tbuckley/cabot-search huggingface dataset:
Integrated genomics-based discovery of new oncoproteins as a biomarker and a molecular target for lung cancer.
Authors: Y. Daigo, A. Takano, Y. Nakamura
Journal: Journal of Clinical Oncology (2010)

10632 Background: Identification of cancer-specific oncoproteins is an effective approach to develop novel diagnostics and therapeutics. Methods: We have established a strategy as follows to identify new oncoproteins; i) To identify up-regulated genes in lung cancers using the cDNA microarray representing 27,648 genes and 120 lung cancers, ii) To verify the candidate genes for their low expression in 23 normal tissues by northern-blot analysis, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering 422 non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth of cancer cells by siRNA assays, and v) To measure their serum protein levels by ELISA using three independent sets of samples. Results: We identified 25 oncoproteins and selected a cell surface protein, Nectin- 4. Nectin-4 protein positivity in tumors was associated with poor prognosis for NSCLCs (p < 0.0001; n = 422), and multivariate analysis confirmed its independent prognostic value (p < 0.0001). We established an ELISA for serum Nectin-4 and found that serum Nectin-4-positive cases was 88 (53.7%) of 164 NSCLCs, while 3 (2.3%) of 131 healthy volunteers were falsely diagnosed, which was superior to carcinoembryonic antigen (CEA) and cytokeratin 19- fragment (CYFRA21-1). The prognostic value of serum Nectin-4 was examined in two additional sets of serum samples. The median survival time of serum Nectin-4 positive patients with stage I NSCLC after curative surgery (n = 95) or stage IIIB-IV NSCLC treated with an identical protocol of the 1st-line chemotherapy (carboplatin and paclitaxel; n = 62) was shorter than those of patients with serum Nectin-4 negative (p = 0.0219 and p = 0.0269, respectively). In addition, suppression of Nectin-4 expression by siRNAs inhibited lung cancer cell growth, while expression of Nectin-4 increased the lamellipodia formation and the invasive ability of mammalian cells through activation of small GTPase Rac1. Conclusions: Nectin-4 is a biomarker for early cancer detection and for predicting the disease progression and a target for developing new drugs such as nucleic acid drugs, monoclonal antibodies, and cancer vaccines. No significant financial relationships to disclose.
Prognostic Impact of Molecular Mutations in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) on Allogeneic Hematopoietic Cell Transplant (HCT) Outcomes: Adverse Impact of TET2 Mutations
Authors: Betty K. Hamilton, Navneet S. Majhail, Cassandra M Hirsch, Bartlomiej Przychodzen, Lisa A. Rybicki, Marcos De Lima, Matt Kalaycio, Brian J. Bolwell, Aaron T. Gerds, Ronald Sobecks, Rabi Hanna, Mikkael A. Sekeres, Jaroslaw P. Maciejewski
Journal: Blood (2015)
Abstract 4488: Targeted sequencing revealed distinctive and pathogenic mutations in African Americans with colorectal cancer
Authors: Hassan Ashktorab, Hamed Azimi, Mike Nickerson, Sara Bass, Joseph Boland, Meredith Yeager, Sudhir Varma, Mohamed Daremipouran, Zaki Sherif, Shima Ghavimi, Babak Shokrani, Edward Lee, Adeyinka Laiyemo, Hassan Brim
Journal: Cancer Research (2016)

Abstract Background &amp; Aim: We recently analyzed 12 pairs of African American CRC tumors and their matched normal tissue using whole exome sequencing and established a panel of novel mutations that are potentially useful for the detection of CRC in this population. In this study, we examined APC, MSH3, and MSH6 mutations using targeted exome sequencing (TES) to determine distinctive mutations frequencies and their chronology in the neoplastic transformation. Materials &amp; Methods: A total of 140 colon samples: (30 normal, 21 adenomas, 33 advanced adenomas &amp; 56 tumors collected from African Americans were used as our discovery set on an Ion Torrent platform. A subset of 36 samples were used as validation set on an Illumina platform. Bioinformatic analysis was performed on both sets of data. Common mutations were considered validated. Results: Two novel MSH6 mutations were validated. Four known mutations in MSH3 were validated and were located in nonsynonymous (exon 10) and 1synonomous mutation (exon 18). As for the APC, 20 mutations were validated include 4 novel mutations. The novel mutations were 3 stopgain and 1 nonsynonymous located at the EB1 binding site, in the mutational cluster region (MCR), and at the 15 Amino Acid repeat. Conclusion: We here defined novel mutations that target DNA MMR and APC genes in African Americans with colorectal lesions. Greater frequency of mutations in cells defective for DNA repair and APC genes is an advantage in cell growth and genetic instability and relevant to the initiating events of colon tumorigenesis. Citation Format: Hassan Ashktorab, Hamed Azimi, Mike Nickerson, Sara Bass, Joseph Boland, Meredith Yeager, Sudhir Varma, Mohamed Daremipouran, Zaki Sherif, Shima Ghavimi, Babak Shokrani, Edward Lee, Adeyinka Laiyemo, Hassan Brim. Targeted sequencing revealed distinctive and pathogenic mutations in African Americans with colorectal 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 4488.
Abstract 3916: A “moneyball” approach to predicting clinical trial toxicity events
Authors: Kaitlyn Gayvert, Neel Madukhar, Olivier Elemento
Journal: Cancer Research (2016)

