tbuckley/cabot-search huggingface dataset:
Abstract P2-02-02: A review of the accuracy of wire localisation using digital breast tomosynthesis (DBT) in a prospective series of 81 patients
Authors: Simon DH Holt, Khaldoun MY Nadi, Amrita Gurung, Helen R Williams, Anita M Huws, Yousef M Sharaiha
Journal: Cancer Research (2015)

Abstract Introduction: Digital breast tomosynthesis allows identification of impalpable lesions in three-dimensions. We have devised a technique for wire placement using a gridded plate that allows localisation of such lesions for subsequent surgical excision. Method: 81 consecutive cases were studied prospectively between Jan 2012 and May 2014. The localisation is usually performed by the operating surgeon under local anaesthetic shortly before the patient is transferred to the operating theatres. Our surgeons consider the optimal position for the tip of the wire to be 1 cm beyond and 1cm to the side of the lesion placed using only the CC or lateral projection. The patient is positioned with the aperture of a gridded plate over the lesion needing to be surgically removed. A single DBT is acquired and the volumes reviewed. The lesion is identified and the depth in the breast recorded (Z coordinate). The ideal position for the wire is then marked in that plane and the volume scrolled through to bring the calibrated plate into focus. This identifies the X and Y coordinates, which are then recorded. The wire is then placed freehand in the line of the beam and a further DBT performed to check the position of the wire without needing to reposition the patient. A specimen x-ray is performed immediately following excision to confirm the target lesion is included. The results are verified at the subsequent multidisciplinary team (MDT) meeting. Results: Once the target is identified, the average time for the localisation procedure and check DBT was 4 minutes. This series included both diagnostic (N=24, 30%) and therapeutic excisions (N=57, 70%). Patients presented both from screening (N=64, 79%) and symptomatically (N=17, 21%). The age range of the patients was 42-79y (mean 59y). 54 (67%) cases were undergoing excision for calcifications, 15 (19%) for impalpable masses, 11 (13%) for radial scars or distortions and 1 for glandular asymmetry. The final diagnoses following excision were IDC 34 (42%), DCIS 29 (36%), benign 13 (16%) and 1 case each of ILC, spindle cell tumour, mucinous carcinoma, phyllodes and pleomorphic LCIS. In all cases the target lesion was shown to be present in the specimen x-ray, confirmed on histology and ratified by the MDT. Conclusions: Wire localisation using DBT is a quick and accurate method of localising impalpable lesions for surgical excision. Citation Format: Simon DH Holt, Khaldoun MY Nadi, Amrita Gurung, Helen R Williams, Anita M Huws, Yousef M Sharaiha. A review of the accuracy of wire localisation using digital breast tomosynthesis (DBT) in a prospective series of 81 patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-02-02.
Combined Phosphoepitope Specific Flow Cytometry and MHC-Multimer Staining - A New Tool to Monitor Antigen-Specific Signaling in CMV-Specific T-Cells.
Authors: Markus Kapp, Rainer Thiele, Elke Baumeister, Kerstin Fick, Gernot Stuhler, Andreas Opitz, Hermann Einsele, Götz Ulrich Grigoleit
Journal: Blood (2009)
Outpatient Treatment In Patients with Acute Pulmonary Embolism: The Hestia Study
Authors: Wendy Zondag, Inge Mos, Dina Creemers, Lidia Hoogerbrugge, Olaf Dekkers, Anneke Dolsma, Michiel Eijsvogel, Laura Faber, Herman MA Hofstee, Marcel Hovens, Ge Jonkers, Klaas Kralingen, Marieke Kruip, Tom Vlasveld, Marielle Vreede, Menno Huisman
Journal: Blood (2010)
Abstract 4162: Interleukin–6 stimulates defective angiogenesis
Authors: Ganga Gopinathan, Carla Milagre, Oliver M.T Pearce, Louise Reynolds, Kairbaan Hodivala-Dilke, Andrew Leinster, Haihong Zhong, Robert E. Hollingsworth, Richard Thompson, James R. Whiteford, Frances Balkwill
Journal: Cancer Research (2015)

