tbuckley/cabot-search huggingface dataset:
Abstract 3060: EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres through regulating HER3/ERBB3 expression as a therapeutic target against EGFR-positive non-small cell lung cancer
Authors: Chun-Chia Cheng, Kuei-Fang Chou, Cheng-Wen Wu, Nai-Wen Su, Cheng-Liang Peng, Ying-Wen Su, Jungshan Chang, Ai-Sheng Ho, Huan-Chau Lin, Caleb Gon-Shen Chen, Yu-Cheng Chang, Ken-Hong Lim, Yi-Fang Chang
Journal: Cancer Research (2018)

Abstract Objectives: YM155, an inhibitor of interleukin enhancer-binding factor 3 (ILF3), significantly suppresses cancer stemness property, implying that ILF3 contributes to cell survival of cancer stem cells. However, the molecular function of ILF3 inhibiting cancer stemness remain unclear. This study aimed to uncover the potential function of ILF3 involving in cell survival of epidermal growth factor receptor (EGFR)-positive lung stem-like cancer, and investigate the potential role to improve the efficacy of anti-EGFR therapeutics. Materials and Methods: The regulated association of EGFR and ILF3 was investigated at first. ILF3 was knockdowned and RNAseq was utilized to search for the putative genes regulated by ILF3. Meanwhile, HCC827- and A549-derived cancer stem-like cells were used to investigate the role of ILF3 in the formation of cancer stem-like tumorspheres. Results: We found that EGFR induced ILF3 expression, and YM155 reduced EGFR expression. The knockdown of ILF3 reduced not only EGFR expression in mRNA and protein levels, but also cell proliferation in vitro and in vivo, demonstrating that ILF3 was an oncoprotein contributing to cancer cell survival. Moreover, the knockdown and inhibition of ILF3 by shRNA and YM155, respectively, reduced the formation and survival of HCC827- and A549-derived tumorspheres through inhibiting HER3/ERBB3 expression, and synergized the therapeutic efficacy of afatinib, a tyrosine kinase inhibitor, against EGFR-positive A549 lung cells. Conclusion: This study demonstrated that ILF3 played an oncogenic role maintaining the EGFR-mediated cellular pathway as a therapeutic target to improve the therapeutic efficacy of afatinib. Therefore, we suggested that YM155, an ILF3 inhibitor, was potential for utilization in cancer therapy against the EGFR-positive cancers. Citation Format: Chun-Chia Cheng, Kuei-Fang Chou, Cheng-Wen Wu, Nai-Wen Su, Cheng-Liang Peng, Ying-Wen Su, Jungshan Chang, Ai-Sheng Ho, Huan-Chau Lin, Caleb Gon-Shen Chen, Yu-Cheng Chang, Ken-Hong Lim, Yi-Fang Chang. EGFR-mediated interleukin enhancer-binding factor 3 contributes to formation and survival of cancer stem-like tumorspheres through regulating HER3/ERBB3 expression as a therapeutic target against EGFR-positive non-small cell lung 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 3060.
Time finding study of chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L) and oxaliplatin (O) (chronoIFLO) against metastatic colorectal cancer: Results from randomized EORTC 05011 trial
Authors: C. Garufi, C. Focan, S. Tumolo, B. Coudert, S. Iacobelli, N. Tubiana, S. Marreaud, M. Lentz, T. Gorlia, F. Lévi
Journal: Journal of Clinical Oncology (2007)

