tbuckley/cabot-search huggingface dataset:
Abstract 3688: A novel biomarker for pancreatic cancer, sTRA, and CA19-9 define separate subpopulations of PDAC cells with distinctions in behavior and molecular characteristics
Authors: Daniel Barnett, Ying Liu, ChongFeng Gao, Luke Wisniewski, Katie Partyka, Anna Barry, Galen Hostetter, Aatur Singhi, Randall E. Brand, Richard R. Drake, Brian B. Haab
Journal: Cancer Research (2018)

Abstract Cancer cells in pancreatic ductal adenocarcinomas (PDACs) exhibit tremendous diversity in behavior and phenotype, but no biomarkers are available to identify subtypes with clinically significant differences in behavior. We recently identified a new marker of pancreatic cancer, called sTRA, that is expressed on cancer cells with different morphologies and molecular characteristics than cancer cells expressing the biomarker CA19-9. Here we tested the hypothesis that the two types of cells have differences between them in behavior, gene expression, and associations with outcome. In cell line models, sTRA-expressing cancer cells were more resistant to drugs, more invasive, and slower-growing than the CA19-9-expressing cells. Patient-derived xenograft tumors produced either CA19-9 or sTRA, and RNA-seq analysis revealed significant, nonrandom differences between the sTRA-expressing and CA19-9-expressing tumors. Each subpopulation was found in lymph nodes or livers with levels that significantly correlated with their matched primary tumors. In an analysis of two tissue microarrays covering 45 and 41 patients, the tumors containing high levels of sTRA-expressing cancer cells had the shortest survival times. These data support the existence of two distinct subtypes of PDAC cells, respectively marked by CA19-9 and sTRA. Together the markers could have value for predicting the behavior of tumors and for isolating, characterizing, and targeting specific subtypes of cancer cells. Citation Format: Daniel Barnett, Ying Liu, ChongFeng Gao, Luke Wisniewski, Katie Partyka, Anna Barry, Galen Hostetter, Aatur Singhi, Randall E. Brand, Richard R. Drake, Brian B. Haab. A novel biomarker for pancreatic cancer, sTRA, and CA19-9 define separate subpopulations of PDAC cells with distinctions in behavior and molecular characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3688.
Abstract 4509: SATB2/β-catenin/TCF-LEF pathway induces cellular transformation by generating cancer stem cells in colorectal cancer
Authors: Yiming Ma, Wei Yu, Sharmila Shankar, Rakesh K. Srivastava
Journal: Cancer Research (2018)

Abstract Recent studies have demonstrated the involvement of colorectal cancer (CRC) stem cells (CSC) in transformation, cancer progression and metastasis. The main goal of this paper was to examine the molecular mechanisms by which SATB2 induced malignant transformation of colorectal epithelial cells. SATB2 induced malignant transformation and these transformed cells gained the characteristics of CSCs by expressing stem cell markers (CD44, CD133, LGR5 and DCLK1) and transcription factors (c-Myc, Nanog and Sox2). Overexpression of SATB2 in normal colorectal epithelial cells increased cell motility, migration and invasion, which were associated with an increase in N-cadherin and Zeb1, and decrease in E-cadherin expression. SATB2 overexpression also upregulated XIAP and cyclin D1, suggesting its role in cell survival and cell cycle. Furthermore, the expression of SATB2 was positively correlated with β-catenin expression in CRC. In contrary, depletion of SATB2 inhibited cell proliferation, colony formation, cell motility and expression of β-catenin, Snail, Slug, Zeb1 and N-cadherin, and upregulated E-cadherin. Furthermore, SATB2 silencing inhibited the expression of stem cell markers, pluripotency maintaining transcription factors, cell cycle and cell proliferation/survival genes and TCF/LEF targets. Finally, β-catenin/TCF-LEF pathway mediated the biological effects of SATB2 in CSCs. These studies support the role of SATB2/β-catenin/TCF-LEF pathway in transformation and carcinogenesis. Citation Format: Yiming Ma, Wei Yu, Sharmila Shankar, Rakesh K. Srivastava. SATB2/β-catenin/TCF-LEF pathway induces cellular transformation by generating cancer stem cells in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4509.
Abstract 18400: Distinct Endothelial Function in Patients With Chronic Total Occlusion With Preserved Myocardial Viability
Authors: YuichiroArima, SeijiHokimoto, ShinjiTayama, SatomiIwashita, TomonoriAkasaka, NoriakiTabata, KenjiSakamoto, KenichiTsujita, EiichiroYamamoto, TomokoTanaka, SunaoKojima, KoichiKaikita, HisaoOgawa
Journal: Circulation (2014)

