tbuckley/cabot-search huggingface dataset:
Abstract 1496: Quantification of tumor blood perfusion of an orthotopic mouse model of neuroblastoma using nonlinear contrast-enhanced ultrasound imaging
Authors: Suresh Thiagarajan, Abbas Shirinifard, Megan O. Jacus, Abigail D. Davis, Yogesh T. Patel, Stacy L. Throm, Vinay Daryani, Clinton F. Stewart, András Sablauer
Journal: Cancer Research (2015)

Abstract This study quantifies tumor perfusion in individual tumors to estimate blood flow and blood volume parameters of an individualized tumor compartment of a comprehensive physiologically-based pharmacokinetic model of topotecan using an orthotopic xenograft model of pediatric neuroblastoma. We non-invasively imaged perfusion in orthotopic neuroblastoma (NB5) xenograft tumors (n = 3 CD1 nude mice/time point) using nonlinear contrast enhanced ultrasound technique (CEUS). Tumor tissue and organs from the mice were harvested at predefined time-points. We used a programmable syringe pump to inject MicroMarker® microbubbles via tail vein catheter and acquired images using VisualSonics VEVO 2100 imaging system. We used the burst-replenishment technique to image tumor perfusion, which requires a constant concentration of microbubbles in blood during acquisition. To maintain a steady concentration of microbubbles, we programmed the pump to inject a small bolus followed by constant infusion. Our preliminary analysis showed that healthy kidneys rapidly reach a steady state in less than 1 min, significantly shorter than the commonly used constant infusion without an initial bolus. The nonlinear CEUS signal intensities of kidney cortex showed less than 20% variation between mice. We used a custom program to acquire the CEUS perfusion images over a 3D volume that included the tumor and a kidney. We used the kidney as a reference organ to normalize whole tumor perfusion data. We fitted the log-normal perfusion model to estimate perfusion parameters for individual tumors. Our perfusion quantification over the entire tumor volume represents tumor perfusion more accurately than the commonly used methods based on a single 2D plane without a reference organ. Our approach provides population estimates of blood perfusion based on properly normalized estimates of individual blood perfusion parameters. Citation Format: Suresh Thiagarajan, Abbas Shirinifard, Megan O. Jacus, Abigail D. Davis, Yogesh T. Patel, Stacy L. Throm, Vinay Daryani, Clinton F. Stewart, András Sablauer. Quantification of tumor blood perfusion of an orthotopic mouse model of neuroblastoma using nonlinear contrast-enhanced ultrasound imaging. [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 1496. doi:10.1158/1538-7445.AM2015-1496
Abstract 4474: Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy
Authors: Hua Lu, Qi Zhang, Shelya X. Zeng, Rui-Zhi Wu, Yiwei Zhang, Daniel Nguyen, Xiang Zhou, Jun-ming Liao, Bo Cao
Journal: Cancer Research (2015)

Abstract The “ribosomal stress (RS)-p53 pathway” is triggered by any stressor or genetic alteration that disrupts ribosomal biogenesis, and mediated by several ribosomal proteins (RPs), such as RPL11 and RPL5, which inhibit MDM2 and activate p53. IMPDH2 is a rate-limiting enzyme in de novo guanine nucleotide biosynthesis and crucial for maintaining cellular guanine deoxy- and ribonucleotide pools needed for DNA and RNA synthesis. It is highly expressed in many malignancies. We previously showed that inhibition of IMPDH2 leads to p53 activation by causing RS. Surprisingly, our current study reveals that Inauzhin (INZ), a novel non-genotoxic p53 activator by inhibiting SIRT1, can also inhibit cellular IMPDH2 activity, and reduce the levels of cellular GTP and GTP-binding nucleostemin that is essential for rRNA processing. Consequently, INZ induces RS and the RPL11/RPL5-MDM2 interaction, activating p53. These results support the new notion that INZ suppresses cancer cell growth by dually targeting SIRT1 and IMPDH2. Note: This abstract was not presented at the meeting. Citation Format: Hua Lu, Qi Zhang, Shelya X. Zeng, Rui-Zhi Wu, Yiwei Zhang, Daniel Nguyen, Xiang Zhou, Jun-ming Liao, Bo Cao. Dual targeting of the stress-p53 pathway as a potential anti-cancer therapy. [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 4474. doi:10.1158/1538-7445.AM2015-4474
A Novel Heterozygous Point Mutation Causing Coagulation Factor XII Deficiency as the Molecular Mechanism of Fatal Thrombosis Event in a Chinese Pedigree.
Authors: Ying Feng, Ye Xu, Ying Pang, Jing Dai, Wei Xie, Xuhong Zhou, Qiulan Ding, Xuefeng Wang
Journal: Blood (2006)
Abstract 4931: A circulating cell free DNA workflow for targeted sequencing - from isolation through validation
Authors: Dalia Dhingra, Xingwang Fang, Matt Carter, Dumitru Brinza, Charles Scafe, Christopher Davies, Fiona Hyland
Journal: Cancer Research (2015)

