bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4114: Trimeric G protein-CARMA1 axis links smoothened to NF-κB activation in diffuse large B-cell lymphoma.
Authors: Qu Changju , Liu Yadong , Kunkalla Kranthi , Singh Rajesh , Blonska Marzenna , Agarwal Nitin , Lin Xin , Vega Francisco 
Published: August 2014

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. Aberrant activation of Hedgehog (Hh) and NF-κB pathways is ubiquitously observed and known to mediate tumor growth, survival and chemo-resistance in DLBCL. Previously, we found that activation of Hh signaling is positively correlated with NF-κB pathway in DLBCL tumors and that modulating the activity of smoothened (SMO), the signal transducer subunit of Hh pathway, but not GLI1, transcriptional factor of Hh signaling, resulted in modulation of NF-kB pathway activation. Hereby, we investigate the molecular mechanisms that link SMO to NF-kB pathway. To elucidate whether there was interaction between G protein superfamily and SMO, we immunoprecipitated representative members of the Gα subfamilies (Gαi, Gα16, Gαq, Gαs and Gα12), and found that SMO was associated with Gαi, Gαq, and Gα12 in two DLBCL cell lines. Stimulation of SMO with Shh recombinant increased the recruitment of Gαi and Gα12 to SMO and also increased the GTPase activity of Gαi and Gα12. We also found that the activation of SMO with Shh in DLBCL cell lines was associated with increased total activity of PKC, phosphorylation of PKCβ1 and -2, and recruitment of CARMA1-MALT1-BCL10-TRAF6 to SMO receptor complex supporting that G proteins are involved in the transmission of the signal between SMO and NF-κB. Opposite results were seen when SMO was inhibited or silenced. As polyubiquitination of TRAF6 and NEMO (IKKγ) at lysine 63 (K63) are also important events in propagating NF-κB signaling, we examined the effect of SMO overexpression on K63-linked polyubiquitination of TRAF6 and NEMO. Transient overexpressing SMO resulted in increased polyubiquitination of TRAF6 and NEMO, supporting activation of both proteins by SMO. Moreover, functional inhibition of SMO (cyclopamine-KAAD) enhances the cytotoxic effect of NF-κB inhibitor (BAY-11-7082). Altogether, our study reveal a non-canonical Hh signaling pathway, in which SMO activates trimeric G proteins and CARMA1-associated signaling complex, leading to NF-κB activation. This signaling cascade contributes to the survival of DLBCL, and may serve as potential targets for combination therapies in DLBCL.
Citation Format: Changju Qu, Yadong Liu, Kranthi Kunkalla, Rajesh Singh, Marzenna Blonska, Nitin Agarwal, Xin Lin, Francisco Vega. Trimeric G protein-CARMA1 axis links smoothened to NF-κB activation in diffuse large B-cell lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4114. doi:10.1158/1538-7445.AM2013-4114
Abstract 413: Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer.
Authors: Kwon Chae Hwa , Shin Na Ri , Jeong Eun Hui , Choi Chang In , Moon Hyun Jung , Chu In Sun , Kim Gwang Ha , Jeon Tae Yong , Lee Jae Hyuk , Park Do Youn 
Published: August 2014