Backgrounds: Coronary collateral vessels work as a detour and ameliorate ischemic myocardial damage. Induction or enhancement of the collateral growth is a novel therapeutic strategy for the ischemic heart disease, however their mechanisms are almost unknown. Patients with chronic total occlusion (CTO) who keep the intact myocardium maintain rich collateral sources, which perfuse the area of the occluded artery. We tried to assess the characteristics of patients with CTO compared with non-occlusive patients with ischemic heart disease and those with old myocardial infarction (OMI). Methods: Consecutive 264 patients from January 2010 to February 2014 were enrolled this study. First we assessed the myocardial viability using summed rest score (SRS) of thallium perfusion scintigraphy and divided into OMI patients (SRS greater than or equal to 4, OMI group, n=99) and the others with almost normal myocardial viabilities (n=165). Next we divided into CTO group (n=51) and Stenosis group (n=114) from the coronary...
Abstract 758: Head-to-head comparison of ADC and SMDC products, alone and in combination with antibody-IL2 fusion proteins
Authors: Samuele Cazzamalli, Alberto Dal Corso, Fontaine Widmayer, Dario Neri
Journal: Cancer Research (2018)

Abstract In an attempt to improve the therapeutic index of cancer chemotherapy, monoclonal antibodies and small organic ligands have been proposed as delivery vehicles, allowing the construction of antibody-drug conjugates (ADCs) and of small molecule-drug conjugates (SMDCs). Four ADC products have gained marketing authorization for cancer therapy, while SMDCs are still being investigated in clinical trials. SMDCs could in principle offer certain advantages compared to ADCs, such as a more rapid and uniform diffusion into the tumor mass, lower cost-of-goods and lack of immunogenicity, but a direct head-to-head comparison has not yet been reported. Here we describe a novel small molecule-drug conjugate, based on a high-affinity ligand specific to carbonic anhydrase IX. The product features a peptide linker, suitable for cleavage in the tumor extracellular environment, and monomethyl auristatin E as cytotoxic payload. We compared the therapeutic efficacy of the novel SMDC and of an anti-CAIX ADC, which were injected at equimolar doses in nude mice bearing SKRC-52 renal cell carcinoma xenografts. Both products showed a potent anti-cancer activity, although no complete tumor eradication was observed. Instead, when the SMDC was administered together with L19-IL2 (a clinical-stage fusion protein capable of delivering interleukin-2 to the tumor neo-vasculature), all treated mice in the combination group could be rendered tumor-free, in a process which favored the influx of natural killer cells into the tumor mass. The combination of L19-IL2 and the new small molecule-drug conjugate also eradicated cancer in 100% of immunocompetent mice, bearing subcutaneously-grafted CT26 colorectal cancer cells, which stably expressed carbonic anhydrase IX. These findings may be of clinical significance, since carbonic anhydrase IX is over-expressed in the majority of clear-cell renal cell carcinomas and in approximately 30% of colorectal cancers. The targeted delivery of interleukin-2 helps potentiate the action of targeted cytotoxics leading to cancer eradication in models that cannot be cured by conventional chemotherapy. Citation Format: Samuele Cazzamalli, Alberto Dal Corso, Fontaine Widmayer, Dario Neri. Head-to-head comparison of ADC and SMDC products, alone and in combination with antibody-IL2 fusion proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 758.
Prognostic relevance of partial hormone receptor expression in stage I breast cancer.
Authors: Ariel Zwenger, Julieta Leone, Julian Iturbe, Palmira Perez Verdera, Jose Pablo Leone, Bernardo Amadeo Leone, Carlos Teodoro Vallejo
Journal: Journal of Clinical Oncology (2012)

