bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1132: Identification of synthetic lethal genes to MYCN-amplified neuroblastoma.
Authors: Zhang Shuobo , Yu J , Wei N , Silva J , Kandel J J. , Yamashiro D J. 
Published: August 2014

Abstract
Purpose. Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, no drugs that target MYCN have yet been developed, in part due to the inherent difficulty in designing therapeutic molecules that can target transcription factors. An alternative approach is to identify genes that are essential for the growth of MYCN-amplified neuroblastoma.
Methods. We have screened for MYCN synthetic lethal genes using a highly efficient microRNA-short-hairpin RNA (miRNA-shRNA) library that contains more than 200,000 shRNAs targeting almost all predicted genes in the human genome. If a shRNA leads to cellular death, this shRNA will diminish in the cell population. The level of each shRNA was measured both by hybridizing genomic PCR products to microarrays that contain complementary sequence to the shRNA region and by direct high-throughput sequencing of the shRNA region. Selected candidates were further validated in MYCN amplified and non-amplified neuroblastoma cell lines.
Results. We have performed an shRNA screen utilizing the SHEP-21N cell line, which expresses MYCN under a tetracycline controlled promoter. 396 significantly (P&lt;0.01) depleted or enriched genes by both best shRNA and integrated gene level were identified. Gene set enrichment analysis was performed utilizing the Pathway Commons data set. 25 potential synthetic lethal genes were examined by secondary screening utilizing Dharmacon SMARTpool siRNAs. The potential synthetic lethal gene transcription factor AP-4/activating enhancer binding protein (TFAP4) was further validated in three MYCN amplified cell lines and three MYCN non-amplified cell lines. Knocking down TFAP4 by siRNA inhibited cell growth in MYCN amplified cell lines (NGP, SKNDZ, and Be(2)c) by 30%-50%, 96 hours after transfection, while knocking down TFAP4 in MYCN non-amplified lines (CHP212, SKNSH, and SH-SY5Y) did not affect cell growth. Utilizing a tetracycline inducible shRNA system, knocking down TFAP4 significantly reduced colony formation of NGP by70% and Be(2)c by 25%.
Conclusions. By the use of a genome wide RNAi screen, we identified potential synthetic lethal genes to MYCN amplification. The top candidate TFAP4 was validated to inhibit neuroblastoma cell growth and colony formation in a MYCN dependent manner. This may provide novel targets for the treatment of neuroblastoma.
Citation Format: Shuobo Zhang, J Yu, N Wei, J Silva, J J. Kandel, D J. Yamashiro. Identification of synthetic lethal genes to MYCN-amplified neuroblastoma. [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 1132. doi:10.1158/1538-7445.AM2013-1132
Abstract 1161: The relationship between the 14-3-3zeta expression pattern and the clinicopathological variables of the 192 gastric cancer patients.
Authors: Aizawa Tetsuya , Tsukamoto Yoshiyuki , Moriyama Masatsugu , Noguchi Tsuyoshi 
Published: August 2014

Abstract
Gastric cancer remains one of the most common malignant diseases, despite its steady declining trend worldwide. Overall, gastric cancer mortality is estimated to be 700000 cases annually (10.4% of all cancer related death), ranking second only after lung cancer. 14-3-3zeta, a member of 14-3-3 proteins, have important roles in a wide range of biological processes through the interactions with &gt;100 key proteins, such as FOXO3a, Bad and CCND1. Recent studies have revealed that up-regulation of 14-3-3zeta contribute to the transformation phenotype of breast and lung cancer. However, the relevance of 14-3-3zeta expression in gastric carcinogenesis remained poorly understood.
In this study, we aimed to clarify the clinicopathological significance of 14-3-3zeta expression in patients with gastric cancer. A total of 192 gastric cancer specimens were obtained from patients undergoing curative surgery at Oita University Hospital. The expression levels of 14-3-3zeta were investigated by immunohistochemistry. The relationship between the 14-3-3zeta expression pattern and the clinicopathological variables of the gastric cancer patients were analyzed.
14-3-3zeta was strongly expressed in 102of the 192 cases. Strong expression of 14-3-3zeta was correlated with Lymph node metastasis, Histological subtype and Tumor stage (Fisher's exact test, p&lt;0.05). These results suggest that up-regulation of 14-3-3zeta is associated with the clinically malignant features of gastric cancer.
Citation Format: Tetsuya Aizawa, Yoshiyuki Tsukamoto, Masatsugu Moriyama, Tsuyoshi Noguchi. The relationship between the 14-3-3zeta expression pattern and the clinicopathological variables of the 192 gastric cancer patients. [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 1161. doi:10.1158/1538-7445.AM2013-1161
Abstract 1166: Upregulation of microRNAs in colorectal tumors and association with disease stage.
Authors: Makar Karen W. , Wurscher Michelle A. , Habermann Nina , Grady William M. , Ulrich Cornelia M. 
Published: August 2014

