of prostate cancer. However, the critical steps leading to AR-V transactivation remain largely unknown. AR-V7 and ARv567es are two major AR-Vs expressed in human prostate cancer specimens. We found that disruption of AR-V7 and ARv567es homodimerization did not affect their nuclear localization, indicating that they can enter the nucleus as monomers. On the other hand, disrupting the heterodimerization between AR-V7 or ARv567es and AR-FL abolished AR-V7 and ARv567es-induced nuclear translocation of AR-FL, indicating that the heterodimerization is required for AR-FL to be piggy bagged into the nucleus. AR-V7 chromatin immunoprecipitation assay further showed that mutating the dimerization interface of AR-V7 did not decrease the ability of AR-V7 to bind to the promoter of its target genes, UBE2C and CCNA2, indicating that dimerization is not required for AR-Vs to bind to DNA. Moreover, mutating the DNA-binding interface of AR-V7 only partially inhibited AR-V7 homodimerization and had no effect on AR-FL/AR-V7 dimerization, suggesting that DNA binding may not be necessary for AR-V/AR-V or AR-FL/AR-V dimerization. Nonetheless, both the dimerization and the DNA-binding mutants of AR-V7 lost trans-activating activity. Taken together, our data suggests that AR-V DNA binding and dimerization are two independent but indispensable steps for AR-V transactivation. AR-V can enter the nucleus as a monomer, and then either forms a dimer before binding to DNA or binds to DNA as a monomer and then forms a dimer to trans-activate gene transcription. Our study may provide insights into developing more precisely targeted strategies to overcome AR-V-driven castration resistance. Citation Format: Subing Cao, Duo Xu, Yanfeng Qi, Yang Zhan, Oliver Sartor, Yan Dong. A blueprint of androgen receptor splice variant transactivation. [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 4580.
Axitinib treatment among patients with mRCC in a U.S. community oncology setting: A retrospective study of 135 patients.
Authors: Thomas Hutson, Xiaolong Jiao, Thomas Wilson, Laura A. Cisar, Elizabeth A. MacLean
Journal: Journal of Clinical Oncology (2016)

569 Background: We have previously reported differences in a variety of outcome measures between clinical trial and real world use of several therapies for advanced renal cell carcinoma (RCC) (Vogelzang NJ, et al. Clin Genitourin Cancer, 2015, Hutson TE et al. Lancet Oncol, 2013, Motzer RJ, et al. NEJM, 2013). In an attempt to better understand the real-world use of axitinib in patients (pts) with metastatic RCC (mRCC) after one prior systemic therapy, a retrospective study was conducted using the US Oncology’s (USON) iKnowMed electronic health records database and medical record review data. Methods: Eligibility criteria were: pts with mRCC ≥ 18 years of age at first diagnosis, treated with VEGFR-TKIs or immunotherapy including IL-2 and IFN as first line of therapy (LOT), received second or third line axitinib between 1/1/2012 and 10/31/2014, with ≥ 2 visits within the USON. LOT was defined based on treatment sequence. Dosing analysis included duration of therapy, dose change, and reasons for discontinuation. Results: 135 pts met eligibility criteria. The most common prior therapies were sunitinib (48.5%) and pazopanib (48.5%) for pts with axitinib as 2 nd LOT (n=68), and everolimus (55.2%), temsirolimus (19.4%), and pazopanib (14.9%) for pts with axitinib as 3 rd LOT (n=67). 80.7% (109) of pts started axitinib at 5mg BID, and 68.9% remained at this dose. 17.8% had a dose increase mainly due to physician’s choice and 13.3% a dose decrease mainly due to toxicity. The median duration of therapy was 4.57 months (mean 6.32, SD 5.91, range 0.03-35.49). Axitinib was discontinued in 91 (67.4%) pts, and the most common reasons for discontinuation were disease progression (39.3%) and toxicity (17.0%). Conclusions: In the community oncology setting, axitinib was commonly used in the 2nd and 3rd line setting for pts with mRCC. The usage pattern appears to be consistent with published NCCN guideline recommendations. Surprisingly and in contrast to our experience with other agents for RCC, dose changes were less common and duration of therapy was consistent with the pivotal clinical trial results. These findings suggest ease of use among community oncologists and patient tolerance are key features of axitinib.
Abstract 3953: Highly accurate genetic profiling of circulating tumor cells using a label-free inertial microfluidic approach coupled with droplet PCR-based next-generation sequencing
Authors: Yi Fang Lee, Mark Consugar, Kimberly Helzer, Mei Hui Tan, Lori Emrick, Ali Asgar Bhagat
Journal: Cancer Research (2016)

