tbuckley/cabot-search huggingface dataset:
Abstract 4263: Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials
Authors: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong
Journal: Cancer Research (2015)

Abstract Background: Relapsed refractory colorectal adenocarcinoma (CRC) is evolving as a disease with distinct molecular subsets rather than a singular histology. Given the varied outcomes of CRC patients treated on clinical trials particularly with targeted therapies, we aimed to identify a molecular phenotype for future therapeutic targeting. Methods: We identified CRC patients referred to our Phase I clinic with adequate tissue for next generation sequencing (NGS) on a commercially available platform (FoundationOne, Boston, MA). Over 2000 exons of 186 cancer-related genes plus over 30 introns from 14 genes often rearranged in cancer were fully sequenced for point mutations, insertions/deletions, copy number alterations (CNAs) and select gene fusions. Results: Overall, 60 relapsed CRC patients (31 male, 29 female; median age 55 years; 56 colon primary, 4 rectum primary). 48 (80%) patients had a mutation linked to aberrant Wnt pathway signaling (most commonly, APC 43 pts, 90%). Of these 48 patients, over half (n = 26, 54%) demonstrated a concurrent mutation affecting the PI3K cascade (PIK3CA in 12 patients [4 E545K, 3 Q546K, 2 E542K, 1 H1047Y, 1 E453K, 1 R38C]). Of these 26 pts with concurrent aberrant Wnt and PI3K pathways, 22 also demonstrated a concomitant MAPK pathway mutation (17 KRAS and 3 BRAF). Of the 60 CRC pts overall, 22 (37%) patients had coexisting aberrations linked to in all three (Wnt, PI3K, and MAPK) cascades. Conclusions: Concomitant mutations in three pathways (Wnt, MAPK, PI3K) implicated in cancer occur frequently in patients with advanced CRC, emphasizing the need for a combinatorial therapeutic strategy ideally targeting all three cascades. Note: This abstract was not presented at the meeting. Citation Format: Ishwaria M. Subbiah, Filip Janku, Apostolia M. Tsimberidou, Aung Naing, Vivek Subbiah, Jennifer J. Wheler, Ralph Zinner, Cathy Eng, Michael J. Overman, Scott Kopetz, David S. Hong. Concurrent aberrations in the Wnt, MAPK and PI3K pathways identified through next generation sequencing of relapsed refractory colorectal adenocarcinoma (CRC): Implications for future therapeutic trials. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4263. doi:10.1158/1538-7445.AM2015-4263
Effect of Proteasome Inhibitor (Bortezomib) on the Intracellular Level of NF-κBÃ, Â AIκB and P-Gp and the Rate of Apoptosis in Chemotherapy Resistant Myeloid Leukemia Cell Line K562 Induced by Daunorubicin
Authors: Aijun Liao, Beibei Fu, Zhuogang Liu
Journal: Blood (2008)
Classical complement pathway activation in the nasal tissue of patients with chronic rhinosinusitis
Authors: Griet A. Van Roey, Christopher C. Vanison, Jeffanie Wu, Julia H. Huang, Lydia A. Suh, Roderick G. Carter, James E. Norton, Stephanie Shintani-Smith, David B. Conley, Kevin C. Welch, Anju T. Peters, Leslie C. Grammer, Kathleen E. Harris, Kathryn E. Hulse, Atsushi Kato, Whitney W. Stevens, Robert C. Kern, Robert P. Schleimer, Bruce K. Tan
Journal: Journal of Allergy and Clinical Immunology (2016)
Flow Cytometry Detection of Intra-Cellular Tyrosine Kinase Inhibitors (TKI) Showed Variable Uptake in CML CD34+ Cells
Authors: Céline Bourgne, Mahchid Bamdad, Alexandre Janel, Frédéric Libert, Agnès Guerci, Marie-Claude Gagnieu, Chantal Rapatel, Pascale Pigeon, Sylvie Pereira, Eric Hermet, Pascale Cony Makhoul, Atchroue Johnson-Ansah, Jean Yves Cahn, Denis Guyotat, Sébastien Trouillier, Juliette Berger, Nathalie Boiret-Dupré, Marc G Berger
Journal: Blood (2011)
Phase II trial of the dual IGF-1R/IR inhibitor BMS-754807 with or without letrozole in aromatase inhibitor-resistant breast cancer.
Authors: P. Haluska, A. Dhar, X. Hou, F. Huang, D. S. A. Nuyten, J. Park, A. H. Brodie, J. N. Ingle, J. M. Carboni, M. M. Gottardis, A. C. Wolff, F. G. Finckenstein
Journal: Journal of Clinical Oncology (2011)