Abstract
Introduction
MicroRNAs (miRNAs) are small, noncoding RNAs that function as regulators of many critical cellular processes. Increased expression of specific microRNAs in tumor tissue may be indicative of a patient's prognosis. The purpose of this study was to assess miRNA upregulation in fresh frozen colorectal cancer (CRC) tumors compared to paired normal colorectal tissue in a prospective cohort of CRC patients.
Methods
Tumor and normal tissue were collected at the time of surgery from 40 stage I-IV CRC patients participating in the ColoCare Study in Seattle, WA. The Qiagen miRNeasy kit was used to isolate miRNAs for analysis. Expression of candidate miRNAs (e.g., miR-141, miR-31, miR-29a, mir-92a, miR-203) was measured using Taqman qRT-PCR with miRNA-specific stem loop primers. For each miRNA, copy number was determined via standard curves and normalized to miR-16 expression for each sample. Expression in tumor was compared to expression in paired normal tissue for each participant. In addition, we profiled two stage III CRC tumor-normal pairs using the miCURY LNA human panel I qRT-PCR array from Exiqon. Relative expression from the Exiqon panel was calculated using GenEx software and endogenous control assays. The Wilcoxon two sample test was used to compare normalized miRNA upregulation between groups.
Results
Expression of miR-31 was greater than 10-fold higher in tumor compared to normal tissue for 13 of 38 tumor-normal pairs with Taqman data available. Overexpression of miR-31 in tumor tissue was significantly correlated with stage III-IV CRC when compared to stage I-II CRC (p&lt;0.01). The Taqman and miCURY platforms both showed miR-31 upregulation in the two stage III CRC tumors, but the extent of upregulation varied between platforms.
Conclusion
In this study, upregulation of miR-31 in CRC tumor tissue was associated with more advanced disease stage in CRC patients. Future studies will investigate additional miRNAs, and associations with clinicopathological features, patient outcomes, and circulating miRNA levels.
Citation Format: Karen W. Makar, Michelle A. Wurscher, Nina Habermann, William M. Grady, Cornelia M. Ulrich. Upregulation of microRNAs in colorectal tumors and association with disease stage. [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 1166. doi:10.1158/1538-7445.AM2013-1166
Abstract 1209: Next generation sequencing demonstrates multiple gene amplifications and mutations in 3 patients with estrogen receptor-positive breast cancer with responses to treatment with combination aromatase and PI3K/AKT/mTOR pathway inhibition.
Authors: Zinner Ralph , Atkins Johnique T. , Janku Filip , Moulder Stacy , Stephens Phil , Yelensky Roman , Wolff Robert , Kurzrock Razelle , Wheler Jennifer J. 
Published: August 2014