Abstract Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, clinical attrition rates have continued to substantially rise. Clinical trials can fail for a variety of reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (which we term the sensitivity) and drugs that fail clinical trials (specificity). We introduce an approach that integrates chemical properties of a compound, along with that of its targets, to provide a new quantitative measure that helps predict whether drugs in clinical trials will fail for toxicity reasons. When trained on failed clinical trials and FDA approved drugs, this method performs at a high accuracy, specificity and sensitivity (∼0.75), as well as high area under the ROC curve (&amp;gt;0.80). In comparison, none of the drug-likeness approaches were able to successfully maintain both high sensitivity and specificity. A feature analysis of the model indicates that it is critical to consider both structural properties and properties of the drug target, with the target's network connectivity and liver toxicity as two important features. The approach was further evaluated by testing the predictions of the trained model on an established independent dataset. We found that our method was able to significantly distinguish a representative set of bioavailable drugs from a representative set of toxic drugs (D = 0.2133, p&amp;lt;2.2e-16, Kolmogorov-Smirnov test). Additionally, we found that the measure is strongly correlated with severe toxicity events, such as pleural effusion (ρ = −0.9792) and neutropenia (ρ = −0.9613). Altogether, our method provides a novel, broadly applicable strategy that is able to identify drugs likely to possess manageable toxicity in clinical trials. Citation Format: Kaitlyn Gayvert, Neel Madukhar, Olivier Elemento. A “moneyball” approach to predicting clinical trial toxicity events. [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 3916.
Abstract 1144: Detection of a novel ALK fusion variant in lung adenocarcinoma using a comprehensive genomic analysis
Authors: Kazuhiko Shien, Dennis Ruder, Ecaterina E. Ileana, Vassiliki A. Papadimitrakopoulou, Garrett M. Frampton, Carmen Behrens, Neda Kalhor, J. Jack Lee, Ximing Tang, Roy S. Herbst, Ignacio I. Wistuba, Julie G. Izzo
Journal: Cancer Research (2016)

Abstract Background: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in a subset of non-small cell lung cancer (NSCLC), mainly as a result of chromosomal translocation. In ALK-rearranged NSCLC, the growth of tumors is strongly addicted to ALK activity, and suppression of ALK is a potent therapeutic strategy. To date, 6 known fusion partners of ALK onco-kinase have been reported in NSCLC, although the sensitivity to ALK inhibitor according to fusion variant except for EML4-ALK is still unclear. In this study, we reviewed clinical trial samples analyzed by comprehensive genomic profiling approach to detect unknown actionable ALK rearrangements. Materials and methods: We reviewed gene alteration and expression profile of clinical samples in preliminary molecular studies from the ongoing BATTLE-2, phase II clinical trial of targeted drugs in chemo-refractory NSCLC. Results: In 187 NSCLC samples, 3 samples harbored ALK fusion gene: 2 EML4-ALK and 1 novel ALK fusion variant PRKAR1A-ALK in a lung adenocarcinoma of male former smoker patient. The ALK gene expression levels of ALK-rearranged samples were significantly higher compared to other samples. Interestingly, the patient harboring PRKAR1A-ALK was treated with ALK inhibitor crizotinib and showed long time stable disease. Conclusions: Our findings suggest that PRKAR1A-ALK fusion could be a novel oncogenic driver in lung adenocarcinoma and an indicator of ALK inhibitor response. (NHI-NCI CA155196; 2P50CA070907-16A1) Citation Format: Kazuhiko Shien, Dennis Ruder, Ecaterina E. Ileana, Vassiliki A. Papadimitrakopoulou, Garrett M. Frampton, Carmen Behrens, Neda Kalhor, J. Jack Lee, Ximing Tang, Roy S. Herbst, Ignacio I. Wistuba, Julie G. Izzo. Detection of a novel ALK fusion variant in lung adenocarcinoma using a comprehensive genomic analysis. [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 1144.
Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction
Authors: Ana G. Antun, Paul Monahan, Marilyn J. Manco-Johnson, Michael Callaghan, Guy Young, Christine Knoll, Shannon Carpenter, Joanna A. Davis, Michael F. Guerrera, Rebecca Kruse-Jarres, Margaret V. Ragni, Char Witmer, Courtney E. McCracken, Maralee Kanin, Christine L. Kempton
Journal: Blood (2013)
Abstract 3190: Genomic profiling of salivary gland tumors identifies novel and targetable alterations
Authors: Hanna Majewska, Judith Müller, Sotirios Lakis, Piotr Czapiewski, Adam Gorczyński, Mariola Iliszko, Alena Skalova, Rafal Dziadziuszko, Jacek Jassem, Wojciech Biernat, Roopika Menon, Johannes M. Heuckmann, Lukas C. Heukamp
Journal: Cancer Research (2016)