Abstract Background: Circulating tumor cells (CTCs) could provide significant insights into cancer metastatic events and potentially even inform clinical decisions. However, the scarcity of CTCs, compounded by the abundance of circulating white blood cells, poses a major technical challenge in the isolation, yield and downstream molecular analysis. Moreover, next-generation sequencing (NGS) of CTCs has been challenged by low CTC purity and nucleic acid yields commonly derived from existing technologies. Here, we present a label-free microfluidic approach that utilizes curvilinear microchannel geometry for high purity CTC enrichment from 7.5 ml whole blood. Methods: We showed high purity isolation of CTCs using a label-free inertial focusing microfluidics platform, ClearCell® FX. The lung cancer cell line, NCI-H1975, with known EGFR, CDKN2A and TP53 mutations, were spiked into 7.5ml healthy donor peripheral blood samples at varying concentrations (50, 100, 200 cells). DNA was extracted using the QIAamp Micro kit. The Thunderbolts Cancer Panel droplet digital PCR NGS library preparation method was used to enrich 230 loci in 50 known cancer genes from the isolated CTC gDNA. The libraries were sequenced on a MiSeq system. Results: The CTCs were sufficiently enriched with an average recovery of 45.8% and purities ranging from 1% - 70%. All libraries were successfully generated and sequenced with ≥1400× mean coverage, even with as little as 2 ng of starting material. Known EGFR, CDKN2A and TP53 mutations in H1975 were successfully detected in all the samples (n = 9), with a significant variant frequency that correlates with CTC purity levels. Conclusion: We have demonstrated a highly accurate and sensitive workflow utilizing a combination of inertial focusing and digital droplet microfluidics to detect low numbers of rare CTCs and interrogate their molecular profiles from as little as 10 cells/mL frequency. This workflow has the potential for further development and adoption as a liquid biopsy approach for non-invasive genomic profiling of metastatic cancers. Citation Format: Yi Fang Lee, Mark Consugar, Kimberly Helzer, Mei Hui Tan, Lori Emrick, Ali Asgar Bhagat. Highly accurate genetic profiling of circulating tumor cells using a label-free inertial microfluidic approach coupled with droplet PCR-based next-generation sequencing. [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 3953.
Abstract 2624: Possibility of prostate cancer prevention based on cancer stem cell theory
Authors: Nobuya Shiozawa, Ryosuke Sugahara, Ayami Sato, Masako Ota, Tomohiro Yano
Journal: Cancer Research (2016)

Abstract Cancer stem cells are considered to be one of the causes of cancer. In recent years, stemness (stem like) of gene expression patterns in the development process of cancer has been observed. Stemness and pathology of cancer are closely related. Elucidation of the stemness regulation of cancer is an important key to the development of new cancer prevention methods. However, as far as we know, there exist no cancer prevention studies focusing on cancer stem cells. In this study, we have investigated the possibility of prostate cancer prevention with a focus on cancer stem cells. We utilized prostate cancer cell lines PC3, DU145 (androgen-independent) and LNCaP (androgen-dependent) cells. Then, using spheroid formed cells, mRNA expression levels of cancer stem cells markers were estimated by RT-real time-PCR. Cancer cells have several malignant phenotypes under hypoxia, and we investigated for the cancer stem cells induced malignant alteration under hypoxia. In addition, under hypoxia, we investigated cell viability effect under tocotrienol-rich fraction (TRF) from annatto. TRF almost consists of delta- tocotrienol (δ-T3) that has the strongest anti-cancer activity. We observed spheroid formation capacity and compared the spheroid sizes and mRNA levels of DU145, PC3 and LNCaP cells. Size of DU145 spheroid is smaller in comparison to spheroids of PC3 and LNCaP. mRNA expression levels of cancer stem cells marker were elevated in PC3 and LNCaP cells. This means that PC3 and LNCaP cells have higher concentration of cancer stem cells. Furthermore, stemness decreases with increase of passage number, the number of cultures. We confirmed the presence of stemness in the formation capacity of spheroid until passage 4. Under hypoxia, cell viability of cancer stem cells was elevated compared to normal cultured prostate cancer cells. In addition, under hypoxia and TRF treatment, cell viability of cancer stem cells decreased with increase in TRF concentration compared to control (0 μg/ml). Our results suggest that TRF suppress cell viability of prostate cancer stem cells under hypoxic states and is effective in prostate cancer prevention. Citation Format: Nobuya Shiozawa, Ryosuke Sugahara, Ayami Sato, Masako Ota, Tomohiro Yano. Possibility of prostate cancer prevention based on cancer stem cell theory. [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 2624.
Identification of Low Frequency Multiple Novel Aspergillus Fumigatus Specific MHC Class II Epitopes and Rapid Generation of An Aspergillus-Specific T-Cell Product Based On Activation Dependent Expression of CD154.
Authors: Nina Khanna, Claudia Stuehler, Sarah Lurati, Barbara Conrad, Michaela Kruhm, Eike Kallmeyer, Sven Krappmann, Hermann Einsele, Max Topp
Journal: Blood (2009)
The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction
Authors: Nicole E Scharping, Ashley V Menk, Rebecca S Moreci, Ryan D Whetstone, Rebekah E Dadey, Simon C Watkins, Robert L Ferris, Greg M Delgoffe
Journal: Immunity (2016)