Abstract
Background:
Gene amplifications in breast cancer may indicate poor prognosis disease, particularly for patients with multiple amplifications. Endocrine response and resistance in breast cancer maybe revealed to PI3K/AKT/mTOR pathway activation.
Patients and Methods:
We analyzed tissue with next generation sequencing (NGS) from 3 patients with estrogen receptor (ER)-positive breast cancer treated on a dose escalation study with anastrozole, an aromatase inhibitor, and everolimus, an mTOR inhibitor. Genomic libraries were captured for 3230 exons in 182 cancer related genes plus 37 introns from 14 genes, often rearranged in cancer (Foundation Medicine, Cambridge, MA).
Results:
Twelve of 50 evaluable patients with ER-positive breast and gynecologic tumors treated with anastrozole (1mg PO daily) and everolimus (either 5mg PO daily or 10mg PO daily) had SD ≥ 6 months/PR/CR. NGS analysis on 3 of the 12 patients tumors demonstrated multiple amplifications, including: CCND1, CCNE1, FGFR1, MYC, IRS2 and MCL1. One patient had a complete response (CR) and two patients achieved partial responses (PR) with an 80% decrease in disease in one patient and a 38% decrease in disease in the other. All 3 patients had ER-positive breast cancer and previously experienced progression of disease while receiving hormone therapy. These amplifications seen have all been linked to hormone therapy resistance in ER-positive breast cancers. Two of these patients also had direct alterations in the PI3K/AKT/mTOR pathway: PIK3CA and PIK3R1 mutations in one patient and PTEN loss in another.
Conclusions:
Molecular profiling of 3 patients with ER-positive breast cancer with PR/CR on treatment with anastrozole/everolimus revealed multiple genetic alterations. Among these alterations were amplifications that may be associated with resistance to hormone therapies. Further exploration of combination hormonal therapies and correlative molecular profiling is warranted.
Citation Format: Ralph Zinner, Johnique T. Atkins, Filip Janku, Stacy Moulder, Phil Stephens, Roman Yelensky, Robert Wolff, Razelle Kurzrock, Jennifer J. Wheler. Next generation sequencing demonstrates multiple gene amplifications and mutations in 3 patients with estrogen receptor-positive breast cancer with responses to treatment with combination aromatase and PI3K/AKT/mTOR pathway inhibition. [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 1209. doi:10.1158/1538-7445.AM2013-1209
Abstract 1213: Clinicopathological significance of ALK alterations in colorectal carcinoma.
Authors: Jehan Zeenath , Prabhakaran Sarita Esther , Bu Rong , Al-Sanea Nasser , Abduljabbar Alaa , Ashari Luai , Al-Homoud Samar , Al Dayel Fouad , Uddin Shahab , Bavi Prashant , Al-Kuraya Khawla Sami 
Published: August 2014

Abstract
ALK has been shown to be a putative oncogene in lung cancer and neuroblastoma that can be potentially targeted with selective inhibitors. Ongoing clinical trials using ALK inhibitors such as Crizotinib have shown promising results. ALK gene copy gain number in colorectal cancer (CRC) patients have been shown to be associated with tumors that have a more aggressive phenotype. We investigated the alterations in ALK gene by FISH analysis, immunohistochemistry and screened for ALK mutations by sequencing the ALK gene in 737 CRC. We screened for mutations in ALK by sequencing the tyrosine kinase domain that covers exons 20 -28. ALK alterations were correlated with tumor pathological features including TNM staging, MSI status, KRAS and BRAF mutations, as well as clinical outcome. Overall survival was analyzed using Kaplan Meyer plots. On FISH analysis in colorectal cancers, ALK amplifications were observed in 2.6%. Amplifications and gain with increase in gene copy number(4 to 6 copies) were seen in 3.4%. No translocations were seen in our study. There were no associations with nodal metastasis and other clinical or molecular parameters. However in Stage III & IV, ALK amplification was associated with KRAS mutations. CRC subgroup with ALK amplifications showed a poor overall survival overall survival and ALK gene amplifications was an independent prognostic marker in multivariate Cox proportional Hazards model. IHC showed cytoplasmic overexpression in 14.7% CRCs and no associations with any clinical or molecular parameters. We are screening for ALK mutations in 100 CRC samples and results are awaited. The insights gained from our current study and future clinical trials are likely to directly benefit subgroups of CRC patients whose tumors are driven by ALK and will pave the way to more targeted approaches to cancer treatment.
Citation Format: Zeenath Jehan, Sarita Esther Prabhakaran, Rong Bu, Nasser Al-Sanea, Alaa Abduljabbar, Luai Ashari, Samar Al-Homoud, Fouad Al Dayel, Shahab Uddin, Prashant Bavi, Khawla Sami Al-Kuraya. Clinicopathological significance of ALK alterations in colorectal carcinoma. [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 1213. doi:10.1158/1538-7445.AM2013-1213
Abstract 1219: Identification of synthetic lethal interactions with the BRAF oncogene in colorectal cancer.
Authors: Vecchione Loredana , Gambino Valentina , D'Ario Giovanni , Sun Tian , Simon Iris , Popovici Vlad , Delorenzi Mauro , Bernards Rene’ , Tejpar Sabine 
Published: August 2014

