tbuckley/cabot-search huggingface dataset:
Abstract 637: MEHD7945A, an EGFR/ErbB3 dual specific antibody, overcomes acquired resistance to EGFR inhibitors in head and neck and lung tumors
Authors: Shyhmin Huang, Chunrong Li, Mark X. Sliwkowski, Paul M. Harari
Journal: Cancer Research (2011)

Abstract The development of acquired resistance to EGFR inhibitors is emerging as a potential treatment barrier for EGFR targeted therapies. Efforts to better understand underlying mechanisms of acquired resistance to EGFR inhibitors, and strategies to overcome this resistance are highly desired. We have previously identified that acquired resistance to EGFR inhibitors may result from the trans-activation of ErbB3 by EGFR. We therefore examined the capacity of the EGFR/ErbB3 dual specific antibody, MEHD7945A to overcome acquired resistance to EGFR inhibitors. We first examined the antiproliferative effects of MEHD7945A across a panel of human head and neck (HNSCC) and non-small cell lung (NSCLC) tumor cell lines. MEHD7945A significantly inhibited the proliferation in tumors cells that express EGFR and ErbB3. We then applied MEHD7945A to EGFR inhibitor-resistant clones from HNSCC (SCC-1 and SCC-6) and NSCLC lines (H226) that have been chronically exposed to cetuximab or erlotinib and show EGFR inhibitor-resistant phenotypes. Using identical doses of MEHD7945A and cetuximab, we found that MEHD7945A inhibited the growth of tumor cells that exhibit resistance to cetuximab. Similar results were observed in our erlotinib-resistant clones. MEHD7945A also significantly inhibited EGFR and ErbB3-dependent downstream signaling. Additional studies to confirm the antitumor activity of MEHD7945A in xenograft models using EGFR inhibitor-resistant clones are in progress. In addition, studies to investigate the impact of MEHD7945A on radiation response profiles in a panel of HNSCC, NSCLC and EGFR-inhibitor resistant cell lines are underway. These data not only support an important role of ErbB3 in acquired resistance to EGFR inhibitors but also suggest MEHD7945A may provide a valuable treatment strategy for patients who develop acquired resistance to EGFR targeting agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 637. doi:10.1158/1538-7445.AM2011-637
Abstract LB-206: A new platform for diagnosis and therapeutic targeting of cancer stem cells
Authors: Server A. Ertem, Malcolm AS Moore
Journal: Cancer Research (2012)

Abstract The present failure of most current therapies to cure cancers is thought to be the relative resistance of cancer initiating cells (CIC), also known as cancer stem cells, to chemotherapy and radiation. Following repeated cancer treatments, tumors can remain with a high percentage of CIC and become more aggressive and resistant to further treatment. What has been missing up to now is a therapy directed at CIC also known as cancer stem cells. Without elimination of these cells, cancer recurrence is inevitable. We believe that the major objective of cancer therapy should be to target CIC specifically. However, there has not been a reliable method for detecting CIC within tumors that would allow prospective isolation of these cells in sufficient numbers for analysis, characterization and evaluation of novel therapeutics. This has proved to be a major barrier to development of effective CIC targeted cancer therapeutics. Advances in cancer therapy will depend on development of reliable early detection methods and targeting strategies specific for CIC. We have discovered a unique cell type with cancer initiating cell characteristics in metastatic cancers. These cells have a protective pericellular coat, divide rapidly and grow as chains of cells - thus the name catena = chain. In xenograft studies in mice, nearly every catena cell was shown to be a CIC. Catena are resistant to standard therapies (e.g. paclitaxel, cisplatin) and more than 1,000 pharmaceutical agents that are in development for cancer treatment. Catena lack all of the biomarkers currently used for cancer detection and are undetectable by current diagnostic tests that utilize monoclonal antibodies (e.g. to CA125, HE4, Mesothelin, WT1, CD44, EPCAM, CD133). We subsequently developed the CATENAE cell culture technology to propagate these cells in vitro while maintaining their cancer initiating properties. This technology provides for the first time adequate number of CIC for detailed analysis and could be the key to both better therapies and more efficient detection of cancer at an early stage when it is curable. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-206. doi:1538-7445.AM2012-LB-206
Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia
Authors: Daniel Gaudet, Veronica J. Alexander, Brenda F. Baker, Diane Brisson, Karine Tremblay, Walter Singleton, Richard S. Geary, Steven G. Hughes, Nicholas J. Viney, Mark J. Graham, Rosanne M. Crooke, Joseph L. Witztum, John D. Brunzell, John J.P. Kastelein
Journal: New England Journal of Medicine (2015)

Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).
Endoscopic removal of an impacted bile duct self-expanding metal stent (SEMS) using the SEMS-in-SEMS technique
Authors: N. González, J. Ramesh, C. Wilcox, K. Mönkemüller
Journal: Endoscopy (2013)