Abstract
Background: Epithelial-mesenchymal transition (EMT) plays a significant role in tumor progression and invasion. Snail is a known regulator of EMT in various malignant tumors. This study investigated the role of Snail in gastric cancer.
Methods: We examined the effects of silenced or overexpressed Snail using lenti-viral constructs in gastric cancer cells. Immunohistochemical analysis of tissue microarrays from 314 patients with gastric adenocarcinoma (GC) was used to determine Snail's clinicopathological and prognostic significance. Differential gene expression in 45 GC specimens with Snail overexpression was investigated using cDNA microarray analysis.
Results: Silencing of Snail by shRNA decreased invasion and migration in GC cell lines. Conversely, Snail overexpression increased invasion and migration of gastric cancer cells, in line with increased VEGF and MMP11. Snail overexpression (≥75% positive nuclear staining) was also significantly associated with tumor progression (P &lt; 0.001), lymph node metastases (P = 0.002), lymphovascular invasion (P = 0.002), and perineural invasion (P = 0.002) in the 314 GC patients, and with shorter survival (P = 0.023). cDNA microarray analysis revealed 213 differentially expressed genes in GC tissues with Snail overexpression, including genes related to metastasis and invasion.
Conclusion: Snail significantly affects invasiveness/migratory ability of GCs, and may also be used as a predictive biomarker for prognosis or aggressiveness of GCs.
Citation Format: Chae Hwa Kwon, Na Ri Shin, Eun Hui Jeong, Chang In Choi, Hyun Jung Moon, In Sun Chu, Gwang Ha Kim, Tae Yong Jeon, Jae Hyuk Lee, Do Youn Park. Overexpression of Snail is associated with lymph node metastasis and poor prognosis in patients with gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 413. doi:10.1158/1538-7445.AM2013-413
Abstract 4134: Development of MUT-MAP, a high-throughput multi-analyte mutation panel for cancer biomarkers discovery.
Authors: Tam Rachel Nga Wan , Schleifman Erica , Huw Ling-Yuh , Desai Rupal , Patel Rajesh , Raja Rajiv 
Published: August 2014

Abstract
Molecular profiling plays an increasingly vital role in determining treatment options in oncology. These include expression profiling, mutation detection as well as copy number variation analysis (CNV). Hence there is an increasing need for a robust and high-throughput technology to detect oncogenic hotspot mutations - and copy number variation (CNV) in various kinds of cancer. Although there are commercial assays or kits available to detect genetic aberrations in a given oncogene, there is a need to simultaneously detect these hotspots in more than a few of these genes using very little DNA. Recent technological advances such as next-generation sequencing (NGS) platforms are the powerful tools to unravel the complex biological and genetic mechanisms in different human diseases. However, there are several challenges facing NGS platforms, such as high cost, and DNA input requirement, and difficult data analysis pipeline which require much longer data turnaround time that is not feasible in the clinical setting.
We have developed a high-throughput microfluidic panel for detecting 120 somatic mutations across 11 genes of therapeutic interest using TaqMan or allele-specific PCR (AS-PCR) technologies. The 11-gene mutation panel is designed to detect hotspot mutations that have higher oncogenic potential. Additionally, we can detect (CNV) changes in a total of 18 genes. This mutation panel only requires as little as 2 ng of high quality (fresh frozen) or 100 ng of formalin-fixed, paraffin-embedded (FFPE) genomic DNA. A pre-amplification of 38 amplicons is carried out to enrich DNA carrying the targeted mutations, using custom-designed primer sets followed by detection of the mutations using TaqMan/AS-PCR assays carried out on a Biomark microfluidics system. Mutation, CNV calls including an automated data analysis process have been implemented to run 88 samples per day. We will present data showing validation of this platform using plasmids and archival samples, including correlation between amplified and unamplified samples on alternate mutation detection platforms that will demonstrate sensitivity and selectivity. The platform is being routinely used in our labs to analyze tissues from patients enrolled in clinical trials.
Citation Format: Rachel Nga Wan Tam, Erica Schleifman, Ling-Yuh Huw, Rupal Desai, Rajesh Patel, Rajiv Raja. Development of MUT-MAP, a high-throughput multi-analyte mutation panel for cancer biomarkers discovery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4134. doi:10.1158/1538-7445.AM2013-4134
Abstract 4138: Fluorescence laparoscopy with an LED light source enables fluorescence-guided resection of pancreatic cancer, labeled with fluorophore-conjugated antibodies, in mouse models.
Authors: Metildi Cristina A. , Kaushal Sharmeela , Luiken George A. , Talamini Mark A. , Hoffman Robert M. , Bouvet Michael 
Published: August 2014