Abstract The aim of this study was to investigate the effects of IL-6 in normal and tumour angiogenesis. In previous studies we found that elevated levels of the inflammatory cytokine interleukin-6, IL-6, were linked with poor prognosis in ovarian cancer patients by influencing tumour growth, invasion, angiogenesis and chemo-resistance. A clinical trial conducted in parallel with pre-clinical studies showed an anti-IL-6 antibody to have some activity in ovarian cancer patients and in xenograft models, with systemic and local reduction in pro-inflammatory and angiogenic factors such as TNF, IL-8 and VEGF. IL-6 directly induced vessel sprouting in the ex vivo aortic ring model, as well as stimulated endothelial cell proliferation and migration, with similar potency to VEGF. However, IL-6 itself did not induce VEGF in the endothelial cells tested. In contrast to VEGF, IL-6-stimulated aortic ring vessel sprouts had defective pericyte coverage. The mechanism of the IL-6 action on pericytes involved stimulation of the Notch ligand Jagged1 as well as Angiopoietin 2. When peritoneal ovarian cancer xenografts were treated with an anti-IL-6 antibody, pericyte coverage of vessels was restored. In addition, in human ovarian cancer biopsies there was an association between levels of IL-6mRNA, Jagged1 and Angiopoeitin2. Our findings have implications for the use of cancer therapies that target VEGF or IL-6 and for understanding abnormal angiogenesis in cancers, chronic inflammatory disease and stroke. Citation Format: Ganga Gopinathan, Carla Milagre, Oliver M.T Pearce, Louise Reynolds, Kairbaan Hodivala-Dilke, Andrew Leinster, Haihong Zhong, Robert E. Hollingsworth, Richard Thompson, James R. Whiteford, Frances Balkwill. Interleukin–6 stimulates defective angiogenesis. [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 4162. doi:10.1158/1538-7445.AM2015-4162
Outcome of Pediatric-Type Therapy for Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA): A Study by the Japan Adult Leukemia Study Group (JALSG ALL202-U study)
Authors: Toru Sakura, Fumihiko Hayakawa, Toshiaki Yujiri, Yasutaka Aoyama, Eisei Kondo, Katsumichi Fujimaki, Yasunori Ueda, Shigeki Ohtake, Yasushi Miyazaki, Shuichi Miyawaki, Kazunori Ohnishi, Tomoki Naoe
Journal: Blood (2012)
Abstract 355: In Vivo Targeting Of GTF2B Selectively Inhibits Transcription Of Cardiomyopathy-related Genes And Partially Blunts Development Of Cardiac Hypertrophy
Authors: Danish Sayed, Zhi Yang, Minzhen He, Maha Abdellatif
Journal: Circulation Research (2013)

Transcriptional profiling of cardiac genome during hypertrophy identified two categories of genes with distinct modes of regulation. The first set of genes involved in the cells essential functions (e.g. RNA splicing) and whose transcription is expected to be incremental and contribute to the increasing cardiac mass is regulated by promoter clearance of RNA polymerase II (pol II). On the other hand, the second set that include genes with specialized function and show a robust increase in expression upon growth stimulus (cytoskeletal, extracellular matrix) are regulated by de novo pol II recruitment to promoters. Our goal was to identify the transcriptional mechanisms that distinguish these two sets of genes and then to selectively inhibit those that participate in contractile dysfunction, while preserving the expression of genes necessary for essential functions. General Transcription factor IIB (GTF2B), is one of the essential components of transcription machinery and is required for pol II recruitment. Thus, we hypothesized that inhibition of GTF2B would result in inhibition of only the specialized genes, sparing the essential genes. Our in vitro results with shRNA mediated inhibition of GTF2B in hypertrophying neonatal myocytes showed decreased expression of genes that required de novo pol II recruitment for transcription (eg. ACTA1), while no change was observed in the genes regulated by promoter clearance of pol II (Vdac1). Similarly, preliminary results with in vivo knockdown of GTF2B (~80% reduction in mRNA and ~36% in protein) via intravenous injection of modified antisense oligo in mice subjected to transaortic coarctation (TAC) showed inhibition of only cardiomyopathy-related genes that require pol II recruitment (ANF), while expression of essential genes (Vdac1) remained unchanged. Inhibition of GTF2B restricted increase in TAC-induced heart wt to 9%, compared to 29% in TAC hearts with control oligo. Echocardiography showed partial normalization of ejection fraction with GTF2B inhibitor during TAC from 61.5% to 66.4% compared to sham hearts with 71%. Thus, we conclude that by targeting GTF2B we can selectively restrict the expression of detrimental genes during hypertrophy, thereby delaying the onset of cardiac dysfunction and failure
Frontline Autologous Stem Cell Transplantation As Intensive Consolidation in Patients with Peripheral T Cell Lymphomas: Multicenter Phase II Trial in Korea
Authors: Jae-Sook Ahn, Deok-Hwan Yang, Yee Soo Chae, Sang Kyun Sohn, Jae-Yong Kwak, Ho-Young Yhim, Se-Ryeon Lee, Sung-Hoon Jung, Soo-Young Bae, Yeo-Kyeoung Kim, Hyeoung-Joon Kim, Je-Jung Lee
Journal: Blood (2011)
Nitric Oxide (NO) induced sensitization of tumor cells to TRAIL-mediated apoptosis via induction of RKIP and DR5 expression and inhibition of YY1
Authors: Stavroula Baritaki, Alina Katsman, Amy Wu, Sara Huerta-Yepez, Kam Yeung, Demetrios Spandidos, Benjamin Bonavida
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4868 

We have recently reported that the induction of NO or the use of NO donors can reverse tumor cell resistance to death ligands via inhibition of NF-κB and the transcription repressor Yin Yang 1 (YY1) activities and upregulation of death receptors (Baritaki et al., 2007). The underlying molecular mechanisms of these NO-induced effects are not well defined. The metastatic suppressor gene Raf kinase inhibitor protein (RKIP), has been reported to inhibit NF-κB activity (Yeung et al., 1999,2000). Therefore, we hypothesized that NO may induce RKIP expression leading to inhibition of NF-κB and YY1 and upregulation of DR5, leading to sensitization to TRAIL-induced apoptosis. The involvement of RKIP and its interplay with YY1 and DR5 in the NO-induced sensitization to TRAIL was investigated using the resistant prostate tumor cells PC3 and the Non-Hodgkin’s lymphoma cell line Ramos. Treatment of tumor cells with the NO donor DETA/NONOate (1000 uM) resulted in significant sensitization to TRAIL-induced apoptosis and concomitantly induction of RKIP mRNA and protein levels. In contrast, YY1 promoter activity and YY1 expression (both in transcript and protein levels) were significantly reduced after DETA/NONOate treatment. Since we have recently shown that YY1 negatively regulates DR5 transcription and expression, tumor treatment with DETA/NONOate also resulted in upregulation of DR5. The role of YY1 in the regulation of DR5 and sensitization to TRAIL was corroborated by the use of YY1 siRNA which resulted in sensitivity to TRAIL. The direct role of RKIP in the NO-based tumor cell sensitization to TRAIL was confirmed by significant inhibition of NO-induced cell sensitization to TRAIL following treatment of tumor cells with RKIP siRNA. The above findings provide evidence that NO-induced sensitization to TRAIL is mediated, in large part, via induction of RKIP expression and subsequently, inhibition of NF-κB and YY1 activities and upregulation of DR5 expression. Preliminary findings in tissues nude mice bearing PC3 tumor xenografts and treated with DETA/NONOate showed upregulation of DR5 expression and inhibition of YY1 by IHC. These findings suggest that for successful anti-cancer immunotherapeutic approaches there is a need to use sensitizing agents that can upregulate RKIP/DR5 or inhibit NF-κB/YY1. Such sensitizing agents, like NO donors, may reverse TRAIL-resistance when used in combination with TRAIL/anti-DR4 or DR5 monoclonal antibodies.