TPS111 Background: Resistance to endocrine therapy in breast cancer is a major clinical problem. Evidence shows that insulin-like growth factor (IGF) pathway signaling contributes to tamoxifen resistance. Thus, blockade of IGF signaling may enhance the activity and reverse resistance to endocrine therapy. Preclinical evaluation with the oral IGF-1R/insulin receptor (IR) kinase inhibitor BMS-754807 showed synergistic in vitro anti-proliferative activity in combination with tamoxifen, letrozole or fulvestrant in the aromatase expressing breast cancer model, MCF-7/AC-1. In treatment-naïve tumors and in tamoxifen- or letrozole-resistant tumors, the combination of letrozole with BMS-754807 induced significant tumor regression in vivo, which was not observed with an anti-IGF-1R monoclonal antibody. The lack of activity of the IGF-1R specific antibody and IR isoform expression analyses suggested that IR-isoform A blockade was important for this synergy. Methods: These preclinical data led us to start a phase II non-comparative clinical trial investigating the combination of BMS-754807 and 2.5 mg letrozole or single agent BMS-754807 in patients with locally advanced/metastatic, estrogen receptor-positive, non-steroidal aromatase inhibitor resistant breast cancer. The primary objective is 6-month progression free survival for the combination. Secondary endpoints include response rate, safety profile, and the 6-month treatment failure rate for BMS-754807 and for the combination. The Study will accrue through sites in the US, including the Translational Breast Cancer Research Consortium. Tumor biopsy and serum assessments will be made prior to and during (Day 28) treatment to determine the effects of BMS-754807 ± letrozole on IR isoforms expression and activity of IGF pathway components in tumor tissue and circulating tumor cells (CTCs), serum levels of receptor ligands and IGF binding proteins, and numbers of total and IGF-1R positive CTCs. Pre-study and Day 14 FLT-PET will assess anti-proliferative effects of single agent and combination treatment. Clinical Trials.gov #: NCT01225172. Funded by Bristol-Myers Squibb and NIH (CA116201 and CA090628).
452. RegenVOX - Translational Exploitation Strategy for Stem Cell-Based Tissue-Engineered Laryngeal Implants Undergoing Phase I/II Clinical Trial
Authors: Emily J. Culme-Seymour, Carla Carvalho, Owen Bain, Eugene Omakobia, Sophie Wilson, Helen Knowles, Susan Tebbs, Kim Champion, Jeff Round, Gareth Ambler, Martin A. Birchall, Mark W. Lowdell, Chris Mason
Journal: Molecular Therapy (2016)

The larynx ('voicebox') regulates breathing, voice and airway protection during swallowing - all critical human activities. For patients who lose laryngeal function due to trauma or cancer, there are no satisfactory long-term solutions, hence quality of life would be dramatically improved if a living, tissue-engineered laryngeal replacement could be transplanted. Based on prior experience from 'first-in-man' successes, a Phase I/II clinical trial (NCT01977911) of these autologous cell-based, tissue-engineered laryngeal implants is now underway for ten UK patients with severe irreversible structural disorders of the larynx, unresponsive to conventional treatment. The trial has regulatory approval in the UK from the MHRA and the first patient has been enrolled for treatment. Safety and efficacy of the RegenVOX technology are the primary output for the Phase I/II trial. However, a considered commercialisation strategy is vital if the technology is to successfully translate to clinical application. Alongside the clinical and manufacturing developments essential for treating the first patient enrolled for the trial, the RegenVOX team have thus given careful consideration to a number of aspects of business modelling, in order to product accurate data to use in planning how to deliver the product within a clinical setting. Economic modelling performed to date and planned for the future is described here, along with other aspects of translational and business model development. Further work on exploring the potential market for a RegenVOX technology, as well as understanding patient costs and implications for product uptake and delivery will be discussed, as well as additional considerations for onward commercialisation and translation into routine healthcare.
Abstract 558: Correlations of FGFR1 with ligand signaling in small-cell lung cancer
Authors: Hui Yu, Andrzej Badzio, Theresa Boyle, Xian Lu, Christopher J. Rivard, Ashley Kowalewski, Brad Rikke, Kim Ellison, Leslie Rozeboom, Biftu Hassan, Fred R. Hirsch
Journal: Cancer Research (2015)