Abstract Background Salivary gland neoplasms represent a heterogeneous group of benign and malignant tumors that comprise 6% of all head and neck cancers. Due to their low incidence, these tumors are poorly understood and remain a diagnostic and therapeutic challenge. Methods Out of 182 analyzed salivary gland tumors with various histologies, eight were positive for ALK immunohistochemistry. The cut-off was 15% positive cells in either membranous, nuclear or cytoplasmic compartments. The ALK positive tumors were first subjected to FISH analysis. Subsequently, these tumors were analyzed using hybrid capture based next generation sequencing to confirm possible ALK gene fusions or copy number alterations, and to detect additional genomic alterations of clinical relevance. Results An in-depth genomic analysis of the samples resulted in the detection of inactivating mutations in BRAF (p.D594N) and TP53 (p.C238S), as well as amplifications of ERBB2 and ALK. Strikingly, a novel MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion was detected in a patient with adenocarcinoma not otherwise specified. This tumor was FISH positive and 100% of cells showed strong membranous staining for ALK. MYO18A (Exon1-40)-ALK (exon 20-29) gene fusion resulted in the retention of the kinase domain of ALK and the coiled-coil domain of MYO18A. Similarly to other ALK fusions, we hypothesize that the coiled-coil domain of MYO18A mediates the dimerization and activation of MYO18A-ALK, thereby resulting in an overexpression of constantly activated ALK. Conclusion Using hybrid capture based next generation sequencing, we identified in salivary gland tumors numerous genomic alterations in therapeutically relevant genes and a novel gene fusion (MYO18A-ALK). Patients harboring this fusion may potentially benefit from treatment with ALK inhibitors. Citation Format: Hanna Majewska, Judith Müller, Sotirios Lakis, Piotr Czapiewski, Adam Gorczyński, Mariola Iliszko, Alena Skalova, Rafal Dziadziuszko, Jacek Jassem, Wojciech Biernat, Roopika Menon, Johannes M. Heuckmann, Lukas C. Heukamp. Genomic profiling of salivary gland tumors identifies novel and targetable alterations. [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 3190.
Abstract 4546: Ubc9 sumoylation is required for its interaction with CDK6 through SUMO-interacting motif (SIM) and regulates CDK6 sumoylation in glioblastoma
Authors: Anita Bellail, Chunhai Hao
Journal: Cancer Research (2016)

Abstract Small ubiquitin-like modifier-1 (SUMO1) is a conserved member of the ubiquitin-related protein family. Recently we have shown that the cell cycle G1 phase cyclin-dependent kinase-6 (CDK6) is modified by SUMO1 in glioblastoma (Bellail et al., Nat Commun. 2014). CDK6 sumoylation stabilizes CDK6 protein and its kinase activity and drives cell cycle progression for the cancer development and progression. SUMO1 is covalently attached to the Lysine 216 of the CDK6 protein through catalytic reactions by an E1 (SUMO-activating enzyme 1/2) and an E2-conjugating enzyme (UBC9). In this study, we further showed that UBC9 is phosphorylated by CDK1 kinase during mitosis and UBC9 phosphorylation increases the interaction of UBC9 with CDK6 and enhances SUMO1-CDK6 conjugation. Knockdown of SUMO1 by small hairpin RNA (shRNA) abolishes the interaction of UBC9 and CDK6 and SUMO1-CDK6 conjugation. UBC9 is conjugated by SUMO1 and recognizes its substrate protein through interaction of SUMO1 and SUMO-Interacting motif (SIMs) on the substrate protein. Indeed, the survey of CDK6 amino acid sequence and structure identified four SIMs on CDK6 protein. Each SIM was mutated to abrogate its binding property. Of the 4 SIMs, the CDK6-SIM4 is responsible for UBC9-CDK6 interaction as demonstrated by the finding that mutation of the first two amino-acids of the SIM sequence abolishes UBC9-CDK6 interaction and SUMO1-CDK6 conjugation. Our data show that UBC9 sumoylation is required for its interaction with CDK6 protein through SIM and thus involved in glioblastoma progression. Citation Format: Anita Bellail, Chunhai Hao. Ubc9 sumoylation is required for its interaction with CDK6 through SUMO-interacting motif (SIM) and regulates CDK6 sumoylation in glioblastoma. [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 4546.
Composition of the Sepsis Definitions Task Force
Authors: Gentle S. Shrestha
Journal: JAMA (2016)