2566 Background: We previously showed that a) irinotecan (I) could be combined with chronoFLO in MMC patients; b) least toxic times (LTT) for combined I and oxaliplatin respectively correspond to the middle of the rest-phase and the middle of acivity-phase in tumor-bearing mice; c) chrono I showed adequate activity in a randomized phase II trial; and d) MMC resistance can be partly overcome with chronoIFL. Methods: The objective was to identify the LTT for I characterized by a minimal dose reduction/delay among the first 3 courses (c). Assuming that the toxic effect of I had a 24-h periodicity patients were randomized in 6 groups with I peak delivery (180 mg/m 2 , 6-h sinusoidal infusion on day 1) at 1:00, 5:00, 9:00 am, 1:00, 5:00, or 9:00 pm. . All the groups received also chronoFLO on days 2–5, q 3 weeks (F 700 mg/m 2 /d &amp; L 150 mg/m 2 /d; from 22:15 to 9:45 with peak delivery at 4:00 , O 20 mg/m 2 /d from 10:15 to 21:45, with peak delivery at 16:00). Based on a logistic regression model, a 15% reduction in toxic events in the first 3 c, 186 patients were considered necessary to estimate the LTT with a 95% CI (calculated by bootsrap) of less than 6 h. Results: 197 of 199 randomized MMC patients were considered for tolerability and safety with median age 61 years (30–81), sex (M 68% - F 32%) and PS (0/1/2 73/23/4%); therapy was 1 st line in 77 patients and 2 nd line in 23%. Thithy-one percent of severe protocol violations occurred, 16% of pump malfunctions (&gt;10% dose delivery deviation). Median number of c was 6 (1–18). There were 3 toxic deaths. The observed LTT for I tolerability was 3:15 am (95 CI: 3:40–1:50 pm, NS). Grade 3–4 diarrhea ranged from 34 to 51.6% with LTT at 1:53 pm (4:29 -2:53 am, not significant, NS); neutropenia from 9 to 25% with LTT at 3:26 pm (10:50 - 4:55 am, NS). Age was a negative prognostic factor for diarrhea (p =0.01). Conclusion: This trial failed to show a statistically significant LTT for this combination in MCC patients. The safety profile of I combined with ChronoIFLO was acceptable, with diarrhea and neutropenia within previously reported range. No significant financial relationships to disclose.
Abstract 3814: TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life
Authors: Holger Wesche, Wade Aaron, Richard J. Austin, Patrick A. Baeuerle, Adrie Jones, Bryan Lemon, Kenneth Sexton, Timothy Yu
Journal: Cancer Research (2018)

Abstract T cell engagers are antibody-based therapeutics that transiently tether T cells via the T cell receptor complex (TCR) to surface antigens on tumor cells. This leads to activation of T cells and redirected lysis of the attached target cell. The therapeutic potential of this modality was demonstrated by blinatumomab, a CD19/CD3-bispecific T cell engager approved for the treatment of adult patients with relapsed/refractory acute lymphoblastic leukemia. Despite success of this T cell-engaging therapy in a hematologic malignancy, clinical studies in solid tumors with other T cell engagers have been less encouraging so far. The TriTAC (Tri-specific T cell Activating Construct) platform was developed to address shortcomings of existing T cell engagers, including short serum half-life, limited tissue penetration, and suboptimal activity. TriTAC constructs are made of a single polypeptide designed to bind to a cancer surface antigen, the CD3 epsilon subunit of the TCR, and to human serum albumin. CD3 is bound by a single-chain variable fragment (scFv) while both tumor targeting and albumin binding are achieved by single domain antibodies. The latter allow TriTACs to be very small, stable, and easily produced and purified. Noncovalent binding to serum albumin has been validated as an effective way to extend the serum half-life of other proteins up to several weeks. Even though TriTACs have three binding domains, their overall size is only ~50 kDa, one third of the size of a monoclonal antibody. This is expected to allow for faster diffusion into human tumor tissues than is possible with antibodies given the high interstitial pressure and dense extracellular matrix in solid tumors. TriTACs can induce T cell to kill tumor cells in vitro at single-digit picomolar to femtomolar concentrations with concomitant induction of inflammatory cytokine release and T cell proliferation. TriTACs can diffuse much faster across an extracellular matrix than antibodies, and eradicate tumors in mouse xenograft models supplemented with human T cells. In nonhuman primates, TriTAC molecules have serum half-lives of approximately 4 days, and appear well tolerated. Citation Format: Holger Wesche, Wade Aaron, Richard J. Austin, Patrick A. Baeuerle, Adrie Jones, Bryan Lemon, Kenneth Sexton, Timothy Yu. TriTACs are novel T cell-engaging therapeutic proteins optimized for the treatment of solid tumors and for long serum half-life [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 3814.
Spatiotemporal Characteristics of Junctional and Nonjunctional Focal Ca2+ Release in Rat Atrial Myocytes
Authors: Sun-HeeWoo, LarsCleemann, MartinMorad
Journal: Circulation Research (2003)