Abstract Introduction: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been under-studied relative to novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor (FGFR1) has recently emerged as a contributing factor in the pathogenesis and progression of non-small cell lung cancer (NSCLC). However, knowledge of FGFR1 and ligand expression in SCLC is limited. Methods: FGFR1 gene copy number, mRNA levels and protein expression were determined by silver in situ hybridization (SISH), mRNA ISH and immunohistochemistry (IHC) in primary tumors from 78 SCLC patients. Expression of the ligands FGF2 and FGF9 mRNA and protein were determined by mRNA ISH and IHC, respectively. Spearman's correlations were conducted using SAS 9.4. Results: FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 gene copy number (p = 0.03) and FGFR1 mRNA levels (p&amp;lt;0.0001). The positivity of FGFR1 mRNA in the SCLC cohort was 21%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.0018) mRNA levels, as well as with FGF2 (0.0105) and FGF9 (0.0012) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. Conclusions: FGFR1 amplification and mRNA levels correlate with FGFR1 protein expression. The SCLC cohort has a substantially higher proportion of FGFR1 mRNA positive cases (21%) compared to FGFR1 gene copy number positive cases (7.8%). Combined analysis of FGFR1 and ligand expression may be valuable to determine which SCLC patients may respond to FGFR1 inhibitor therapy. Key Words: small cell lung cancer; FGFR1; FGF2; FGF9 Citation Format: Hui Yu, Andrzej Badzio, Theresa Boyle, Xian Lu, Christopher J. Rivard, Ashley Kowalewski, Brad Rikke, Kim Ellison, Leslie Rozeboom, Biftu Hassan, Fred R. Hirsch. Correlations of FGFR1 with ligand signaling in small-cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 558. doi:10.1158/1538-7445.AM2015-558
Fibroblast Growth Factor 23 Levels Associate with AKI and Death in Critical Illness
Authors: David E. Leaf, Kirolos A. Jacob, Anand Srivastava, Margaret E. Chen, Marta Christov, Harald Jüppner, Venkata S. Sabbisetti, Aline Martin, Myles Wolf, Sushrut S. Waikar
Journal: Journal of the American Society of Nephrology (2016)

Elevated plasma levels of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) have emerged as a powerful biomarker of cardiovascular disease and death in patients with CKD. Whether elevated urinary or plasma FGF23 levels are prospectively associated with AKI and death in critically ill patients is unknown. We therefore conducted a prospective cohort study of 350 critically ill patients admitted to intensive care units at an academic medical center to investigate whether higher urinary FGF23 levels associate with the composite end point of AKI or in-hospital mortality (AKI/death). We measured urinary FGF23 levels within 24 hours of admission to the intensive care unit. In a subcohort ( n =131) we also measured plasma levels of FGF23, calcium, phosphate, parathyroid hormone, and vitamin D metabolites. Urinary and plasma FGF23 levels, but not other mineral metabolites, significantly associated with AKI/death. In multivariate analyses, patients in the highest compared with the lowest quartile of urinary FGF23 had a 3.9 greater odds (95% confidence interval, 1.6 to 9.5) of AKI/death. Higher urinary FGF23 levels also independently associated with greater hospital, 90-day, and 1-year mortality; longer length of stay; and several other important adverse outcomes. In conclusion, elevated FGF23 levels measured in the urine or plasma may be a promising novel biomarker of AKI, death, and other adverse outcomes in critically ill patients.
Adoptive Transfer of Ex Vivo Costimulated Autologous T-Cells in Conjunction with Pneumococcal Conjugate Vaccine Immunizations Accelerates Post-Transplant T-Cell Recovery after Autotransplantation for Myeloma: Results of a Randomized Study.
Authors: Aaron P. Rapoport, Edward A. Stadtmauer, Bruce L. Levine, Ashraf Badros, Gorgun Akpek, Julio Cotte, Lisa Chrisley, Elizabeth Veloso, Sandra Westphal, Zhaohui Zheng, Rebecca Mair, Nina Chi, Bashi Ratterree, Sabrina Natt, Joanne Hinkle, David Porter, Selina Luger, Kathleen Ruehle, Chuanfa Guo, Dean Mann, Alan Cross, Carl H. June
Journal: Blood (2004)
141. A Screening Platform for Generating Cas9 Mutants with Improved Function
Authors: Jeffrey M. Spencer, Xiaoliu Zhang
Journal: Molecular Therapy (2016)