Abstract Circulating cell free DNA has been shown to have the potential as a non-invasive substrate for the detection of cancer and its progression as well as the determination of therapeutic resistance. As circulating tumor DNA is often present at low frequencies within circulating cell free DNA, targeted sequencing is an optimal tool for mutation detection. Here, we demonstrate a complete workflow from isolation through validation of circulating tumor DNA. We have optimized a protocol using magnetic beads to isolate circulating cell free DNA. This protocol is easily automated to process up to 192 samples a day. It is also easily scalable for any input volume and can elute in volumes down to 15 μL resulting in no loss of low frequency alleles. We demonstrate comparable performance between this bead based isolation and column based isolation. We then completed molecular characterization of the isolated circulating cell free DNA using the multiplexing capabilities of AmpliSeq™ and the Ion PGM™. With the Ion AmpliSeq™ Cancer Hotspot Panel v2, we performed targeted sequencing of 50 genes of interest, covering 2800 COSMIC mutations. We demonstrate good reproducibility of amplicon representation as well as allelic frequencies. Through saturation studies and subsampling, we have determined the limit of detection of hotspots circulating cell free DNA on the Ion PGM™ to be below 1%. We further demonstrate proof of principle of this workflow on circulating cell free DNA and matched FFPE samples complete with TaqMan® validation. Our results validate the accuracy and ease of our workflow. This protocol, from isolation through targeted sequencing and validation, will not only result in a simple sample preparation for circulating cell free DNA but also facilitate rapid mutation detection to advance cancer research. Citation Format: Dalia Dhingra, Xingwang Fang, Matt Carter, Dumitru Brinza, Charles Scafe, Christopher Davies, Fiona Hyland. A circulating cell free DNA workflow for targeted sequencing - from isolation through validation. [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 4931. doi:10.1158/1538-7445.AM2015-4931
Phase II study of everolimus in combination with octreotide LAR as first line setting for patients with neuroendocrine tumors (I.T.M.O. study): a 5-years update
Authors: E. Bajetta, L. Catena, S. Pusceddu, N. Fazio, G. Blanco, S. Ricci, M. Aieta, F. Pucci, I. Sarno, F. Spada, G. Di Menna, L. Dottorini
Journal: Annals of Oncology (2015)
Abstract 2215: Transcriptional co-regulation of Nox4 by p53 and SMAD3
Authors: Howard E. Boudreau, Jonathan J. Park, Thomas L. Leto
Journal: Cancer Research (2015)

Abstract Recent studies suggest p53 plays an important role in TGF-beta-mediated cell signaling and migration. Previously, we showed that wild-type (WT) and mutant forms of p53 differentially regulate reactive oxygen species (ROS) generation by NADPH oxidase-4 (Nox4). We found that WT-p53 is a potent suppressor of TGF-beta-induced Nox4, ROS production, and cell migration, whereas tumor-associated mutant p53 proteins enhanced Nox4 mRNA and protein expression and cell migration by both TGF-beta-dependent and independent mechanisms (Boudreau et al. Br J Cancer. 2014 May 13;110(10):2569-82). In this study, we examined the basis of human Nox4 promoter regulation by p53 and SMAD3. By constructing a deletion series of Nox4 promoter-reporter constructs, we discovered two regions (-4.76kb to -3.9kb and -1.8kb to - 0.2kb) upstream of the transcription start site that induce promoter activity upon activation of the TGF-beta/SMAD3 pathway. Interestingly, TGF-beta/SMAD3-mediated Nox4 promoter activity was abolished by heterologous expression of p53-WT in p53-null cell lines Hep3B (hepatocytes) and H1299 (lung epithelial). This activity was repressed by wild-type p53 in a dose-dependent manner. In contrast, expression of common tumor-associated mutant-p53 proteins (R175H, R248H, R249Q, R273H) did not repress but enhanced Nox4 promoter activity. We observed this enhancement of Nox4 promoter activity by mutant p53 (R273H) in H1299 cells expressing T204D, a constitutively active TGF-beta receptor. When individual p53 response elements were mutated, however, both untreated and R273H-expressing cells showed 50% reduction in promoter activity. These results indicate that the Nox4 promoter region between -3.97kb and -4.76kb, containing candidate p53 response elements, plays a role in modulating Nox4 expression. Preliminary chromatin immunoprecipitation results suggest that endogenous mutant p53 R249S in PLC/PRF/5 hepatoma cells complexes with the Nox4 promoter region between -3.97kb and -4.76kb. Furthermore, constructs lacking this region show significantly reduced Nox4 promoter activity in response to TGF-beta. Our results provide a basis for Nox4 co-regulation by SMAD3 and mutant p53 that may be involved in tumor progression and metastasis. Citation Format: Howard E. Boudreau, Jonathan J. Park, Thomas L. Leto. Transcriptional co-regulation of Nox4 by p53 and SMAD3. [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 2215. doi:10.1158/1538-7445.AM2015-2215
Abstract 2289: A novel mouse model of endometrial cancer: epithelial specific <i>Pten</i> deletion with <i>lactoferrin-iCre</i>
Authors: Takiko Daikoku, Jumpei Terakawa, Sudhansu K. Dey
Journal: Cancer Research (2015)