Atrial myocytes have two functionally separate Ca2+ release sites: those in peripheral sarcoplasmic reticulum (SR) adjacent to the Ca2+ channels of surface membrane and those in central SR not associated with Ca2+ channels. Recently, we have reported on the gating of these two different Ca2+ release sites by Ca2+ current. In the present study, we report on the spatiotemporal properties of focal Ca2+ releases (sparks) occurring spontaneously in central and peripheral sites of voltage-clamped rat atrial myocytes, using rapid 2-dimensional (2-D) confocal Ca2+ imaging. Peripheral and central sparks were similar in size and release time (≈300 000 Ca2+ ions for ≅12 ms), but significantly larger and longer than ventricular sparks. Both sites were resistant to Cd2+ and inhibited by ryanodine. Peripheral sparks were brighter and flattened against surface membrane, had ≈5-fold higher frequency, ≈2 times faster diffusion coefficient, and dissipated abruptly. Central sparks, in contrast, occurred less frequently, wer...
Mitochondrial Coupling Factor 6 Is Present on the Surface of Human Vascular Endothelial Cells and Is Released by Shear Stress
Authors: TomohiroOsanai, SatokoOkada, KenichiSirato, TakaoNakano, MasayukiSaitoh, KojiMagota, KenOkumura
Journal: Circulation (2001)

Background— We showed that mitochondrial coupling factor 6 (CF6), an endogenous inhibitor of prostacyclin synthesis, is present in the systemic circulation as a pressor substance in rats. We investigated the possibility of vascular endothelial cells as a source of circulating CF6. Methods and Results— We used 2 cultured endothelial cell lines, human umbilical vein endothelial cells (HUVECs) and ECV 304 cells (transformed HUVECs), for this study. Immunofluorescence microscopy of both ECV 304 and HUVECs confirmed the surface-associated immunoreactivity of anti-CF6 antibody on the plasma membrane. The concentration of CF6 in the medium increased gradually with time in both ECV 304 and HUVECs in static conditions. Exposure of ECV 304 and HUVECs to a fluid shear stress enhanced the release of CF6: In ECV 304, the concentration of CF6 in the medium (ng · well−1 · 6 hours−1) was 2.1±0.8 at baseline, 4.3±0.8 after shear at 15 dynes/cm2, and 57.7±8.4 after shear at 25 dynes/cm2. CF6 contents in the cell homogenate...
Abstract LB-242: PTEN regulates mitotic checkpoint complex during mitotic progression
Authors: Byeong Hyeok Choi, Steve Xie, Wei Dai
Journal: Cancer Research (2018)

Abstract PTEN is a well-known tumor suppressor through the negative regulation of the PI3K signaling pathway. Recently, it has been reported that nuclear PTEN plays an important role in cellular function. To understand the molecular basis by which PTEN mediates mitotic progression, we examined whether PTEN regulated the formation of mitotic checkpoint complex (MCC). Here we observed that arsenic trioxide, a mitotic inducer, stimulated nuclear translocation of PTEN in a time-dependent manner. PTEN physically interacted with Cdc20 and Mad2, two important components of MCC. Arsenic treatment diminished the physical association of PTEN with BubR1 and Bub3 but not with Cdc20 and Mad2. Our further studies revealed that downregulation of PTEN via RNAi enhanced formation of MCC during the cell cycle. Moreover, PTEN silencing induced chromosomal instability. Given the crucial role of PTEN in suppressing tumor development, our study strongly suggests that PTEN also functions to maintain chromosomal stability, partly through suppressing unscheduled formation of MCC. Citation Format: Byeong Hyeok Choi, Steve Xie, Wei Dai. PTEN regulates mitotic checkpoint complex during mitotic progression [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 LB-242.
Abstract 304: Dual PI3K/BCL-2 family inhibition in colorectal cancers withApcandPik3camutations
Authors: Devon D. Miller, Christopher P. Babiarz, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Dustin A. Deming
Journal: Cancer Research (2018)