CRISPR-Cas systems, RNA-guided endonucleases (RGENs), have been utilized for gene editing in a multitude of organisms. The robust editing ability of these nucleases promises to deliver novel therapeutics. CRISPR-derived therapeutics will benefit from performance enhancing modifications made to the system such as improved nuclease activity. We developed an in vivo plasmid-cleavage-based screening platform with the ability to screen libraries of Cas9 mutants for improved function. Expression of Cas9 is controlled by a titratable promoter which provides the ability to modulate the stringency of selection. The selection system has the ability to select for both the cleavage of a specific substrate or the inability to cleave a similar, inaccurate target. Together these parameters provide a flexible platform for screening and discovery of Cas9 or alternate RGEN variants with improved endonuclease characteristics. Optimization of Cas9, other CRISPR-associated proteins, and their system components will facilitate adaptation of these technologies into powerful precision research tools with the potential to transform clinical therapeutics.
Systemic chemotherapy for pulmonary pleomorphic carcinoma
Authors: Kaname Nosaki, Eiko Inamasu, Shin-ichiro Shimamatsu, Tsukihisa Yoshida, Goji Toyokawa, Fumihiko Hirai, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama, Yukito Ichinose
Journal: Annals of Oncology (2015)
Abstract 3049: BRAF status and low glutamine/glucose influence glutamine addiction modulated by oxidative stress in human melanoma cells
Authors: Manuel Rieber, Valery Chavez-Perez, Mary Strasberg-Rieber
Journal: Cancer Research (2015)

Abstract BACKGROUND.- Cancer cells from solid tumors become metabolically stressed, when nutrients are insufficient within poorly vascularized regions. Metabolic stress results from severe deprivation of oxygen, glutamine and glucose, partly through excessive reactive oxygen species (ROS) production. Mutant BRAF can stimulate the accumulation of hypoxia-inducible factor-1alpha (HIF-1α) in physiological glucose and supplementation with supra-physiological glutamine in melanoma cells (Kumar SM et al, Cancer Res. 2007;67:3177-84).Although HIF1α reprograms melanomas to become highly glycolytic, this can be impaired in a microenvironment with sub-physiological levels of glutamine and glucose (Kwon SJ, Lee YJ.Clin Cancer Res. 2005;11:4694-700).,because melanomas require glycolysis and mitochondrial glutamine utilization. PURPOSE.- To compare proliferation and survival in response to glutamine and glucose restriction in wt-BRAF or mutant BRAF melanoma. EXPERIMENTAL. Determination of metabolic activity/proliferation and cell survival by fluorometric assays and crystal violet staining. RESULTS.- Glutamine depletion diminished survival even in physiological 5 mM glucose, particularly during hypoxia. However, 2.5 mM glucose or exogenous pyruvate when added together with another anti-oxidant N-acetylcysteine (NAC) partly substituted for glutamine in normoxic wt-BRAF cells. A much lower attenuation was seen in glutamine-depleted mutant BRAF cells when supplemented with NAC and pyruvate, particularly, under hypoxia. CONCLUSIONS.-1) glutamine restriction decreases metabolic activity and tumor cell survival, irrespective of BRAF status, being more toxic to mut-BRAF cells, either under hypoxia or in physiological glucose and normoxia,. 2) Antagonizing glutamine addiction may decrease tumor recurrence if combined with anti-BRAF targeted therapy. Citation Format: Manuel Rieber, Valery Chavez-Perez, Mary Strasberg-Rieber. BRAF status and low glutamine/glucose influence glutamine addiction modulated by oxidative stress in human melanoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3049. doi:10.1158/1538-7445.AM2015-3049
Abstract 2384: CD151-integrin complexes suppress ovarian tumor growth by repressing slug-mediated emt and canonical wnt signaling
Authors: Xiuwei H. Yang
Journal: Cancer Research (2015)