In contrast to covered self-expanding metal stents (c-SEMS), retrieval of uncovered SEMS (u-SEMS) from the bile duct may be quite difficult or impossible. We describe the endoscopic removal of an impacted u-SEMS using the SEMS-in-SEMS technique.
Abstract P2-06-07: Exome sequencing identifies somatic mutations in basal-like breast cancer before and after neoadjuvant chemotherapy
Authors: Y-Z Jiang, K-D Yu, Z-M Shao
Journal: Cancer Research (2012)

Abstract Purpose: Among the five breast cancer subtypes, basal-like breast cancers (BLBCs) have drawn much attention, because they are associated with poor clinicopathological features, lack of effective treatment targets, and have poor prognosis. We designed the experiment to test the hypothesis that significant mutational evolution of BLBCs might occur during chemotherapy. Methods: We performed exome sequencing (100-fold coverage) to examine the exomes of 11 paired BLBC samples (pretreatment tumor biopsies and posttreatment tumors). The molecular subtype of BLBC was proven by gene-expression profile as well as by immunohistochemistry assay. Firstly, we sequenced the tumor genomic DNA obtained before and after neoadjuvant chemotherapy and their matched normal breast tissues. After analyzing and comparing potential somatic single nucleotide variations (SNVs) and insertions &amp; deletions (indels), we focused on the functional mutations in certain genes or pathways. Furthermore, after validation of the mutations by Sanger sequencing, we investigated their biological functions (e.g. drug-resistance, cell proliferation, etc.). Results: Compared with pretreatment biopsies, analysis of whole-exome sequence data identified and validated TEKT4 (tektin 4) — a constitutive protein of microtubules in cilia, flagella, basal bodies and centrioles — as a significantly mutated gene in posttreatment tumors with a mutation frequency of approximately 17.6% in an independent extension cohort of 84 paired BLBC samples. TEKT4 mutations are biologically relevant, as ectopic expression of mutant TEKT4 increased paclitaxel resistance of BLBC cell lines both in vitro and in vivo. Additionally, compared with the normal breast tissues, 16 significantly mutated genes were identified and validated in the paired cancer samples, including TP53, ARID1A, BEND5, LCT, COL4A4, GAP43, COL6A6, LOC728369, STAP1, KCNK17, LZTS2, TST, IL9R, HDLBP, RASL11A and FAM22D. These genes have functions that could be broadly grouped into five biological classes: (i) MAPK signaling, (ii) PI3K/AKT signaling, (iii) cell cycle, (iv) metabolism and (v) loss of genome stability. Conclusion: Our data reveal the novel concept that significant evolution might occur during chemotherapy and mutational heterogeneity could be a property of BLBCs. In addition, the identification of somatic mutations as biomarkers for pCR (pathologic complete remission) prediction and prognosis might help us optimize choice for sequential therapy and improve patients' survival. Prospective clinical trials based on these findings might illustrate the drug-resistant mechanism and identify resistance pathways that can be exploited for therapeutic selection. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-06-07.
Abstract 5540: Non malignant breast cancer tissue identification scoring system
Authors: Serenella Eppenberger-Castori, Thierry Sengstag, Mauro Delorenzi, Uwe Gueth, Edward Wight, Urs Eppenberger, Luigi Terracciano, Ellen Obermann, Ellen Obermann, Vincent Vuaroqueaux, Rosanna Zanetti-Daellenbach
Journal: Cancer Research (2012)

Abstract Abstract: Introduction. Molecular pathology tools are increasingly important in routine diagnostic. Histological determination remains mandatory, while gene expression profiles (GEP) are successfully classifying breast cancer specimens also when minimal amount of tissue, such as core biopsies (CB), is available. The limit of this application resides however in the fact that the part of material used for RNA extraction could not represent the entire biopsy. To overcome this problem in the present work we calculated an algorithm for the identification of malignant cells in a giving CB. Patients and methods. The quantitative expression levels of 60 selected genes representative for relevant pathways in breast cancer (BC) oncogenesis were assessed by real time PCR in a total of 106 CB samples obtained from patients with neoplasia or invasive BC and in 12 biopsies with known good differentiation grade (Grade 1). The GEP of 48 CBs and of the 12 Grade 1 specimens were used as training set to build the scoring system based on the Welsh variant of t-test and best-fit logistic curves. The remaining GEPs were used as validation set. Results. A 15-genes classifier was built and cross-validated with 1000 iterations of a leave −10% out in which each of the 10 subset is used. The 15 genes were representative for proliferation (thymidine phosphorylase and E2F1), cell matrix degradation (CTSD, MMP1, MMP11, PLAU, PLAUR, SERPINE1), as well as angiogenesis (VEGFA, VEGFD, TGFbeta1). EGFR and GSTP1 were also part of this classifier able to discriminate non-malignant from malignant breast tissue with an accuracy of almost 90%. Discussion. The calculated classifier, which could also be reduced to only six genes, is robust and useful in the discrimination of malignant from non-malignant breast cancer tissue. Such an algorithm identifying normal proliferation rate and inability of invasion should be integrated in the evaluation of GEP data from microarrays before using them for other predictive purposes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5540. doi:1538-7445.AM2012-5540
Abstract LB-484: Molecular regulation of HIF-1α by CDK1 and the cell cycle
Authors: Noel A. Warfel, Wafik S. El-Deiry
Journal: Cancer Research (2012)

