tbuckley/cabot-search huggingface dataset:
Abstract 5058: Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer
Authors: Alejandra V. Paez, Carla Pallavicini, Federico Schuster, Jimena Giudice, Pia Valacco, Estefania Labanca, Nicolas Anselmino, Emiliano Ortiz, Maria Binaghi, Javier Cotignola, Marcelo Marti, Luciana Bruno, Valeria Levi, Nora Navone, Elba Vazquez, Geraldine Gueron
Journal: Cancer Research (2016)

Abstract Prostate Cancer (PCa) is the second leading cause of cancer in men. PCa cells display abnormal expression of cytoskeletal proteins resulting in an augmented capacity to resist chemotherapy and colonize other organs. We have previously shown that heme-oxygenase 1 (HO-1) has a strong anti-tumoral effect in prostate cancer (PCa) and regulates the adhesive properties of PCa cells. Innovative high-throughput proteomic platforms are now identifying and quantifying new specific and sensitive biomarkers for PCa detection, stratification and treatment. Towards this end, we undertook an in-depth mass spectrometry-based proteomics study to build the Heme-oxygenase 1 (HO-1) interactome in PCa, in an effort to identify HO-1 molecular partners associated to the integrity of the cellular architecture and assess actin dynamics of PCa cells under HO-1 modulation. The proteomics analysis of HO-1 interacting proteins yielded several cytoskeletal-associated proteins regulating actin filament dynamics, such as gelsolin, lasp1, SIPA1L1, testin, moesin, tropomodulin and vinculin. The bioinformatics screening across the Oncomine platform revealed that the RNA expression profiles of the cytoskeletal HO-1 interacting proteins, lie within the 10 percent of the most consistently low-expressed genes in prostate adenocarcinoma compared to normal tissue. Motility changes were assessed on fiber-like 2D migration scenarios displaying a reduced frequency in migration events and in migration speed under hemin exposure, a specific pharmacological inducer of HO-1. A significant higher proportion of filopodia-like protrusions among neighboring cells and cellular contacts were observed when HO-1 was induced; effects reversed under HO-1 silencing. Altogether, our experimental findings demonstrate that HO-1 modulation in PCa induces the remodeling of the actin filament architecture at filopodia, alters the migratory patterns and cellular morphology, showcasing the relevance of the cytoskeletal proteins as potential therapeutic targets against the aggressive and metastatic disease. Citation Format: Alejandra V. Paez, Carla Pallavicini, Federico Schuster, Jimena Giudice, Pia Valacco, Estefania Labanca, Nicolas Anselmino, Emiliano Ortiz, Maria Binaghi, Javier Cotignola, Marcelo Marti, Luciana Bruno, Valeria Levi, Nora Navone, Elba Vazquez, Geraldine Gueron. Hitting the brakes on the migratory capacity of tumoral cells: Targeting key regulators of actin dynamics in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5058.
Abstract 975: Hypoxic long noncoding RNA NDRG1-OT1 inhibit NDRG1 in MCF-7 breast cancer cell line
Authors: Hsin-Chen Lin, Liang-Chuan Lai, Hsing-Guang Chen, Hung-Hsin Chen, Mei-Hung Chang, Mong-Hsun Tsai, Eric Y. Chung
Journal: Cancer Research (2016)