Abstract
Background
Approximately 8-15% of colorectal (CRC) patients carry an activating mutation in BRAF. This CRC subtype is associated with poor outcome and with resistance, both to chemotherapeutic treatments and to tailored drugs.
We recently showed that BRAF (V600E) colon cancers (CCs) have a characteristic gene expression signature (1, 2) which is found also in subsets of KRAS mutant and KRAS-BRAF wild type (WT2) tumors. Tumors having this gene signature, referred as “BRAF-like," have a similar poor prognosis irrespective of the presence of the BRAF (V600E) mutation.
By using a shRNA-based genetic screen in BRAF mutant CC cell lines we aimed to identify genes and pathways necessary for survival and growth of BRAF mutant CC. Such studies may reveal additional targets for therapy and potentially provide new biomarkers for patient stratification.
Method
We identified 363 genes that are selectively overexpressed in BRAF mutant tumors as compared to WT2 type tumors, based on gene expression profiles of the PETACC3 (1) and Agendia (1) datasets.
The TRC human genome-wide shRNA collection (TRC-Hs1.0) was used to generate a 1815 hairpins sub-library targeting those identified genes (BRAF library). BRAF(V600E) CC cell lines were infected with the BRAF library and screened for shRNAs that cause lethality. LIM1215 CC cell line (WT2) was used as a control. Cells stably expressing the shRNA library were cultured for 13 days, after which shRNAs were recovered by PCR. Deep sequencing was applied to determine the specific depletion of shRNA in BRAF(V600E) cells as compared to LIM1215 cells.
Results
Candidate genes were identified by using following filtering criteria: depletion in BRAF(V600E) cells by at least 50% and depletion in BRAF(V600E) cells 1,5-fold higher than in control cells with the corresponding p-value to be ≤ 0.1. A total of 34 genes met our criteria of which 6 genes were presented with more than one hairpin and were concordant across the cell lines selected for validation.
Conclusion
We identified candidate synthetic lethal genes in BRAF mutant CC cell lines. Functional analysis is ongoing. Data will be presented.
Citation Format: Loredana Vecchione, Valentina Gambino, Giovanni D'Ario, Tian Sun, Iris Simon, Vlad Popovici, Mauro Delorenzi, Rene’ Bernards, Sabine Tejpar. Identification of synthetic lethal interactions with the BRAF oncogene in colorectal 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 1219. doi:10.1158/1538-7445.AM2013-1219
Abstract 1222: Simultaneous detection of 30 cytokines in human sera using barcoded magnetic bead technology.
Authors: Zhang Aiguo , Chuang Rachel , Chen Lily , Zhu XiNing , Diaz Rachel , Tsao Dean 
Published: August 2014

Abstract
Cytokines mediate a wide range of physiological responses including immunity, inflammation, and hematopoiesis, which are important circulating proteins. It has been well demonstrated that cytokines are associated with a spectrum of diseases ranging from tumor growth to infection and to Parkinson. Traditionally, cytokines are measured by immunoblot or immunoassay, which are both time consuming and not cost effective. There is an increasing need for multiplexing assays in this field. With the development of bead array technology, which uses fluorescent color-coated microspheres analyzed with a dedicated reader, simultaneous detection of multiple analytes becomes possible in a single well of a microtiter plate. Although the bead array technology becomes more and more popular and dominated in the multiplexing assay market, there are still some limitations and potential issues from this technology, such as photobleaching of the fluorescent color-coated beads and expensive laser detector. Recently, a new generation of the reader has been developed, which replaces laser detector with CCD camera. However, it still uses fluorescent color-coated beads, which makes the assay sensitive to light and unstable. Here we present a new Barcoded Magnetic Bead technology, which employs a permanent bar code on magnetic beads with high resolution CCD camera for scanning. This technology has successfully solved the problems from fluorescent color-coated bead and makes the multiplex assay much more stable and reliable. We can detect 30 cytokines from human sera with limit of detection less than 5 pg/ml, while inter- and intra assay CV less than 10%. The results are correlated very well with the bead array technology and traditional ELISA. In addition, our multiplex protein assays have unique internal control in each sample well, which makes the assay much more reliable and robust. This multiplex technology can be used in both life science research and clinical fields.
Citation Format: Aiguo Zhang, Rachel Chuang, Lily Chen, XiNing Zhu, Rachel Diaz, Dean Tsao. Simultaneous detection of 30 cytokines in human sera using barcoded magnetic bead technology. [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 1222. doi:10.1158/1538-7445.AM2013-1222
Abstract 1223: Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein.
Authors: Ochoa Maria Carmen , Berraondo Pedro , Melero Ignacio 
Published: August 2014