Abstract The hypoxia-inducible factor 1 (HIF-1) transcription factor is a critical mediator of the cellular response to oxygen deprivation. HIF-1α is frequently overexpressed in human cancers due to intratumoral hypoxia as well as genetic alterations that promote HIF-1α synthesis or inhibit its degradation (i.e. gain of function mutations in oncogenic pathways, such as RAS and PI3K, or loss of function mutations to the tumor suppressor, VHL, respectively). Under hypoxic conditions, HIF-1α is stabilized and translocates to the nucleus where it activates the transcription of genes that promote angiogenesis, cell proliferation/survival, and metastasis, among other processes. While the role of HIF-1 in the regulation of the cell cycle has been well studied, the effect of the cell cycle stage on HIF-1 expression and activity remains unknown. To address this question, HCT116 colon cancer cells were synchronized in G1, S, or G2/M-phase and exposed them to hypoxia (0.2% O2). Interestingly, HIF-1α expression was nearly abolished upon G2/M-phase arrest, and a significant increase was observed following arrest in S-phase. Therefore, cell cycle position influences the expression of HIF-1α, independent of oxygen concentration. Previous data in our lab indicates that knockdown of CDK1 decreased HIF-1α expression under hypoxic conditions. To further characterize this effect, we demonstrate that acute inhibition of CDK1 kinase activity with small molecules significantly decreases the stability of HIF-1α at the protein level, without affecting HIF-1α mRNA levels. Furthermore, cycloheximide chase experiments reveled that HIF-1α protein levels decreased at a significantly faster rate in the presence of a CDK1 inhibitor, R0-3306, (t1/2 = 38.2 ± 6.1 min) compared to controls (t1/2 = 54.6 ± 3.2 min). These results indicate that the half-life of HIF-1α is significantly decreased upon inhibition of CDK1. Taken together, these data indicate that CDK1 activity regulates the stability of HIF-1α, and suggests that CDK1 activity stabilizes HIF-1α through a post-translational modification that promotes its stability. Thus, we have discovered that CDK1 and the cell cycle position regulate the expression of HIF-1α. There is a subset of tumors that express HIF-1α under normoxic conditions, driving tumor progression and therapeutic resistance. Therefore the identification of alternative mechanisms that regulate HIF-1α expression would be extremely valuable in the clinical setting, as well as to aid the basic understanding of the role of HIF-1 in tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-484. doi:1538-7445.AM2012-LB-484
Abstract 4959: Deregulation of microRNA expression patterns during cervical carcinogenesis
Authors: Saskia M. Wilting, Peter JF Snijders, Mark A. van de Wiel, Wessel N. van Wieringen, Chris JLM Meijer, Renske DM Steenbergen
Journal: Cancer Research (2011)