Abstract
Orthotopic mouse models of human pancreatic cancer were established with the BxPC-3 RFP pancreatic cancer cell line. Two weeks after implantation, mice were randomized to undergo bright light laparoscopic resection (BLR) (n=19) or fluorescence-guided laparoscopic resection (FLR) (n=19). Fluorescence laparoscopy was performed with a 495-nm emission filter and a Stryker L9000 LED light source 24 hours after tail vein injection of anti-CEA-Alexa 488 antibodies. Bright light laparoscopy was performed with a Stryker X8000 xenon light source. Pre- and postoperative images were taken with the Olympus OV-100 Small Animal Imaging System to assess completeness of resection. Postoperatively, whole body images were obtained to assess for recurrence and follow tumor progression. Intravital and ex vivo images were obtained at termination to evaluate tumor burden. FLS enabled real-time identification and localization of brightly-fluorescent BxPC-3 RFP tumor labeled with anti-CEA-Alexa 488. Furthermore, there was adequate background illumination for surgical navigation permitting improved resection. At termination at 12 weeks, mice in the FLS group had a smaller pancreatic tumor burden compared to mice from the BLS group (5.75 mm2 vs 28.43 mm2; p=0.012). Mice in the FLS group also experienced decreased local recurrence (47.4% vs 78.9%, p=0.046) and distant recurrence (68.4% vs 94.7%, p=0.045) compared to mice in the BLS group. Fluorescence-guided surgery has significant potential to improve laparoscopic approaches in the treatment of pancreatic cancer.
Citation Format: Cristina A. Metildi, Sharmeela Kaushal, George A. Luiken, Mark A. Talamini, Robert M. Hoffman, Michael Bouvet. Fluorescence laparoscopy with an LED light source enables fluorescence-guided resection of pancreatic cancer, labeled with fluorophore-conjugated antibodies, in mouse models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4138. doi:10.1158/1538-7445.AM2013-4138
Abstract 4139: Could dielectrophoretic testing of oral brush biopsies aid early detection and diagnosis of oral cancer?.
Authors: Graham Karen A. , Fedele Stefano , Porter Stephen R. , Kalavrezos Nicholas , McCaul James A. , Lewis Mark P. , Hughes Michael P. , Labeed Fatima H. 
Published: August 2014

Abstract
Cancer of the oral cavity and pharynx was the 9th most common cancer in US males in 2009, and has a 5-year survival rate of 50%, which has remained relatively unchanged for several decades. This low survival rate is partly attributed to patients being diagnosed in advanced stages of the disease, and has lead to the consensus that early detection and diagnosis are key to improving survival. The objective of this research was to use a technique called dielectrophoresis (DEP) to study the electrophysiological characteristics of cells from normal, dysplastic and cancerous oral mucosa, collected via oral brush biopsies (OBBs) from patients with oral squamous cell carcinoma (OSCC) or oral epithelial dysplasia (OED), and from healthy volunteers. DEP testing involved applying AC electric fields to the cells collected via brush biopsies, whilst they were suspended in a conductivity-controlled medium. Interactions between the cells and the electric field resulted in cellular movement, dependent both on frequency of the applied electric field and cell properties. The electrophysiological properties of the cells’ cytoplasm and membrane were then deduced as a result of analysing this cellular movement. After obtaining favourable ethical opinions from all institutions involved, OBB samples were collected from 61 patients with OSCC or OED and from 12 healthy volunteers. At the time of abstract submission, 38 OSCC OBB and 12 OED OBB samples (grouped as Abnormal samples, N = 50), 36 patient-matched OBB samples of visually healthy oral mucosa from OSCC and OED patients and 21 OBB samples from the mucosa of healthy volunteers (grouped as Normal samples, N = 57) had been successfully tested and studied using DEP. Statistical analysis of these preliminary results of DEP testing showed statistically significant differences (p&lt;0.025) in cell membrane electrophysiological properties of Abnormal versus Normal OBB samples, OSCC samples versus Healthy Normal samples and OED samples versus Healthy Normal samples. These preliminary results suggest that DEP testing of oral brush biopsies has the potential to form the basis of a minimally invasive bench-top diagnostic tool for rapid identification of cancerous and potentially malignant lesions.
Citation Format: Karen A. Graham, Stefano Fedele, Stephen R. Porter, Nicholas Kalavrezos, James A. McCaul, Mark P. Lewis, Michael P. Hughes, Fatima H. Labeed. Could dielectrophoretic testing of oral brush biopsies aid early detection and diagnosis of oral cancer?. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4139. doi:10.1158/1538-7445.AM2013-4139
Abstract 4144: Improvement of tumor cell transduction with lentiviral vectors using chemical and cell targeting approaches.
Authors: Höfig Ines , Atkinson Michael J. , Thirion Christian , Anastasov Natasa 
Published: August 2014