Abstract
Interleukin 15 (IL-15) effects on CD8 T and NK lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I, IL-15 and IL-15Rα’s sushi domain. Apolipoprotein A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα's sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (&lt;2.5μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα-/- mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL and displayed immuno-therapeutic effects against metastatic disease.
Citation Format: Maria Carmen Ochoa, Pedro Berraondo, Ignacio Melero. Antitumor immunotherapeutic and toxic properties of an HDL-conjugated chimeric IL-15 fusion protein. [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 1223. doi:10.1158/1538-7445.AM2013-1223
Abstract 1228: AV-203, a fully humanized ERBB3 inhibitory antibody, reverses ERBB3-induced resistance to targeted therapies.
Authors: Tyler Steven M. , Vincent Sylvie , Fleet Christina , Bottega Steve , McIntosh Donna , Meetze Kristan , Gyuris Jeno 
Published: August 2014

Abstract
Targeted therapies have changed the treatment paradigm of cancer. Specifically, the use of tyrosine kinase inhibitors (TKIs) has improved therapeutic responses in a number of tumor types. However, initial response to TKIs is often followed by rapid relapse due to the acquisition of molecular features that lead to resistance. ERBB3, a receptor of the epidermal growth factor receptor (EGFR/ERBB1) family, has been linked to the development of resistance to multiple ERBB targeting TKIs. A proposed potential mechanism is the recruitment and activation of ERBB3 as a bypass mechanism to activate PI3K dependent pro-survival pathways. We investigated whether the inhibition of ERBB3 could reverse TKI resistance linked to ERBB3 activation. AV-203 is a humanized IgG1 antibody directed against ERBB3. AV-203 potently inhibits both ligand dependent and ligand independent activation of ERBB3. AV-203 was shown to inhibit the binding of NRG1 to ERBB3 and promote ERBB3 degradation. The tumor growth inhibitory activity of AV-203 was demonstrated in numerous xenograft models representing major human carcinomas (breast, lung, ovarian, kidney and pancreas). Here, we investigated the ability of AV-203 to restore TKI sensitivity in models with activated ERBB3. First, we demonstrated that ligand mediated (NRG1) activation of ERBB3 leads to acquired resistance to the EGFR TKI erlotinib in a lung cancer model bearing EGFR TKI sensitizing mutation, to the ERBB2/HER2 inhibitor lapatinib in a HER2 amplified breast cancer model, and to the EGFR inhibitory antibody cetuximab in head and neck cancer models. AV-203 was able to restore sensitivity to these RTK inhibitors. This data suggest that the combination of AV-203, with EGFR/HER2 targeted therapies could potentially extend the efficacy of these agents by preventing the emergence of ERBB3 mediated resistance. This hypothesis will be tested in future clinical trials. AV-203 is currently in Phase I development for the treatment of solid tumors.
Citation Format: Steven M. Tyler, Sylvie Vincent, Christina Fleet, Steve Bottega, Donna McIntosh, Kristan Meetze, Jeno Gyuris. AV-203, a fully humanized ERBB3 inhibitory antibody, reverses ERBB3-induced resistance to targeted therapies. [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 1228. doi:10.1158/1538-7445.AM2013-1228