Abstract The majority of human ovarian cancer is diagnosed in the late, metastatic stages and is highly resistant to current chemotherapies. The molecular and cellular mechanisms underlying the malignancy of ovarian cancer remain poorly understood. We report a surprising functional link between CD151-α31 integrin complexes and the malignancy of serous ovarian cancer. Analyses of clinical specimens indicate that CD151 expression is significantly reduced or diminished in approximately 90% of metastatic lesions, while it remains detectable in &amp;gt;40% of primary ovarian tumors. These observations suggest a putative tumor-suppressing role of CD151 in ovarian cancer. Indeed, our analyses with multiple ovarian cancer cell lines show that knocking down CD151 or α3β1 integrin markedly enhances tumor cell proliferation, growth and ascites production in nude mice. These changes are accompanied by impaired cell-cell contacts and aberrant expression of E-cadherin, Mucin 5AC and fibronectin, largely reminiscent of an epithelial to mesenchymal transition (EMT)-like change. Importantly, Slug, a master regulator of EMT, is markedly elevated upon CD151 removal. Knocking down Slug partially restores CD151-α3β1 integrin complex-dependent suppression of cell proliferation. Moreover, disruption of these adhesion protein complexes is accompanied by a concomitant activation of canonical Wnt signaling, including elevated levels of β-catenin and Axin-2 as well as resistance to the inhibition in β-catenin-dependent transcription complexes. Taken together, our study demonstrates that CD151-α3β1 integrin complexes suppress ovarian cancer malignancy by repressing Slug-mediated EMT and canonical Wnt signaling. Citation Format: Xiuwei H. Yang. CD151-integrin complexes suppress ovarian tumor growth by repressing slug-mediated emt and canonical wnt signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2384. doi:10.1158/1538-7445.AM2015-2384
Bcl-2 inhibitors reduce steroid-insensitive airway inflammation
Authors: Bao-ping Tian, Li-xia Xia, Zheng-qiang Bao, Hao Zhang, Zhi-wei Xu, Yuan-yuan Mao, Chao Cao, Luan-qing Che, Jin-kai Liu, Wen Li, Zhi-hua Chen, Songmin Ying, Hua-hao Shen
Journal: Journal of Allergy and Clinical Immunology (2017)
Abstract 4647: Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1
Authors: Jin-Rong Zhou, Yi Gong, Hamid Abdolmaleky
Journal: Cancer Research (2015)

Abstract Prostate cancer (CaP) is the most common invasive malignancy and the second leading cause of cancer-related death in U.S. men. Androgen-independent/hormone-refractory CaP remains the primary cause of CaP death. The search for effective therapeutic and preventive strategies, particularly the ways to intervene in the progression of androgen-independent tumors remains the top priority of CaP research. Prostate cancer stem cells (CSCs) are suggested to be responsible for initiation, progression, drug resistance, recurrence and metastasis of CaP. Strategies that target prostate CSCs may significantly prevent and/or delay cancer progression and metastasis. The objective of this study was to identify the potent natural bioactive compounds for targeting prostate CSCs. The sphere-forming efficiencies in LNCaP, DUCaP, PC3 and DU145 prostate cancer cell lines were 2.8%, 15.7%, 1%, and 5.6%, respectively. The expression of several CSC related biomarkers, such as c-met, c-kit, bmi1 and CD44 were increased, whereas the expression of androgen receptor was decreased in prostate spheres. Natural compounds, especially tanshinones (tanshinone I (T1), tanshinone IIA (T2A), cryptotanshinone) and tea compounds (epigallocatechin gallate (EGCG) and theaflavines), inhibited the sphere-forming efficiency of CaP cells with T1 and T2A the most potent. Furthermore, T1 and EGCG significantly downregulated Bmi1 gene expression and protein level. Since Bmi1 has been reported to be a crucial regulator of stem cell self-renewal and malignant transformation, we further studied the functional role of bmi1 in self-renewal of prostate CSCs. Silencing of bmi1 dramatically inhibited the growth and decreased the sphere-forming ability of CaP cells. Animal studies showed that T1 and EGCG inhibited the growth and metastasis of prostate tumors associated with downregulation of bmi1 expression. The results derived from our preliminary studies suggest that bmi1 may play an important role in self-renewal ability of prostate CSCs, and that some natural bioactive agents, such as T1 and EGCG, may inhibit self-renewal of prostate CSCs in part via downregulation of bmi1 gene expression and function. Supported in part by NCI/NIH R21 CA153355. Note: This abstract was not presented at the meeting. Citation Format: Jin-Rong Zhou, Yi Gong, Hamid Abdolmaleky. Bioactive tanshinones and tea polyphenols inhibit prostate cancer stem cells by targeting bmi1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4647. doi:10.1158/1538-7445.AM2015-4647