Abstract
Although lentiviral transduction methods are widely used in cancer research their application is frequently hindered by the low transduction efficiency seen for a number of different cell types, in particular primary cells. We have previously reported that a mixture of poloxamer synperonic F108 and polybrene combines reduced toxicity and increased lentiviral gene delivery into a range of different primary cell cultures (1). We now report further improvement in efficiency through a novel combination of the poloxamer-based adjuvant with a modified lentiviral envelope. The envelope was rendered cell specific by fusing monoclonal antibody fragments directed against specific cell-surface epitopes with the viral attachment glycoprotein VSV-G.
For specific cellular targeting we inserted chimeric antiCD30 or antiEGFR antibody-VSV-G fusion proteins into the lentiviral genome. The combination of VSV-G-fused antibody fragments against specific tumor cell antigens and the improved adjuvant resulted in a 3-fold higher transduction rate using a GFP reporter containing lentivirus in CD30-positive lymphoma and EGFR-positive epithelial breast cancer cells. The combination of optimized transduction enhancer molecules and retargeted lentiviral vectors enabled quantitative transduction of previously hard-to-transduce cell types. When mixtures of antigen-negative and antigen-positive tumor cells were selected the modified lentivirus particles showed a preference for infecting antigen-positive cells by a factor 4.
These results demonstrate that improvements in both chemical charge protecting adjuvants and membrane targeting can lead to increased transduction efficiency without a loss of specificity. The combination of chemical adjuvant and envelope design can lead to the optimization of lentiviral transductions in large-scale systems.
*1. Höfig I, Atkinson MJ, Mall S, Krackhardt AM, Thirion C, Anastasov N. Poloxamer synperonic F108 improves cellular transduction with lentiviral vectors. J Gene Med. 2012 Aug;14(8):549-60.
Citation Format: Ines Höfig, Michael J. Atkinson, Christian Thirion, Natasa Anastasov. Improvement of tumor cell transduction with lentiviral vectors using chemical and cell targeting approaches. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4144. doi:10.1158/1538-7445.AM2013-4144
Abstract 4148: Sensitive detection of tumor nucleic acids in plasma by mutation-enriched next generation sequencing.
Authors: Marziali Andre 
Published: August 2014

Abstract
We have demonstrated a novel somatic mutation enrichment methodology that allows DNA sequencing to work beyond its usual limit of detection to accurately profile solid tumors by detecting their mutation signature in plasma, even when the tumor DNA is present in abundances below 0.01%.
Next Generation DNA Sequencing (NGS) is becoming the new standard for mutational profiling of tumor tissue, due to its flexibility, speed, and decreasing cost. While generally exceptional in performance, NGS suffers from a sequencing error rate of 0.1% - 1%, largely due to amplification induced artifacts in its workflow. While this does not constitute a significant problem in application of NGS to sequencing of most tumour tissues, it makes NGS impractical as a method to search for low abundance mutation signatures in plasma samples.
Numerous publications have shown the presence of tumor signatures in the cell-free DNA (cfDNA) circulating in plasma, but concordance between the tumor signature and the plasma signature has been limited. This is likely due to limitations in the detection technologies used to search for cfDNA in plasma. To maximize concordance between plasma and tissue, it will be essential that sensitivities reaching 0.01% and below (as little as a single tumor mutant allele per sample) be achieved, and ideally that multiple mutational hot spots be analyzed to maximize the chance of detection. Current technologies are incapable of such sensitivity over a large number of mutation loci.
We have developed a novel electrophoretic method that can enrich nucleic acid samples over 1,000,000-fold for up to 100 somatic mutations, enabling reliable profiling of samples containing as little as 0.01% mutant. By enriching nucleic acid samples for specific targets prior to amplification and sequencing, we enable the use of NGS in plasma-based mutation detection and profiling.
We present data demonstrating highly sensitive multiplexed mutation detection in plasma samples, demonstrating 0.01% sensitivity. We also report on concordance studies between mutation incidence in tissue and matched plasma in human samples.
Citation Format: Andre Marziali. Sensitive detection of tumor nucleic acids in plasma by mutation-enriched next generation sequencing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4148. doi:10.1158/1538-7445.AM2013-4148
Abstract 4154: Rapid, highly multiplexed somatic mutation analysis of FFPE tissues by deep amplicon sequencing on MiSeq®.
Authors: Upsall Elizabeth , Chang Katherine , Lewis Ian , Tian April , Iyer Anita , Shen Richard , Lin Charles 
Published: August 2014