Abstract Endometrial cancer is a common gynecological malignancy, causing approximately 8,000 deaths each year in the United States. Underlying causes of endometrial cancer are not clearly understood, and treatment options for patients with advanced stages are limited. Animal models that spontaneously develop cancer are powerful tools for studying the mechanism of cancer initiation and progression and for developing treatment strategies. We previously created a mouse model of endometrial cancer in which the floxed phosphatase and tensin homologue (Pten) gene was deleted by Cre expression under the control of a progesterone receptor (PR) promoter. Pten is a tumor suppressor with the highest frequency of mutation in human endometrial cancer. In the PtenloxP/loxP/PR-Cre mouse model, uterine deletion of Pten resulted in complex atypical hyperplasia of the uterine epithelium by three weeks of age with cancer occurring by one month. As PR is expressed in the epithelium, stroma, and myometrium compartments, the question remains whether Pten deletion in the uterine epithelium alone contributes to endometrial cancer since human endometrial cancer is derived from epithelial cells. To address this question, we used lactoferrin-iCre (Ltf-Cre) mice to specifically delete Pten in the uterine epithelium, since lactoferrin is restricted to the epithelium of adult mice. We found that PtenloxP/loxP/Ltf-Cre mice develop complex atypical hyperplasia in uterine epithelium by three months of age, whereas uteri from immature mice are normal. These results demonstrate that Pten deletion specifically in the uterine epithelium can contribute to toward endometrial cancer in mice. This mouse model will help us to study in detail the initiation and progression of endometrial cancer. This study was supported in parts by grants from NIH-P01-CA-77839 (S. K. D). Citation Format: Takiko Daikoku, Jumpei Terakawa, Sudhansu K. Dey. A novel mouse model of endometrial cancer: epithelial specific Pten deletion with lactoferrin-iCre. [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 2289. doi:10.1158/1538-7445.AM2015-2289
Autologous Gamma-Delta T (GD-T) Cells in Acute Myeloid Leukemia (AML): Potential Immune Effector Cells for Minimal Disease?.
Authors: Joerg M. Aswald, Xing-Hua Wang, Sandra Aswald, Loralyn A. Benoit, Mark Minden, Hans A. Messner, Armand Keating
Journal: Blood (2004)
Optimization of the HA-1-Specific T Cell Receptor for Gene Therapy of Hematological Malignancies.
Authors: Marleen M van Loenen, Renate S. Hagedoorn, Renate de Boer, Esther M. van Egmond, Roelof Willemze, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk
Journal: Blood (2009)
Comparable Outcome after Allogeneic Hematopoietic Cell Transplantation from Matched Unrelated and Sibling Donors in Elderly Patients with Acute Myeloid Leukemia - Results of a Retrospective Analysis in 368 Patients.
Authors: Johannes Schetelig, Martin Bornhäuser, Christoph Schmid, Bernd Hertenstein, Rainer Schwerdtfeger, Hans Martin, Matthias Stelljes, Ute Hegenbart, Kerstin Schäfer-Eckart, Monika Füssel, Beate Wiedemann, Christian Thiede, Herrad Baurmann, Arnold Ganser, Hans-Jochem Kolb, Gerhard Ehninger
Journal: Blood (2007)
Predictive and prognostic value of gender in early-stage colon cancer: A pooled analysis of 33,345 patients from the ACCENT database.
Authors: W. Y. Cheung, Q. Shi, M. O'Connell, J. Cassidy, C. D. Blanke, D. J. Kerr, E. Van Cutsem, S. R. Alberts, G. A. Yothers, D. J. Sargent
Journal: Journal of Clinical Oncology (2011)