Abstract 2334: Disruption of TGF-β-regulated CTCF suppression of telomerase links a human stem cell disorder to tumorigenesis
Authors: Jian Chen, Jiun-Sheng Chen, Zhixing Yao, Wilma Jogunoori, Bibhuti Mishra, Franklin H. Herlong, Yun Seong Jeong, Nipun A. Mistry, Jianping Zhang, Xiaoping Su, Asif Rashid, Marta Davila, John R. Stroehlein, Jerry W. Shay, Lopa Mishra
Journal: Cancer Research (2015)

Abstract Background: Beckwith-Wiedemann syndrome (BWS) is a human stem cell disorder with a prevalence of 1 in 14,000. Its clinical manifestations include an 800-fold increased risk of tumorigenesis; yet the precise mechanism of BWS-associated tumorigenesis remains elusive. In a previous study, we showed that epigenetic silencing of β2-spectrin (β2SP, gene SPTBN1), a cytoskeletal protein and a Smad adaptor for Transforming Growth Factor-beta (TGF-β) signaling, was a causal factor in BWS. To determine the mechanism for the oncogenic switch, and whether it is related to the role of β2SP in TGF-β signaling transduction or secondary to its cytoskeletal functions, we analyzed disruption of two elements of the TGF-β pathway by generating double heterozygous Sptbn1+/−/Smad3+/− mice. Materials &amp; Methods: Tumorigenesis analysis in Sptbn1+/− /Smad3+/− mice. Whole-transcriptome sequencing and IPA analyses were performed in the BWS cells and Sptbn1+/−; Sptbn1−/−; Smad3+/−; and Sptbn1+/−/Smad3+/− MEFs. Immunohistochemical analyses were performed for determining the expression of TERT in BWS tumors and mice liver, pancreas and stomach tissue specimens. ChIP assays were performed for examining the recruitment of β2SP/Smad3/CTCF complex at the promoter of TERT. Results: (1) 80% of Sptbn1+/−/Smad3+/− mice developed multiple tumors that were phenotypically similar to those of patients with BWS. (2) Somatic mutations in SPTBN1 and SMAD3 occur in multiple human sporadic cancers. (3) Disruption of the TGF-β pathway in Sptbn1+/−/Smad3+/− mice and BWS cells. (4) β2SP Interacts with SMAD3 in a TGF-β-dependent manner. (5) β2SP and SMAD3 interact with CTCF in the cell nucleus. (6) Dysfunction of the β2SP/SMAD3/CTCF complex increases hTERT levels in BWS and in β2SP+/-/Smad3+/- mice. Conclusions: We present a novel model of the molecular pathogenesis of BWS by demonstrating a potential shift arising from disruption of TGF-β signaling leading to BWS-associated tumorigenesis and human sporadic cancer development. Citation Format: Jian Chen, Jiun-Sheng Chen, Zhixing Yao, Wilma Jogunoori, Bibhuti Mishra, Franklin H. Herlong, Yun Seong Jeong, Nipun A. Mistry, Jianping Zhang, Xiaoping Su, Asif Rashid, Marta Davila, John R. Stroehlein, Jerry W. Shay, Lopa Mishra. Disruption of TGF-β-regulated CTCF suppression of telomerase links a human stem cell disorder to tumorigenesis. [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 2334. doi:10.1158/1538-7445.AM2015-2334
An engineered anti-CA19-9 cys-diabody for PET imaging of pancreas cancer and targeting of polymerized liposomal nanoparticles.
Authors: M. D. Girgis, K. McCabe, T. Olafsen, F. Bergara, V. Kenanova, N. Federman, A. Wu, J. S. Tomlinson
Journal: Journal of Clinical Oncology (2011)

198 Background: Antibody-based therapeutics is a rapidly growing field. Small engineered antibody fragments, such as the cys-diabody demonstrate similar antigen affinity compared to the parental antibody but have a shorter serum half-life (4hrs) and possess the ability to be conjugated to nanoparticles. Our goal was to engineer an anti-CA19-9 cys-diabody fragment in hopes of imaging and targeting pancreatic cancer. Methods: The anti-CA19-9 cys-diabody was created by cloning the variable region of the parental antibody, engineering a C-terminus cysteine, expressing in NS0 cells followed by protein purification utilizing HPLC. Maleimide chemistry was used to conjugate the cys-diabody to PLNs through the engineered cysteine residues. Immunofluorescence and flow cytometry were used to evaluate targeting of cys-diabody and diabody conjugated PLNs to human pancreatic cancer cell lines. The cys-diabody was evaluated in a mouse xenograft model harboring CA19-9 positive (BxPC3) and negative (MiaPaca) tumors. The cys-diabody was radiolabeled with a positron emitter (I-124) and microPET/CT were performed after tail vein injection. Percent of injected dose per gram (%ID/g) of radioactivity was measured in blood and tumor to provide objective confirmation of the microPET images. Results: Immunofluorescence and flow cytometry showed specific binding of the anti-CA19-9 cys- diabody. Tumor xenograft imaging of the anti-CA19-9 cys-diabody demonstrated an average tumor:blood (%ID/g) ratio of 3.3 and positive:negative tumor ratio of 7.4. Successful conjugation of the cys-diabody to PLNs was indicated by immunofluorescence showing specific targeting of PLN-cys- diabody conjugate to human pancreatic cancer cells in vitro. Conclusions: Our results show that the anti-CA19.9 cys- diabody targets pancreatic cancer providing specific molecular imaging in tumor xenograft models. Furthermore, the PLN-cys-diabody conjugate targets human pancreatic cancer cells with the potential to deliver targeted treatment. Further studies evaluating the in vivo ability of the PLN-cys-diabody conjugate to target pancreatic cancer need to be performed. No significant financial relationships to disclose.