Although tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment.
LFA-1 integrin antibodies inhibit leukocyte α4β1–mediated adhesion by intracellular signaling
Authors: Mikaela Grönholm, Farhana Jahan, Ekaterina A. Bryushkova, Sudarrshan Madhavan, Francesca Aglialoro, Laura Soto Hinojosa, Liisa M. Uotila, Carl G. Gahmberg
Journal: Blood (2016)
MicroRNA-196a and –196b Are Differentially Expressed Between and within Cytogenetic and Molecular Subtypes of Pediatric Acute Myeloid Leukemia, and High Expression Is Correlated to Overexpression of HOX Genes.
Authors: Astrid A Danen-van Oorschot, Jenny E Kuipers, Susan T Arentsen-Peters, Valerie de Haas, Jan Stary, Andre Baruchel, Dirk Reinhardt, C. Michel Zwaan, Marry M van den Heuvel-Eibrink
Journal: Blood (2009)
Abstract 4149: Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1
Authors: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Masakazu Toi
Journal: Cancer Research (2016)

Abstract BACKGROUND: We previously reported that direct co-culture of triple negative breast cancer cell line MDA-MB-231 and immune cells results in reduction of EGFR expression on cell surface of MDA-MB-231 (AACR 2015 #2349). However, a role of reduction of EGFR on MDA-MB-231 via co-culture with immune cells still remains unclear. Therefore, we evaluated a role of reduction of EGFR on MDA-MB-231 at the immunological point of view by testing expression of immune related genes including PD-L1. METHODS: In order to verify the importance of direct immune cell contact to breast cancer cell, MDA-MB-231 cells were co-cultured directly or indirectly with THP-1 cells (human monocytic cell line) at 1:50 cellular ratios. In order to study indirect co-culture assay, we used cell culture insert to avoid direct cancer cell-immune cell contact. We analyzed gene expression by quantitative real time PCR and membrane protein expression by flow cytometry of EGFR, also other HER family on MDA-MB-231 which is directly or indirectly co-cultured with THP-1. We also evaluated the expression of immune related genes including PD-L1. RESULTS: Both mRNA and protein level of EGFR on MDA-MB-231 cells directly co-cultured with THP-1 were significantly decreased as compared to those with indirectly co-cultured MDA-MB-231 cells. There are no significant differences in EGFR expression between indirectly co-cultured MDA-MB-231 cells and control MDA-MB-231 cells. Importantly, PD-L1 expression on MDA-MB-231 cells directly co-cultured with THP-1 was significantly decreased as compared to that with indirectly co-cultured MDA-MB-231 cells. CONCLUSION: It has been reported that PD-L1 expression in cancers is regulated by phosphatidylinositol 3-kinase (PI3K) and Akt signaling. Thus, our findings may give a novel insight on regulation of PD-L1 expression on cancer cells in tumor microenvironment that tumor infiltrated immune cell directly contact with cancer cells and EGFR down-regulation leads to reduction of PD-L1 expression on cancer cells. Further investigation is needed to elucidate the mechanism of reduction of EGFR by direct immune cell contact to cancer cells and its interaction with modulation of PD-L1 expression. This will provide novel aspects for immune therapy of breast cancer patients. Citation Format: Ayane Yamaguchi, Eiji Suzuki, Kosuke Kawaguchi, Mariko Nishie, Moe Tsuda, Masakazu Toi. Direct immune cell contact to basal-like triple negative breast cancer cells evokes downregulation of EGFR and PD-L1. [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 4149.