e11021 Background: Patients whose tumors express only one hormone receptor (1HR) are usually considered hormone-sensitive regarding treatment decisions. However, certain retrospective analyses suggest that patients bearing ER+/PR- or ER-/PR+ tumors may have worse outcomes than those with ER+/PR+ (HR) phenotype. The aim of this study was to correlate partial expression of hormone receptors (ER+/PR- or ER-/PR+) with several well known prognostic factors and their possible influence on the incidence of local and distant failure, relapse free survival (RFS) and overall survival (OS) in women with early breast cancer treated at GOCS institutions. Methods: We evaluated 327 patients with stage I breast cancer (T1a,b,cN0M0; AJCC 2010) diagnosed between January 1991 and December 2009. Further analyses were conducted upon a cohort of 282 patients who were divided between those whose tumors expressed both HR and those with only 1HR. Results: The median age was 54.2 years (29-89). Median follow-up was 9.4±4.4 years (0.2-22.9). Both HR and 1HR were expressed in 242 and 40 patients respectively. Similar adjuvant treatment was administered in both groups although the number of mastectomies was higher in the subgroup with only 1HR (22.5% vs. 5.8%, P =. 0003). Univariate analyses showed no difference between both groups when correlated with age, body mass index, histologic type, T stage, histologic and nuclear grade, mitotic index, vascular invasion, necrosis and margin status. However, 1HR tumors had a higher rate of lymphovascular invasion (21.9% vs. 9.5%, P =.038) and HER2 expression (57.1% vs. 21.9%, P = .035). Treatment failure was more frequent in patients with only 1HR (12.5% vs. 5%, P =.064). Distant progression was also more common in this subgroup (80% vs. 58.3%, P =.334). There were no statistically significant differences in RFS and OS among groups. Conclusions: The expression of only 1HR constitutes a phenotype that could have a more aggressive biology and be associated with higher risk of recurrence than tumors with both receptors. Analysis of more patients, larger tumor size and N1 disease is warranted to confirm this hypothesis and have a better prognostic assessment.
Abstract 633: Application of a novel analytical metric that quantifies copy number alterations in low-coverage, genome-wide sequencing of cell-free DNA to monitor and differentiate response to immunotherapy in cancer patients
Authors: Taylor J. Jensen, Aaron M. Goodman, Christopher K. Ellison, Shumei Kato, Gregory A. Daniels, Lisa Tran, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich, Razelle Kurzrock
Journal: Cancer Research (2018)

Abstract Inhibitors of the PD-1/PD-L1/CTLA4 immune checkpoint pathway have transformed the cancer treatment paradigm. It has been observed that even some patients with advanced, refractory malignancies achieve durable responses; however, only a minority of patients benefit, demonstrating the importance of developing new biomarkers to predict patient outcome. The most commonly used biomarkers for predicting response to checkpoint inhibitors are the expression of PD-1/PD-L1, microsatellite instability, and tumor mutational burden. While these markers have been shown to have varying degrees of predictive power, they have not been used to monitor and differentiate response during treatment and require invasive procedures. Interrogating cell-free DNA (cfDNA) isolated from plasma (liquid biopsy) provides a promising noninvasive method for monitoring response. We describe the use of low-coverage (~0.3X) genome-wide sequencing of cfDNA, validated extensively for detecting chromosomal abnormalities in non-invasive prenatal testing (NIPT) and previously shown to enable incidental detection of occult maternal malignancies, to detect tumor-specific copy number alterations; and the development of a new metric–the genome instability number (GIN)–to monitor response to these drugs. Using a series of more than 450 plasma aliquots taken from more than 75 patients throughout their treatment, we demonstrate how the GIN can be used to discriminate clinical response from progression, differentiate progression from pseudoprogression, and identify hyperprogressive disease, as early as 4-6 weeks after treatment initiation. Finally, we provide evidence for a delayed therapeutic response to checkpoint inhibitors relative to targeted therapies. While this study is still ongoing, these initial data provide proof of concept for using this method for monitoring treatment outcome in cancer patients receiving immunotherapy. Citation Format: Taylor J. Jensen, Aaron M. Goodman, Christopher K. Ellison, Shumei Kato, Gregory A. Daniels, Lisa Tran, Prachi Nakashe, Erin McCarthy, Amin R. Mazloom, Graham McLennan, Daniel S. Grosu, Mathias Ehrich, Razelle Kurzrock. Application of a novel analytical metric that quantifies copy number alterations in low-coverage, genome-wide sequencing of cell-free DNA to monitor and differentiate response to immunotherapy in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 633.
Abstract 15894: Adaptations of Innate Immunity in Hibernation: Mechanisms for Protection Against Acute Organ Injury
Authors: Quintin J Quinones, Qing Ma, Michael P Smith, Janet Staats, Cliburn Chan, Brian M Barnes, Mihai V Podgoreanu
Journal: Circulation (2015)