Abstract Hypoxia is a crucial factor that associated with solid tumor progression by driving multiple signaling pathway. Our lab previously reported that NDRG1 was oxygen-responsive genes and could affect cellular function in a breast cancer cell line MCF-7. Long-non coding RNAs (lncRNAs) have recently emerged as important regulators of tumor progression by participating in several process of gene expression. However, it is unclear whether lncRNAs are responsed to oxygen concentrations in breast cancer. Therefore, the aim of this study is to identify lncRNAs which are responsive upon changes in oxygen concentrations, and its regulatory mechanism in the breast cancer MCF-7 cells. We investigated the differentially expressed lncRNAs in different oxygen concentrations using next-generation sequencing (NGS) and validated these results through quantitative reverse transcription polymerase chain reaction (qRT-PCR). We found an lncRNA, NDRG1-OT1, that was up-regulated during hypoxia and down-regulated during reoxygenation. Next, we identified the differentially expressed genes regulated by NDRG1-OT1 using microarrays and confirmed these results through qRT-PCR and Western blotting. We found an oxygen responsive gene, NDRG1, was inhibited by NDRG1-OT1. Furthermore, Ingenuity Pathway Analysis(IPA) indicated that NDRG1-OT1 could involve in the Ubiquitin-proteasome pathway. We considered NDRG1-OT1 might regulate NDRG1 stability and ubiquitination, and we are proving these possibility by immunoblotting and immunoprecipitation. These findings may provide new insights into epigenetic regulation of breast cancer during hypoxia. Citation Format: Hsin-Chen Lin, Liang-Chuan Lai, Hsing-Guang Chen, Hung-Hsin Chen, Mei-Hung Chang, Mong-Hsun Tsai, Eric Y. Chung. Hypoxic long noncoding RNA NDRG1-OT1 inhibit NDRG1 in MCF-7 breast cancer cell line. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 975.
Prognostic Impact of a Monosomal Karyotype on the Outcome of Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Stem Cell Transplantation
Authors: Philipp G. Hemmati, Theis H. Terwey, Philipp D. le Coutre, Christian Ziegler, Grzegorz Kofla, Gero Massenkeil, Bernd Dörken, Renate Arnold
Journal: Blood (2011)
Abstract 3907: Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes
Authors: Rikke Y. Brogaard, Rasmus Eliasen, Fredrik Melander, Anders E. Hansen, Andreas Kjær, Thomas Lars Andresen
Journal: Cancer Research (2016)

Abstract Introduction: Drug bioavailability following intra-tumoral accumulation is a major challenge in existing drug delivery systems. A site-specific trigger for obtaining drug release specifically in tumor tissue would overcome this problem and enhance the antitumor effect of the carried drug. Our aim was to develop a new drug delivery platform based on liposomes that are sensitive to matrix metalloproteinases (MMPs). Methods: In the present work, we have designed a matrix metalloproteinase (MMP)-sensitive liposomal drug delivery system encapsulating oxaliplatin, which by tumor-specific enzymatic dePEGylation allows for controlling the precision of drug release. The dePEGylation is provided by a cholesterol-anchored PEGylated lipopeptide containing a short peptide sequence cleavable by MMP-2 and MMP-9. These MMP-sensitive liposomes are designed to make a charge-reversal transformation upon encountering MMPs in the tumor environment. The surface charge of the liposome turns from slightly negative to positive, resulting in cationic liposomes. In vitro cellular uptake of the liposomes was assessed using flow cytometry and ICP-MS, and further confirmed by confocal microscopy in CT26 and HT1080 cell lines. In vivo studies was evaluated in a syngeneic murine model of MMP-positive CT26 colon cancer. Results: We successfully formulated MMP-sensitive, oxaliplatin encapsulated liposomes and characterized their zeta potential, size, stability and encapsulation efficiency. The results showed uniformly dispersed particles, and the charge-reversal properties were confirmed as the surface charge changed from slightly negative to distinct positive upon enzymatic cleavage generating cationic liposomes. These MMP-sensitive liposomes were evaluated in vitro and in vivo with a high correlation. In vivo studies showed a prolonged circulation profile with minimal leakage, and similar accumulation in tumors as conventional Stealth liposomes. Efficacy experiment in the same model demonstrated significantly improved antitumor activity relative to free oxaliplatin, and with a superior effect compared to the conventional Stealth liposomes. Conclusion: With this study, we establish a promising liposomal drug delivery platform for the carriage and release of numerous anticancer drugs into the microenvironment of an MMP-positive tumor. Citation Format: Rikke Y. Brogaard, Rasmus Eliasen, Fredrik Melander, Anders E. Hansen, Andreas Kjær, Thomas Lars Andresen. Enhanced chemotherapeutic effect with matrix metalloproteinase sensitive liposomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3907.
Abstract LB-102: A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma
Authors: Maria Shabbir, Minakshi Nihal, Chandra K. Singh, B Jack Longley, Nihal Ahmad
Journal: Cancer Research (2016)