3619 Background: While gender has been shown to be a predictive and prognostic factor in certain cancers, data for colon cancer (CC) are conflicting, with prior studies mainly focusing on 5-fluorouracil (5-FU) alone. To clarify the influence of gender on CC outcomes, our aims were to 1) compare outcomes between men and women in a large cohort of patients (pts) with early stage disease and 2) describe whether the effect of gender varies based on age, stage, time period and type of adjuvant therapy received. Methods: A pooled, retrospective analysis of individual data from 33,345 CC pts enrolled in 24 trials of various adjuvant systemic therapies was conducted. Chemotherapy consisted of 1) 5-FU, 2) 5-FU variations, 3) oxaliplatin, 4) irinotecan, or 5) oral-based regimens. The primary endpoint was disease-free survival (DFS); secondary endpoints included overall survival (OS) and time to recurrence (TTR). Cox proportional hazard models and interaction analyses were used to explore the effect of gender on outcomes. Results: We included 18,245 men and 15,100 women. Baseline characteristics were comparable between genders: median age was 61 years; 91% were White; 31% and 69% had stage II and III disease, respectively, in the entire cohort. Overall, men had inferior prognoses when compared to women for all endpoints, even after adjusting for age, stage and treatment (Table). Gender was not a predictive factor of treatment efficacy (interaction p for gender and treatment = 0.39, 0.61 and 0.78 for DFS, OS and TTR, respectively). In exploratory analyses, worse outcomes in men were more prominent in the older subset (HR 1.08 in age≤65 vs. 1.19 in age>65, interaction p=0.006 for DFS and HR 1.11 in age≤65 vs. 1.19 in age>65, interaction p=0.02 for OS). Stage of disease, study time period and type of adjuvant regimen did not modify the prognostic value of gender. Conclusions: Gender is a modest independent prognostic marker in early stage CC, particularly in older pts. Prognostic value of gender. Outcome Gender Hazard ratio (95% CI) 5-year outcome rate P value DFS Women 1.0 64.7% <0.001 Men 1.12 (1.08-1.16) 62.2% OS Women 1.0 72.7% <0.001 Men 1.13 (1.09-1.18) 70.3% TTR Women 1.0 67.4% <0.001 Men 1.06 (1.02-1.09) 66.2%
THROMBUS FORMATION AROUND AN ENDOCARDIAL PACEMAKER ELECTRODE : A SCANNING ELECTRON MICROSCOPIC STUDY AND ITS RELATIONSHIP TO ABNORMAL THRESHOLD ELEVATION
Authors: Keiichiro Katsumoto, Toyohiko Itoh, Tatsuru NIIBORl, Shogo Yamamoto, Hajime YAMAZAKl, Tatsuji Fujiwara, Tadashi Inoue
Journal: Circulation (1976)

The author experienced an abnormal increase in stimulation threshold in one patient to whom a permanent endocardial electrode was implanted according to the temporary-permanent technique, but could safely exchange the electrode at the fifth postoperative day before exit block would have occurred. Around the extracted electrode there was a thrombus which was considered to be the main causative factor of abnormally increased stimulation threshold. The morphology of the surface of the thrombus and surface of the electrode was examined using a scanning electron microscope, and the author found that the membranous thrombus which surrounded the neck of the lead had a very fine network of configuration with multilayers and that, though microscopically the electrode tip was clean and the metal was brilliant, there were scattered white masses strongly adhered to the surface of it. Thus in a case of rapid increase of stimulation threshold within a few days after implantation, it is advisable to withdraw the catheter and to implant another new one.
Comment on “A small-molecule antivirulence agent for treating <i>Clostridium difficile</i> infection”
Authors: Greg L. Beilhartz, John Tam, Zhifen Zhang, Roman A. Melnyk
Journal: Science Translational Medicine (2016)

New insights into the mechanism of action of ebselen, a small-molecule antivirulence agent that reduces disease pathology in a mouse model of Clostridium difficile infection, suggest a different molecular target may be responsible for its efficacy.
65. A Novel Aptamer Targeting Agent for Prostate Cancer
Authors: Bethany Powell Gray, Linsley Kelly, Matthew Levy, Bruce A. Sullenger
Journal: Molecular Therapy (2015)