Introduction: Hibernation is a natural molecular adaptation to extreme environmental conditions with important implications for perioperative organ protection. Hypothesis: We hypothesized that the hibernator cardioprotective phenotype is accompanied by altered expression of innate immune pattern-recognition receptors (PRRs) and inflammatory pathways. Methods: LV myocardium, peripheral blood monocytes (PBMC), and plasma were collected from rat, summer AGS, and winter AGS after sham, 3h or 24h ischemia/reperfusion (I/R). Results: Plasma troponin I detection confirmed greater I/R injury in rat compared to AGS (Fig 1). Proteomic profiling of LV myocardium detected multiple differences including higher expression of MyD88 dependent toll-like receptors (TLR) in rat compared to AGS; average levels of TLRs were 1.8 fold higher in rat compared with hibernating AGS. Comparison of PBMCs from rat, summer, and hibernating AGS revealed increased PRR expression and cytokine production in the rat compared to the AGS, along the TLR3/TICAM (Fig2), TLR/MyD88, and AIM2/inflammasome axes. Conclusions: Compared to AGS, rats experience robust inflammasome activation in response to I/R as evidenced by &gt;30-fold increases in AIM2 and Caspase 1. Hibernation state differences in innate immunity exist, including reduced expression of PRRs(TLR1,3, and AIM2); additionally signaling via TLR 3 and 4 is greatly dampened in winter AGS due to nearly absent expression of TICAM1. Circulating immune effector cells in winter AGS have an abrogated response to DAMPs compared to cells from summer AGS or rat, as evidenced by reduced cytokine production.
Abstract 2572:HSD3B1genotype and abiraterone metabolism in patients with prostate cancer
Authors: Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Tae Hyun Hwang, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi
Journal: Cancer Research (2018)

Abstract Background The common HSD3B1 (1245C) germline variant encodes for a 3βHSD1 missense that increases enzyme activity that allows tumors to utilize extragonadal androgens and is a predictive biomarker of resistance to ADT and sensitivity to CYP17A1 inhibition by the nonsteroidal drug ketoconazole. However, 3βHSD is also the first enzyme necessary in the conversion from abiraterone, a steroidal CYP17A1 inhibitor, to 5α-abiraterone, which stimulates the androgen receptor (AR) and prostate cancer progression. The HSD3B1 (1245C) variant might therefore increase 5α-abiraterone synthesis in patients on abiraterone therapy, possibly limiting clinical benefit. Significance This work aims to characterize the pharmacokinetics of steroidal metabolites of abiraterone and to determine the association between HSD3B1 genotype and the generation of 5α-abiraterone metabolites. Patients and Methods Part 1: 15 healthy male volunteers received a single oral dose of 1000 mg abiraterone acetate plus 240 mg of the AR antagonist apalutamide, steroidal metabolites of abiraterone were quantitated at 12 time points from 0.5-96 hours post-dose. Part 2: 5α-abiraterone metabolites and HSD3B1 genotype was determine in 30 patients with castration-resistant prostate cancer (CRPC) on abiraterone therapy. Metabolite concentrations were normalized to the 8 hour time point of the pharmacokinetic study and the association between HSD3B1 genotype and 5α-abiraterone metabolites was determined. Results There were 8, 19, and 3 pts with homozygous wild-type, heterozygous, and homozygous variant HSD3B1 genotypes. Patients who inherit 0, 1 and 2 copies of the HSD3B1 (1245C) variant have a stepwise increase in serum concentrations of 5α-abiraterone metabolites (p=0.002). Conclusion The generation of 5α-abiraterone preferentially in patients with the HSD3B1 (1245C) variant might negate the benefits of abiraterone specifically in a patient subset that is otherwise more likely to benefit from CYP17A1 inhibition by the nonsteroidal drug ketoconazole. Citation Format: Mohammad Alyamani, Hamid Emamekhoo, Sunho Park, Jennifer Taylor, Nima Almassi, Sunil Upadhyay, Allison Tyler, Michael P. Berk, Tae Hyun Hwang, Petros Grivas, Brian Rini, Jorge Garcia, Richard J. Auchus, Nima Sharifi. HSD3B1 genotype and abiraterone metabolism in patients with prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2572.
Endothelial Dysfunction in Men With Small LDL Particles
Authors: JuhaVakkilainen, SariMäkimattila, AnneliSeppälä-Lindroos, SatuVehkavaara, SanniLahdenperä, Per-HenrikGroop, Marja-RiittaTaskinen, HanneleYki-Järvinen
Journal: Circulation (2000)