Abstract Malignant melanoma is one of the deadliest forms of skin cancer that remains resistant to existing therapeutic strategies. According to the SEER (Surveillance, Epidemiology, and End Results) program database of the National Cancer Institute, the 5-year survival rate for metastatic melanoma is a dismal 16%. Further, of the seven most common cancers in the USA, melanoma is the only neoplasm with constantly increasing incidence. Therefore, it is important to intensify our efforts to better-understand the genetics and biology of melanoma. This may lead to development of novel targets and biomarkers for management of this hard-to-treat neoplasm. This study was undertaken to determine the role and potential significance of polo-like kinase 4 (PLK4) in human melanoma. PLK4 is a serine/threonine kinase that has been shown to localize to centrioles and regulate centriole duplication during the cell cycle. While the potential role of PLK4 in cancer is beginning to be appreciated, there are evidence for its function as a tumor suppressor as well as tumor promoter. However, the role of PLK4 in melanoma is not known. Here, we employed in vitro and ex vivo experiments to determine the role of PLK4 in melanoma. Our data demonstrated that PLK4 was significantly overexpressed, both at mRNA and protein levels in human melanoma cells viz. A375, Hs294T, G361, 451Lu; when compared to the normal human epidermal melanocytes (NHEM). We also found a significant increase in PLK4 immunostaining in clinical melanoma tissues, compared to normal skin and nevus tissues. Further, treatment of melanoma cells with a selective small molecule PLK4 inhibitor, centrinone-B, was found to cause a significant decrease in the cell growth/viability and clonogenic survival in multiple melanoma cell lines. The observed anti-proliferative effects of centrinone-B were found to be accompanied with i) a G0/G1 phase arrest of cell cycle, and ii) induction of apoptosis, in human melanoma cells. Taken together, our study suggests a pro-proliferative role of PLK4 in human melanoma. Additional studies are ongoing in our laboratory to determine the functional significance of PLK4 in melanoma. We suggest that PLK4 should be further evaluated as a potential ‘druggable target’ and biomarker, for the management of melanoma. Citation Format: Maria Shabbir, Minakshi Nihal, Chandra K. Singh, B Jack Longley, Nihal Ahmad. A pro-proliferative function of centriole duplication regulator, polo-like kinase-4 in human melanoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-102.
Abstract 2419: Anastomotic recurrences are clonally related to primary tumors in sporadic colorectal carcinoma
Authors: Efsevia Vakiani, Ronak H. Shah, Christine Iacobuzio-Donahue, David B. Solit, Martin R. Weiser
Journal: Cancer Research (2016)

Abstract Background: Anastomotic recurrences occur in 2-10% of colorectal carcinoma (CRC) cases after surgical resection of the primary tumor. To date there are no molecular data investigating their genetic profile and multiple theories exist as to their pathogenesis including re-growth of tumor cells present within local lymphatics after initial surgery, seeding of anastomosis by metastatic tumor cells and a second primary tumor. The aim of our study was to compare the genomic profile of anastomotic recurrences to that of matched primary tumors and, where available, to that of distant metastases. Design: Thirty-six tumors from 14 patients were genotyped using a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 341 key cancer genes. All patients had resection of their primary tumor with clear margins and recurred either at the anastomotic line or in the peri-anastomotic area 1.1 to 7.0 years following resection of their primary tumor. In 3 patients 2 consecutive anastomotic recurrences were sequenced, while in 6 patients a distant metastasis that occurred 1.2 to 3 years prior to the anastomotic recurrence was also analyzed. All tumors were microsatellite stable except in one patient with genetically confirmed Lynch syndrome. Results: A total of 254 somatic mutations were detected including 140 mutations in the microsatellite stable cases. The most commonly mutated genes (mutated in &amp;gt; 3 patients) were APC, KRAS, TP53, PIK3CA, ATM and PIK3R1. In 13/14 patients the anastomotic recurrence(s) and primary tumor shared between 50-100% of mutations, including mutations in key driver genes such as APC, KRAS and TP53, consistent with these tumors being clonally related. In the patient with the Lynch syndrome the 2 tumors showed distinct somatic mutations suggestive of independent primaries. We identified eleven genetic events present in a distant metastasis and not in a primary tumor and none of these events was detected in the anastomotic recurrence arguing against re-seeding of the anastomotic site by a metastatic clone. All five patients with isolated anastomotic recurrence were free of disease 0.9 to 6.1 years following resection of their recurrent CRC. Conclusions: Anastomotic recurrences appear to be clonally related to the primary tumor in sporadic CRC cases. Our data also provide molecular data in support of the treatment of anastomotic recurrences as localized disease. Citation Format: Efsevia Vakiani, Ronak H. Shah, Christine Iacobuzio-Donahue, David B. Solit, Martin R. Weiser. Anastomotic recurrences are clonally related to primary tumors in sporadic colorectal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2419.
Abstract 4940: Use of whole slide digital image analysis for determination of expression of Twist-1 in normal panceata and stage IV pancreatic ductal adenocarcinomas
Authors: Max Jacobsen, George Sandusky, Kavita Shah
Journal: Cancer Research (2016)