Abstract
DNA extraction from formalin-fixed, paraffin-embedded (FFPE) tumor tissues typically results in low quantities of poor-quality, damaged DNA, which present challenges for sequencing. Here we present a fast, streamlined sample-to-answer workflow using probe design software and sample preparation methods optimized to overcome these challenges. DesignStudio® allows for the targeting of up to 1,536 user-defined genomic regions and supports amplicon sizes (150- and 175-bp) ideal for characterizing genomic hot-spot regions or sequencing of whole exons with FFPE DNA. The TruSeq® Custom Amplicon (TSCA) workflow delivers high target enrichment specificity (&gt;80% of reads on target), robust target multiplexing (up to 1,536 amplicons per reaction), and scalable sample indexing (up to 96 libraries) that supports simultaneous sequencing using the MiSeq. We have optimized the DNA extraction and hybridization processes to achieve higher DNA yields and more uniform target representation, respectively. In addition, the improved TSCA assay and software analysis tools significantly reduce false-positive variant calls. In conclusion, we have developed an integrated solution for highly accurate and reproducible detection of somatic variants implicated in cancer biology.
Citation Format: Elizabeth Upsall, Katherine Chang, Ian Lewis, April Tian, Anita Iyer, Richard Shen, Charles Lin. Rapid, highly multiplexed somatic mutation analysis of FFPE tissues by deep amplicon sequencing on MiSeq®. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4154. doi:10.1158/1538-7445.AM2013-4154
Abstract 4155: Personalized chemosensitivity profiling of cancers isolated from genetically-engineered mice.
Authors: Kamiyama Hirohiko , Rauenzahn Sherri , Shim Joong Sup , Liu Jun O. , Maitra Anirban , Eshleman James R. 
Published: August 2014

Abstract
BACKGROUNDHigh-throughput functional chemosensitivity testing is a potentially effective way to customize personalized chemotherapy treatment. This testing requires low-passage patient-specific cancer cell lines, however, generating such cell lines from patients’ tumors is difficult, due in large part, to contaminating fibroblasts that often overgrow the malignant cells.
METHODSWe constructed a series of hypoxanthine phosphoribosyl transferase (hprt) null immunodeficient mice. These include nude hprt-null, SCID hprt-null and NOD-SCID hprt-null mice. During growth of xenografted human cancers in these mice, hprt-null murine stromal cells replace their human counterparts. Tumors from patients were implanted and expanded in these mice. Explanted tumors were then grown in tissue culture flasks with selection media (hypoxanthine, aminopterin, thymidine; HAT media) to eliminate the mouse biochemically-defective fibroblasts and produce pure human cancer cell lines. We screened one cell line against the Johns Hopkins Drug Library containing ∼3,100 drugs. Selected potent drugs were used for in vivo xenograft tumor inhibition studies.
RESULTSWe successfully established several pancreatic cancer cell lines from patients using the hprt null immunodeficient mice. We performed chemosensitivity profiling on one of the pancreatic cancer cell lines using 3,100 drugs. From the profiling, we selected potent drugs, which are FDA-approved but are not currently used for pancreatic cancer. We chose two drugs that demonstrated greater in vitro chemosensitivity compared to control cell lines. The two drugs were tested against mouse xenografts where both drugs demonstrated superior in vivo efficacy to the sensitive cell line tumors compared to control tumors.
CONCLUSIONSChemotherapy for cancer may be personalized using low passage cell lines derived from patients through biochemically selectable mice. Further tests are needed to determine whether in vitro chemosensitivity testing of low-passage patient-specific cancer cell lines can predict clinical patient response.
Citation Format: Hirohiko Kamiyama, Sherri Rauenzahn, Joong Sup Shim, Jun O. Liu, Anirban Maitra, James R. Eshleman. Personalized chemosensitivity profiling of cancers isolated from genetically-engineered mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4155. doi:10.1158/1538-7445.AM2013-4155