Abstract IA39: The genetic basis of diffuse large B cell lymphoma.
Authors: Laura Pasqualucci
Journal: Clinical Cancer Research (2015)

Abstract Diffuse large B cell lymphoma (DLBCL), the most common form of human lymphoma, is a heterogeneous neoplasm comprising multiple genetic, phenotypic and clinical subtypes, approximately 50% of which are incurable. These tumors may arise de novo or from the transformation of more indolent lymphomas, as observed in 30-40% of follicular lymphoma (FL) cases. Over the past decade, the introduction of next-generation sequencing technologies combined with genome-wide copy number analysis has allowed to comprehensively define the genomic landscape of this disease, leading to the identification of multiple genes and signaling pathways that are dysregulated by genetic lesions and represent potential targets for diagnosis and therapy. In addition to perturbations in the transcriptional control of apoptosis, differentiation and DNA damage responses or NF-κB activation, these efforts revealed the frequent targeting of genes implicated in chromatin remodeling and immune recognition/surveillance. In particular, one of the most commonly disrupted programs in both de novo DLBCL, FL and transformed FL (tFL) comprises genes encoding histone/chromatin modifying enzymes, including methyltransferases (MLL2, EZH2) and acetyltransferases (CREBBP, EP300), which may play a central role during malignant transformation. Interestingly, sequential analysis of tumor samples during transformation of FL to tFL indicates that inactivating mutations of CREBBP and MLL2 are acquired early in the evolutionary history of a common mutated ancestral clone. The disruption of these genes by genetic alterations may thus contribute to malignant transformation by shaping the epigenetic landscape of the cancer cell as well as by perturbing specific biological programs, in part through the altered balance between acetylation-mediated activation of the p53 tumor suppressor and inactivation of the BCL6 proto-oncogene. This talk will cover recent advances in understanding the genetic basis of DLBCL, as revealed by in vitro and in vivo studies. Citation Format: Laura Pasqualucci. The genetic basis of diffuse large B cell lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA39.
569. Precision Editing of the WAS Locus via Homologous Recombination in Primary Human Hematopoietic Cells Mediated by Either TALEN or CRISPR/Cas Nucleases
Authors: Iram F. Khan, Yupeng Wang, Courtnee Clough, Swati Singh, King Hung, David J. Rawlings
Journal: Molecular Therapy (2016)

Wiskott-Aldrich Syndrome (WAS) is an inherited primary immunodeficiency caused by mutations in the WAS gene which encodes a protein (WASp) that regulates the actin cytoskeleton in multiple hematopoietic cell lineages. Currently, allogeneic stem cell transplantation constitutes the only available cure for WAS, although phase I/II clinical trials using lentiviral gene therapy of autologous stem cells are currently underway and have shown improvement in immune system defects. Although effective, the gene therapy approach carries a risk of insertional mutagenesis, and unpredictable expression due to promoter choice as well as influences of the random integration site, including epigenetic status and the presence of neighboring transcription regulatory elements. As a refinement, our goal is to develop gene editing methodologies that would allow the specific targeting of a WASp cDNA to a position within the WAS locus allowing transcriptional regulation by the endogenous WAS promoter. To this end, we first designed and tested the cleavage efficiency of several guide RNAs (delivered as self-complementary AAV along with Cas9, delivered as mRNA), as well as candidate TALEN pairs (delivered as mRNAs), in primary human T cells. Using the T7 endonuclease assay, we identified candidate nucleases from both platforms (CRISPR/Cas9 and TALEN) that achieved a high Indel frequency: 73 and 85%, respectively. We next created a synthetic AAV6 donor template for homology-directed repair (HDR) that contained an MND promoter driven GFP cDNA with 1kb of WAS homology arms flanking it. When delivered with the TALEN or CRISPR/Cas9 nucleases, we observed stable integration of the GFP reporter within >25% of primary human T cells. Subsequently, we utilzed the identical reagents to target integration of the reporter cDNA into the WAS locus in adult human mobilized CD34+ cells, albeit at lower efficiencies. The off-target cleavage sites for TALENs identified using the Prognos software were amplified and sequenced, with no evidence of off-target cleavage observed at any of the predicted loci. Thus, we have generated genome editing tools that possess a high degree of specificity, providing the foundation for site-specific modification of the WAS locus as a therapeutic option.