Background—It is unknown whether LDL particle size is, independent of other lipids and lipoproteins, associated with endothelial dysfunction in vivo. Methods and Results—We determined in vivo endothelial function in 34 healthy men by measuring forearm blood flow responses to intrabrachial artery infusions of acetylcholine (ACh, an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). LDL peak particle size was measured with gradient gel electrophoresis. Men with small LDL particles (LDL diameter ≤25.5 nm, n=10) had a 39% lower blood flow response to ACh than men with large LDL particles (LDL diameter >25.5 nm, n=24, blood flow 6.9±3.6 versus 11.4±5.1 mL/dL · min, P=0.006). The groups had comparable LDL cholesterol concentrations (3.9±0.6 versus 3.7±1.0 mmol/L, men with small versus large LDL particles), blood pressure, glucose concentrations, and body mass indexes. LDL size (r=0.45, P=0.01) but not HDL cholesterol (r=0.31, P=0.09) or triglycerides (r=−0.19, ...
Transurethral Resection of Prostate (TURP) surgery without using a 3-way catheter: 10 years of data
Authors: A. Jones, S.A. Ehsanullah, A. Birring, S. Irfan, M. Megson, S. Rezvani, P. Polson, J. Raju, S. Singh, A. Ginepri, I. Apakama
Journal: International Journal of Surgery (2018)
Abstract 2546: Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors
Authors: Haiyan Chu, Yingjuan Lu, Yong Gu Lee, Leroy Wheeler, Mellissa Nelson, Elaine Westrick, Marilynn Vetzel, Patrick J. Klein, Philip S. Low, Christopher P. Leamon
Journal: Cancer Research (2018)

Abstract Chimeric antigen receptor modified T cell (CAR-T) therapy has revolutionized personalized cancer treatment. The recent FDA approval of two CAR-T therapies for hematological cancers has marked a pivotal milestone in this new era of cellular therapies. CAR-T cells are genetically modified to become activated and proliferate in the presence of tumor antigens. In patients with high tumor burden and rapid T cell expansion, however, severe side effects including severe cytokine release syndrome (sCRS) and life-threatening cerebral edema may occur. To “fine-tune” CAR-T cell activity in real time, we devised a three-pronged therapeutic strategy by using (1) 4-1BB-CD3ζ CARs expressing anti-fluorescein (anti-FITC) scFv instead of an anti-tumor ligand/self-antigen scFv, (2) low-molecular-weight bi-specific adaptors comprised of a FITC hapten linked to a tumor-specific ligand, and (3) competitors that can interfere with the adaptor/CAR-T interaction with tumor cells. Using folate-FITC (EC17) as the bi-specific adaptor molecule, we evaluated the performance of FITC-CAR-T cells in various folate receptor (FR)-positive tumor models. Our results show that CAR-T activation and proliferation in-vivo was EC17- and tumor FR-dependent. Treatment-related toxicity (sCRS) was observed but could be easily controlled, or even prevented, by adjusting the concentration, dosing frequency or timing of bi-specific adaptor administration. Importantly, animals experiencing sCRS could be rescued by administrating competitors of the bi-specific adaptor. In the case of EC17/CAR-T therapy, improved animal behavior was observed as early as a few hours after dosing with a rescue agent and a rapid reduction of interferon-γ was also detected. Circulating CAR-T cells remained functional, and could be re-activated following subsequent EC17 doses. Taken together, our bi-specific adaptor/CAR-T approach offers a unique combination of a man-made hapten (FITC), flexible dosing control, and sCRS prevention/rescue without compromising antitumor activity or permanently removing CAR-T cells. Further studies are warranted to provide a rational basis for translating such therapeutic practice to the clinic. Footnotes HC and JL contributed equally to this work. Citation Format: Haiyan Chu, Yingjuan Lu, Yong Gu Lee, Leroy Wheeler, Mellissa Nelson, Elaine Westrick, Marilynn Vetzel, Patrick J. Klein, Philip S. Low, Christopher P. Leamon. Regulation of CAR-T cell therapy in real time using bispecific small molecule adaptors and monospecific competitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2546.