Abstract Pancreatic cancer is the 4th most common cause of cancer deaths in this country. Close to 50,000 deaths occur every year. This is due to the fact that most patients are not diagnosed until presentation at a stage IV. In a recent study, it is estimated that more than 10 years go by between the first genetic mutation and the formation of invasive cancer. More mutations occur in metastatic lesions after an additional 6 years. Both SNAIL and TWIST have gained more attention as biomarkers because that contribute to E-cadherin dysregulation that allows the tumor cells to invade. In this study we evaluated 17 cases of pancreatic ductal adenocarcinoma using twist-1 antibody to evaluate tumor cell expression in these cases. All paraffin blocks were retrieved from the IU pathology department files via an IRB approved protocol. The unstained slides were stained with primary antibody Twist-1 using the DAKO Flex system. Control sections were treated with an isotype control using the same concentration as primary antibody to verify the staining specificity. The Aperio whole slide system was used to image the slides. Computer-assisted morphometric analysis of digital images was carried out using the Aperio Image scope software using the positive pixel algorithm. The algorithm was used to quantify the Twist-1 positivity of normal pancreas, and pancreatic ductal adenocarcinoma. This algorithm is the only FDA approved algorithm for human clinical trials. The immunostaining of Twist-1 was found only in the ductal epithelial carcinoma cells in the pancreas. There was no staining in the stroma in any of the normal pancreas and ductal pancreatic carcinoma cases. We analyzed 5 normal pancreata, and 12 pancreatic ductal adenocarcinomas. The data from the image analysis was 3.38% expression in normal pancreata and 11.44% expression in the pancreatic ductal adenocarcinoma. In summary, the image analysis data demonstrates the overexpression of Twist-1 in stage IV pancreatic adenocarcinomas compared to the normal pancreas. This suggests that this marker may be a predictor of tumor invasiveness and metastasis. Citation Format: Max Jacobsen, George Sandusky, Kavita Shah. Use of whole slide digital image analysis for determination of expression of Twist-1 in normal panceata and stage IV pancreatic ductal adenocarcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4940.
EGFR mutation screening in non-small cell lung cancer: Results from an access program in Brazil.
Authors: Luciola De Barros Pontes, Carlos E Bacchi, Eduardo M Queiroga, Tony Piha, Paulo Andre Miranda, Sandra Freire, Gilberto Lopes
Journal: Journal of Clinical Oncology (2014)

1526 Background: Epidermal growth factor receptor (EGFR) mutation testing allows for optimal selection of therapy with tyrosine kinase inhibitors in patients with non-small-cell lung cancer (NSCLC). Previous studies have shown a variation in EGRF genotype according to ethnic background, with scarce data about EGFR mutation status among brazilian patients with NSCLC. Methods: Between 2011 and 2013, as part of a program sponsored by a pharmaceutical company in Brazil, tumor samples of patients with stage IIIb/IV NSCLC were submitted, at the discretion of the attending physicians, for EGFR mutation testing. All analysis were performed at 02 reference laboratories, as follows: after microdissection, DNA was isolated from serial sections of formalin-fixed, paraffin-embedded tumor tissue to obtain at least 70% tumor cells. Exons 18, 19, 20 and 21 of the EGFR gene were analysed using Sanger sequencing. EGFR mutation rate was calculated and its frequency compared between clinical subgroups using chi-square test. Data about smoking status was incomplete and thus not included in this analysis. Results: 3,771 (1,799 male; 1,942 female) samples were analysed, of which 3364 provided informative results. Frequency of EGFR mutation was 25.5% (857/3364). Deletions in exon 19 were the most frequent alterations detected (54%; 463/857), followed by point mutations in exon 21 (28%; 240/857), exon 20 (9.7%; 83/857) and, less frequently, mutations in exon 18 (8.3%; 71/857). The median age for patients with a positive test was 66 years (range, 28-95). The most important predictors for the presence of EGFR mutations were adenocarcinoma histology (p<0.001), with 89% of positive tests occurring in this histology (331/370 - available data), and female gender (p<0.001), in which 30.2% of the patients tested were positive. No differences in EGFR mutation frequency were found between age groups. Conclusions: To the best of our knowledge, this is the largest study to assess EGFR mutation status in Latin America and in Brazil. Our findings suggest that the frequency of EGFR mutation in this cohort was lower than that found in Asia, but higher than in Caucasian populations, confirming findings seen in other Latin American countries.
Abstract 1965: CRISPR/cas9, an innovative genomic tool to knock down microRNA
Authors: Hong Chang, Bin Yi, Ruixia Ma, Hongyou Zhao, Yaguang Xi
Journal: Cancer Research (2016)