Abstract At present little is known about the involvement of alterations in microRNA (miRNA) expression patterns during the development of cervical cancer. In this study we investigated genome-wide miRNA expression profiles in normal cervical squamous epithelium, high-grade precancerous lesions (CIN2/3), squamous cell carcinomas (SCC) and adenocarcinomas (AdCAs), all of which were high-risk HPV positive. In addition, miRNA expression profiles were integrated with previously generated genome-wide chromosomal profiles of the same samples. Unsupervised hierarchical clustering showed that miRNA expression profiling enables the distinction of normal cervical squamous epithelium, CIN2/3 lesions, SCCs and AdCAs. Differential miRNA expression analysis comparing normals, CIN2/3 lesions and SCCs identified early (temporal), late, and continuously differentially expressed miRNAs in cervical carcinogenesis (n=106). Differential expression of selected miRNAs could be validated by qRT-PCR in the same samples as well as in cervical scrapes of women with abnormal cytology and underlying high-grade CIN disease compared to control scrapes. In general, miRNAs located in the same cluster showed similar expression profiles, suggesting common regulatory mechanisms. For 5 of the 106 differentially expressed miRNAs, altered expression could be directly linked to underlying chromosomal alterations. Finally, cell viability assays indicated that ectopic expression of 2 selected miRNAs influenced cell proliferation in vitro, indicating functional relevance of differential miRNA expression during cervical carcinogenesis. In conclusion, deregulation of miRNA expression patterns occurs during cervical carcinogenesis and has functional relevance for cervical cancer development. Since deregulated miRNA expression in cervical (pre)malignant disease is reflected and detectable in cervical scrapes, miRNAs represent a highly promising class of disease markers for further improvement of the triage of high-risk HPV positive women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4959. doi:10.1158/1538-7445.AM2011-4959
CILOSTAZOL ENHANCES MOBILIZATION OF CIRCULATING ENDOTHELIAL PROGENITOR CELLS AND IMPROVES ENDOTHELIUM-DEPENDENT FUNCTION MEDIATED BY MODIFYING METABOLIC AND ANGIOGENIC MARKERS IN PATIENTS WITH HIGH RISK FOR CARDIOVASCULAR DISEASE
Authors: Ting-Hsing Chao, I-Chih Chen, Ping-Yen Liu, Wei-Chuan Tsai, Yi-Heng Li, Shih-Ya Tseng, Jyh-Hong Chen
Journal: Journal of the American College of Cardiology (2015)
H7N9 Live Attenuated Influenza Vaccine Is Highly Immunogenic, Prevents Virus Replication, and Protects Against Severe Bronchopneumonia in Ferrets
Authors: Jørgen de Jonge, Irina Isakova-Sivak, Harry van Dijken, Sanne Spijkers, Justin Mouthaan, Rineke de Jong, Tatiana Smolonogina, Paul Roholl, Larisa Rudenko
Journal: Molecular Therapy (2016)

Avian influenza viruses continue to cross the species barrier, and if such viruses become transmissible among humans, it would pose a great threat to public health. Since its emergence in China in 2013, H7N9 has caused considerable morbidity and mortality. In the absence of a universal influenza vaccine, preparedness includes development of subtype-specific vaccines. In this study, we developed and evaluated in ferrets an intranasal live attenuated influenza vaccine (LAIV) against H7N9 based on the A/Leningrad/134/17/57 (H2N2) cold-adapted master donor virus. We demonstrate that the LAIV is attenuated and safe in ferrets and induces high hemagglutination- and neuraminidase-inhibiting and virus-neutralizing titers. The antibodies against hemagglutinin were also cross-reactive with divergent H7 strains. To assess efficacy, we used an intratracheal challenge ferret model in which an acute severe viral pneumonia is induced that closely resembles viral pneumonia observed in severe human cases. A single- and two-dose strategy provided complete protection against severe pneumonia and prevented virus replication. The protective effect of the two-dose strategy appeared better than the single dose only on the microscopic level in the lungs. We observed, however, an increased lymphocytic infiltration after challenge in single-vaccinated animals and hypothesize that this a side effect of the model.
Abstract 1940: Successful eradication of established peritoneal ovarian tumors in SCID-beige mice following adoptive transfer of T cells genetically targeted to the MUC16 antigen
Authors: Alena A. Chekmasova, Dharmarao Thapi, Yan Nikhamin, Kay J. Park, David R. Spriggs, Renier J. Brentjens
Journal: Cancer Research (2010)

Abstract Most patients diagnosed with ovarian cancer will ultimately die from their disease. For this reason, novel approaches to the treatment of this malignancy are needed. Adoptive transfer of a patients own T cells, genetically modified ex vivo through the introduction of a gene encoding an chimeric antigen receptor (CAR), an artificial T cell receptor, targeted to a tumor associated antigen, is a novel and promising approach to cancer therapy applicable to the treatment of ovarian cancer. We have generated several CARs targeted to the retained extracellular domain of MUC16, termed MUC-CD, an antigen highly expressed on a majority of ovarian carcinomas. We investigate the in vitro biology of human T cells retrovirally transduced to express these CARs by co-culture assays on artificial antigen presenting cells (AAPCs) generated from NIH3T3 fibroblasts genetically modified to express the target MUC-CD antigen, as well as by cytotoxicity and proliferation assays utilizing the target human OV-CAR3(MUC-CD) ovarian tumor cell line. Finally, we assess the in vivo anti-tumor efficacy of human MUC-CD targeted T cells in a SCID-Beige orthotopic, xenogeneic OV-CAR3(MUC-CD) murine tumor model. CAR modified MUC-CD targeted T cells exhibited efficient in vitro cytolytic activity against cell lines which expressed the MUC-CD antigen and could be further expanded ex vivo through multiple cycles of co-culture on 3T3(MUC-CD/B7.1) AAPCs. Expanded MUC-CD targeted T cells infused into SCID-Beige mice bearing intraperitoneal human OV-CAR3(MUC-CD) tumors either delayed progression or fully eradicated tumor even in the setting of advanced disease. These promising pre-clinical studies justify further investigation of MUC-CD targeted T cells as a potential therapeutic approach in the clinical setting treating patients with high risk MUC-16+ ovarian carcinomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1940.