Abstract Background: Colorectal cancer (CRC) is a leading cause of cancer-related death in the United States. Approximately 20% of human CRCs possess mutations in the PIK3CA gene, resulting in a constitutively active form of phosphoinositide-3 kinase (PI3K). These PIK3CA mutations most commonly occur concomitantly with the loss of adenomatous polyposis coli (APC). Copanlisib is a beta-isoform sparing PI3K inhibitor. Here we examine the response of CRCs with Apc and Pik3ca mutations to copanlisib alone and in combination with navitoclax, a BCL-2, BCL-xL, and BCL-w inhibitor. Methods: Murine-derived organotypic cancer spheroids (MDOCS) with Apc and Pik3ca mutations generated from transgenic mice were cultured in Matrigel and treated by exchanging feeding media containing desired concentration of each agent over the spheroids. Spheroids were treated with feeding media (control), 200nM ABT263, 200nM copanlisib, or the combination of both treatments. The spheroid culture response was quantified as the median relative change in the sphere diameter, comparing pre- and posttreatment 4x optical microscopic images to those obtained 48 hours post-treatment. Results: Untreated MDOCS had a median growth in sphere diameter of 137%. ABT263 did not significantly affect growth; however, copanlisib significantly reduced median sphere size by 24.6% (p&amp;lt;0.001) and the combination treatment reduced median sphere size by 33% which was significant to both control and copanlisib only treated spheres (p&amp;lt;0.001 and p=0.014, respectively). Phosphorylation of ribosomal protein S6 and 4EBP1 were suppressed with copanlisib treatment. Induction of apoptosis in these spheres treated with the combination regimen was confirmed with immunofluorescence for cleaved caspase 3 with minimal apoptosis observed in those spheres treated with copanlisib alone. Conclusion: In this study, we demonstrated the ability of copanlisib alone and combined with ABT263 to cause a marked decrease in sphere size of CRC MDOCS with Apc and Pik3ca mutations. Future tests will examine this novel regimen in vivo and potentially in future clinical trials. Citation Format: Devon D. Miller, Christopher P. Babiarz, Susan N. Payne, Cheri A. Pasch, Linda Clipson, Kristina A. Matkowskyj, Dustin A. Deming. Dual PI3K/BCL-2 family inhibition in colorectal cancers with Apc and Pik3ca mutations [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 304.
Abstract 862: Effects of fixation and antigen retrieval on the RNA integrity number
Authors: Dennis Otali, Maitlyn Mullen, He Qinghua, Denise Oelschlager, William E. Grizzle
Journal: Cancer Research (2018)

Abstract The effect of fixation and antigen retrieval (AR) on RNA as measured by the RNA integrity number (RIN) has not been adequately explored. RIN is an index (pseudo-measure) used to measure stability of mRNA; however, RIN is an actual measure of the stability of ribosomal RNA and not an actual measure of mRNA. RIN values range from 1 for highly degraded to 10 for intact RNA. Most surgical specimens are fixed in 10% neutral buffered formalin (3.7% formaldehyde) because of its ability to preserve morphological detail and prevent degradation. However, formaldehyde fixation causes changes in proteins through formation of crosslinks, which masks the immunorecognition of some antigens. In immunohistochemical evaluations, antigen retrieval (AR) approaches e.g., boiling of tissue sections under pressure are used to reverse these effects of fixation. It is believed that fresh or snap frozen specimens serve as most the suitable source of intact mRNA, DNA and other macromolecules for molecular analysis. However, more recent studies using rt-Q PCR indicate that RNA and DNA can be measured in formalin fixed paraffin embedded (FFPE) tissue samples which usually have RIN values of 3 or less. The question arises as to what is the usefulness of RIN in FFPE tissues. This study used three cancer cell lines DU145 (prostate), MDA231 (breast) and S2VP10 (pancreas) to examine the relationship between 10% NBF fixation, RIN and AR. The first objective was to analyze whether the duration of fixation of cells in 10% NBF correlated with decreases in RIN. Three fixation times i.e., 5 minutes, 20 minutes and 120 minutes were studied. The second objective was to investigate the effects of two AR approaches on RIN. Two AR conditions at pH 6 and pH 9 were used on the same cell lines and fixation times. For each cell line and treatment i.e., no fixation, or fixation at different times (with and without AR), RNA was extracted and RIN analyzed using the Agilent 2100 Bioanalyzer. RIN values obtained from the Agilent 2100 Bioanalyzer were statistically analyzed. T-tests show that the large decreases to about 3 in RIN values after fixation (5, 20 and 120 minutes) are statistically significant for all cell lines. All p-values are less than 0.0001. This study confirms that fixation of cells in 10% NBF lowers RIN to about 3 the value observed for fixed tissues. RIN did not vary significantly with time of fixation in 10% NBF and RIN did not change from the fixed values after either condition of AR. Thus RIN is not a useful measure of RNA stability in 10% NBF fixed tissue. Citation Format: Dennis Otali, Maitlyn Mullen, He Qinghua, Denise Oelschlager, William E. Grizzle. Effects of fixation and antigen retrieval on the RNA integrity number [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 862.
Abstract 2106: Focal gene expression profiling of counterstained FFPE with correlation to morphology using TempO-Seq
Authors: Elliot Imler, Milos Babic, Deanna Adams, Peter Shepard, Joanne Yeakley, Raymond B. Nagle, Bruce Seligmann
Journal: Cancer Research (2018)