Prostate cancer is both the most common cancer diagnosis and the second most common cause of cancer-related death for men in the United States. An optimal new therapy would selectively deliver the drug to the tumor while also preventing toxicity in normal tissue. Recent exciting clinical advances with antibody drug conjugates have resulted in FDA approval of such tumor-targeting therapies. However, antibodies are difficult to chemically modify and require humanization; additionally, their large size hinders tumor penetration. Aptamers have many advantages over traditional antibody targeting agents, including ease of synthesis and amenability to chemical modification. Moreover, they exhibit antibody-like target affinities and specificities at a fraction of the size, allowing more efficient tumor penetration. We have identified an aptamer, termed E3, which selectively internalizes into prostate cancer cells, but does not target normal cells. Additionally, E3 targets and internalizes into a variety of other cancer types, including breast, ovarian, lung, colon, melanoma, glioblastoma, liver, and leukemia cancers. Linking the E3 aptamer to a deimmunized version of the Pseudomonas exotoxin (PE-LR-8) kills prostate cancer cells in vitro with an IC50 of 0.4-1.1 nM while displaying no measured toxicity towards normal cells, and linking E3 to the highly toxic auristatin drugs, MMAE or MMAF, kills prostate cancer cells in vitro with an IC50 of 5-12 nM. Significantly, E3 maintains its tumor-targeting abilities in vivo, targeting both prostate tumors and patient-derived colon cancer tumors in mice as evidenced by near-infrared in vivo imaging. Together, these studies show the potential therapeutic benefit of E3 drug targeting for the treatment of prostate cancer.
Abstract 1713: IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis
Authors: Janani Panneerselvam, Jiankang Jin, Manish Shanker, Jason Lauderdale, Jonathan Bates, Qi Wang, Daniel Zhao, Stephen Archibald, Timothy Hubin, Rajagopal Ramesh
Journal: Cancer Research (2015)

Abstract Introduction The stromal cell derived factor (SDF)-1/chemokine receptor (CXCR)-4 signaling pathway plays a key role in lung cancer metastasis. Therefore, disrupting the SDF-1/CXCR4 signaling axis will reduce the incidence of lung metastasis. In the present study we investigated whether interleukin (IL)-24 can inhibit the SDF-1/CXCR4 axis and suppress lung cancer cell migration and invasion in vitro. Further, the efficacy of IL-24 in combination with CXCR4 antagonists was investigated. Methods Human H1299 lung tumor cell line was stably transfected with a tetracycline-inducible plasmid vector carrying the IL-24. Upon addition of doxycycline (Dox; 1μg/ml), cells were induced to express IL-24 protein. The expression levels of CXCR4 and its downstream molecular mechanisms in H1299 cells were analyzed. The inhibitory effect of IL-24 on SDF-1/CXCR4 axis is determined by RT-qPCR, western blot, luciferase reporter assay, flow-cytometry and immuno-cytochemistry and the consequence of its inhibition on cell migration, and invasion. Results Endogenous CXCR4 protein expression levels varied among four human lung cancer cell lines with H1299 cells showing the highest expression. Doxycycline-induced IL-24 expression in the H1299-IL-24 cell line resulted in reduced CXCR4 mRNA and protein expression. IL-24 post-transcriptionally regulated CXCR4 mRNA expression by decreasing the half-life of CXCR4 mRNA (&amp;gt;40%). Associated with CXCR4 inhibition was the reduced protein expression of pAKTS473, pmTORS2448, pPRAS40T246 and HIF-1α. IL-24 inhibited tumor cell migration and invasion both in the presence and absence of the CXCR4 agonist, SDF-1. However, the combinatorial effect of either IL-24 combined with CXCR4 inhibitors (AMD3100, SJA5) or with CXCR4 siRNA demonstrated enhanced inhibitory activity on tumor cell migration. Conclusions Our study results demonstrate that IL-24 inhibits lung tumor cell migration and invasion by disrupting the SDF-1/CXCR4 signaling pathway and exhibits enhanced anti-metastatic activity when combined with CXCR4 inhibitors. Citation Format: Janani Panneerselvam, Jiankang Jin, Manish Shanker, Jason Lauderdale, Jonathan Bates, Qi Wang, Daniel Zhao, Stephen Archibald, Timothy Hubin, Rajagopal Ramesh. IL-24 inhibits lung cancer cell migration and invasion by disrupting the SDF-1/CXCR4 signaling axis. [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 1713. doi:10.1158/1538-7445.AM2015-1713
Deferasirox Is the Only Iron Chelator Acting as a Potent NF-KB Inhibitor in Myelodysplastic Syndromes
Authors: Emanuela Messa, Ilaria Defilippi, Antonella Roetto, Francesca Messa, Francesca Arruga, Sonia Carturan, Valentina Rosso, Enrico Bracco, Daniela Cilloni, Giuseppe Saglio
Journal: Blood (2008)