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Abstract 1951: Expression profiling, cellular and clinical implications of mitochondrial miRNAs in colorectal carcinomas
Authors: Faeza Ebrahimi, Vinod Gopalan, Alfred Lam
Journal: Cancer Research (2016)

Abstract Aim: The aim of this study was to determine the expression profiling and cellular implications of mitochondrial miRNAs (Mitomirs) such asmiR-145, miR-15a, miR-335 and miR-126)in colorectal cancer tissues. Expression changes in matched metastatic tissues were also examined. Method: Colorectal tissues from163 primary cancers, 96 lymph node, 48 metastatic, 40 adenoma and 42 non-neoplastic tissues were recruited from 389 patients. The expression of Mitomirs in tissues and colon cancer (SW-480, SW-48) and normal (FHC) cell lines were investigated by qRT-PCR. Functional assays including cell proliferation, cell cycle analysis and apoptosis assays were performed with an exogenous miR-126 mimic to detect its in-vitro changes on cancer cell biology. In addition, Western blot was used to detect the targets of miR-126. Result: Expressions of Mitomirs were down-regulated in colorectal cancer tissues compared to non-tumour colorectal tissues. Higher expression of miR-145 was predominantly noted in colorectal cancers with tumour recurrence (P = 0.058). Expression of miR-335 was significantly reduced distal colorectum compared to proximal colon (P = 0.025). Reduced expression of miR-335 also showed significant correlation with occurrence of lymphovascular permeation (P = 0.019), and late T stage (P = 0.004) of colorectal cancer. Moreover, in microsatellite instability (MSI) positive adenocarcinomas, notable downregulation of miR-15a (P = 0.018) was observed and this reduced expression was significantly correlated with size of tumour (&amp;gt; 40 mm) (P = 0.014). Expression of miR-15a, and miR-145 was reduced in metastatic cell line (SW48). Overexpression of miR-126 in-vitro showed increased apoptosis, reduced cell proliferation and suppression of synthetic phase in cell cycle. Also, overexpression of miR-126 has induced reduced expression of BCL-2 protein and increased expression of P53 protein. Conclusion: This study suggests that expression of Mitomirs significantly reduces in advanced stages of cancer and even in early stages in comparison to normal tissues. In vitro studies indicated that ectopic expression miR-126 has the capability of inducing apoptosis and reducing viability of cancers cells potentially via modulating its target partners such as BCL-2 and p53. Citation Format: Faeza Ebrahimi, Vinod Gopalan, Alfred Lam. Expression profiling, cellular and clinical implications of mitochondrial miRNAs in colorectal carcinomas. [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 1951.
Abstract 345: Olive oil-based oleocanthal and bioisosteres as c-Met inhibitors for the control of triple negative breast cancer
Authors: Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Abu Bakar Siddique, Mohamed R. Akl, Mostafa Ibrahim, Khalid A. El Sayed
Journal: Cancer Research (2016)

Abstract Breast cancer is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. Dysregulation of c Met correlates with aggressive proliferation, invasive character, and pathological motility, especially in triple negative breast cancer (TNBC). The Mediterranean diet is known to reduce the incidence of breast and colon malignancies. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the RTK c-Met. Oleocanthal selectively inhibited the proliferation, migration and invasion of several c-Met dependent breast and prostate tumor cell lines. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Several oleocanthal bioisosteres have been semisynthized of which the analog HVS have shown significant activity improvement against breast cancer in vitro and in vivo models. Selectivity profiling against a TKs panel, structurally related to c-Met, suggested the HVS has high selectivity to both Met and ABL1 kinases. Overexpression of ABL1 kinase is implicated in the progression of several solid tumors concomitantly with c-Met activation, including breast, colon, lung and other cancers. ABL1 interconnects oncogenic Met and p53 pathways and hence dual blockage of c-Met and ABL1 activation adds significant advantages over currently approved c-Met inhibitors and may justify its potent in vitro and in vivo activities. Therefore, the dual c-Met/ABL1 inhibitor HVS could not only be effective in slowing TNBC progression but also could prevent drug resistance. Detailed molecular and cellular mechanistic studies of oleocanthal and its bioisosteres indicate their potential for future use to control TNBC and other c-Met-dependent malignancies. This study was supported by NIH/NCI project 1R15CA167475-01. Citation Format: Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Abu Bakar Siddique, Mohamed R. Akl, Mostafa Ibrahim, Khalid A. El Sayed. Olive oil-based oleocanthal and bioisosteres as c-Met inhibitors for the control of triple negative breast 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 345.