Abstract MicroRNAs are a set of small and non-coding RNA molecules showing the “master” role in regulation of coding-gene expression at the post-transcriptional/translational levels. Several methods have been developed for microRNA loss-of-function study, such as antisense inhibitors and sponges; however, their robustness, specificity, and stability cannot be highly satisfied with the increased demand on microRNA functional research. CRISPR/cas9 system is emerging as a novel genome editing tool that has been exclusively studied in coding-genes knockdown, but its indication in microRNA research has not been explored yet. In this project, we clone CRISPR/cas9 constructs with designated single guide RNAs targeting biogenesis processing sites of the selected microRNAs, miR-200b and miR-17. Our results demonstrate that CRISPR/cas9 can robustly reduce the expression of these microRNAs up to 96%. More significantly, our data support high specificity and low off-target effect of CRISPR/cas9 in editing microRNA genes. Given this feature, it possesses an advantage to knockdown microRNAs in same family or with highly conserved sequences superior to antisense inhibitors and sponges. In addition, for the first time, we demonstrate the long term stability of microRNA knockdown phenotype by CRISPR/cas9 in both in vitro and in vivo models. In conclusion, we develop a novel method by adapting CRISPR/cas9 system to downregulate microRNA expression, which shows improved robustness, specificity, and stability than the previously established methodologies. Citation Format: Hong Chang, Bin Yi, Ruixia Ma, Hongyou Zhao, Yaguang Xi. CRISPR/cas9, an innovative genomic tool to knock down microRNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1965.
Abstract 2966: Preclinical combinations of the antibody-drug conjugate SGN-LIV1A with chemotherapies show increased activity
Authors: Fu Li, Martha Anderson, Joshua Hunter, Jaime Miyamoto, Michelle Ulrich, Ana Kostic, Che-Leung Law, Django Sussman
Journal: Cancer Research (2016)

Abstract SGN-LIV1A is an antibody-drug conjugate (ADC) currently being evaluated in a phase 1 clinical trial for metastatic breast cancer. SGN-LIV1A consists of the microtubule disrupting agent, monomethyl auristatin E (MMAE), conjugated to the anti-LIV-1 humanized monoclonal antibody hLIV22. LIV-1, as a downstream target of STAT3, promotes the epithelial to mesenchymal transition that is important in the malignant progression to metastasis. We have previously shown that as a single agent, SGN-LIV1A displays target specific internalization and cytotoxic activity against a breast cancer cell line in vitro and also demonstrates antitumor activity in in vivo preclinical xenograft models with significant delay of tumor growth. We report here additive and synergistic effects when combining SGN-LIV1A with current chemotherapeutic modalities used in the treatment of metastatic breast cancer. Specifically, we show synergy between SGN-LIV1A in combination with either doxorubicin or Abraxane in MCF-7 breast cancer tumor model. In addition, we show additive effects when carboplatin or protein kinase inhibitors are dosed in combination with SGN-LIV1A in this tumor model. These findings support further evaluation and development of SGN-LIV1A in combination with standard of care chemotherapeutic agents for the treatment of breast cancer. Citation Format: Fu Li, Martha Anderson, Joshua Hunter, Jaime Miyamoto, Michelle Ulrich, Ana Kostic, Che-Leung Law, Django Sussman. Preclinical combinations of the antibody-drug conjugate SGN-LIV1A with chemotherapies show increased activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2966.