Abstract We previously reported on use of the whole transcriptome TempO-Seq® assay to profile gene expression from 1 mm2 focal areas of 5 µm thick FFPE sections of normal and cancerous tissue to identify disease biomarkers and mechanistic pathways. We are now presenting data demonstrating that the TempO-Seq assay can be performed as an “in situ” assay on slides by an automated slide stainer, followed by counterstaining. Then, using an automated digital imaging platform, areas as small as 30 μm in diameter within the FFPE section can be profiled, permitting the gene expression data to be correlated directly to the specific morphology of that focal area. The pathologist uses a computer interface to select areas for profiling during the course of the histologic examination of the section, and then the TempO-Seq probes are automatically recovered from those region(s) of interest. After depositing them into PCR tubes, the assay is completed with PCR amplification and sample barcoding before pooling the samples into a library for sequencing. Analysis of the sequencing data is carried out automatically to report results. There is no use of laser capture or destruction of the tissue. The TempO-Seq processed slides can be archived and additional areas may be sampled at a later date. In this study, we sample replicate areas of matched normal vs. cancerous tissue, measuring gene biomarkers of clinical utility, gene fusions, and SNPs. We present gene expression profiles for replicate areas of pure stroma, single normal glands, single high-grade PIN glands, and single cancerous glands from prostate FFPE, demonstrating the statistical power of the TempO-Seq in situ assay as well as the correlation to focal histology and the use of focal differential expression to elucidate molecular pathways involved in the transition from normal tissue to cancer. We report measurements of clinically relevant biomarkers and signatures from clinical FFPE samples, plus therapeutic targets and drug resistance genes. This new approach demonstrates that complex molecular tests can be carried out by any pathologist in their own lab, and makes moot the issues of “% cancer” and amount of tissue required for testing. The approach we present brings extraction-free complex molecular testing of FFPE into the pathology lab and takes molecular pathology to a new level of simplicity, focal precision and correlation to morphology. Citation Format: Elliot Imler, Milos Babic, Deanna Adams, Peter Shepard, Joanne Yeakley, Raymond B. Nagle, Bruce Seligmann. Focal gene expression profiling of counterstained FFPE with correlation to morphology using TempO-Seq [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 2106.
Abstract 16022: Failed Defibrillation Shocks Change Activation Patterns Following Prolonged but Not Short Duration Ventricular Fibrillation
Authors: Li Li, Jian Huang, Nuttanont Panitchob, Raymond E Ideker, Derek J Dosdall
Journal: Circulation (2016)

Introduction: Recent studies have demonstrated that as ventricular fibrillation (VF) persists past the first 1-2 minutes, 3 distinct patterns of activity can be present subendocardially: chaotic, r...