tbuckley/cabot-search huggingface dataset:
Abstract 1502: DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development
Authors: Wanglong Qiu, Gloria Su
Journal: Cancer Research (2015)

Abstract BACKGROUND &amp; AIMS: Recently DCLK1 has been controversial as a biomarker of progenitor cells in both intestinal tract and pancreas. Pancreatic intraductal papillary mucinous neoplasm (IPMN), in contrast to pancreatic intraepithelial neoplasia (PanIN), has been relatively less investigated. Here, we explored whether DCLK1-expressing cells were involved in the genesis of pancreatic IPMNs using mouse models. METHODS: We compared the incidence of DCLK1-positive cells in pancreatic tissue samples derived from mouse models for IPMNs, PanINs, acinar to ductal metaplasia (ADM), and human IPMN samples by immunohistochemistry. And how the DCLK1+ cells engage ADM and IPMNs and its origin were investigated by in vitro culture and in vivo lineage tracing. RESULTS: The DCLK1+ cells were identified exclusively in the pancreatic tissues with activated oncogene compared to wild-type. Mouse lineage tracing experiments showed that DCLK1+ cells might originate from a cell lineage distinct from pancreatic PDX1 (+) progenitors. The pancreatic DCLK1+ cells shared the features of tuft cells but absence of IPMN tumor biomarkers. DCLK1+ cells presented in the acinar clusters prior to formation of metaplastic ductal cells, and enriched in the “IPMN niches”. Oncogenic signaling pathways such as SHH and DLL4 were activated or upregulated in the tumor cells but not the DCLK1+ cells of IPMNs. DCLK1 was also expressed in a subpopulation of tumor cells in 20% of human IPMN patients. CONCLUSIONS: DCLK1 labels a unique pancreatic cellular lineage in mouse. The clustering of DCLK1+ cells is an early event in oncogene-induced tumorigenesis. Pancreatic DCLK1+ cells may contribute to the initiation of ADM and its progression to IPMNs. Key words: Pancreatic IPMN; ADM; DCLK1; SOX9. Citation Format: Wanglong Qiu, Gloria Su. DCLK1 labeling a unique pancreatic cellular lineage contributes to intraductal papillary mucinous neoplasm development. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1502. doi:10.1158/1538-7445.AM2015-1502
CBIO-31MECHANISMS OF RESISTANCE TO EGFR INHIBITION REVEAL METABOLIC VULNERABILITIES IN HUMAN GBM
Authors: Andrew McKinney, Olle Lindberg, Jane Engler, Henry Gong, Joseph Shieh, Joanna Phillips
Journal: Neuro-Oncology (2015)

Therapeutic targeting of EGFR signaling in GBM has had largely disappointing results in the clinic. We sought to identify cell vulnerabilities that could be targeted in combination with EGFR. Using a murine model for GBM, primary patient-derived xenografts (PDXs), and human tumor tissue, we identify cellular metabolic changes as an important mechanism of EGFR resistance. Rather than acquired resistance, we observe a subpopulation of tumor cells with unique properties, including increased 3D tumor cell invasion, expression of progenitor cell markers, and altered lipid metabolism, that are uniquely poised to resist EGFR inhibition. Interestingly, this subpopulation of cells is selectively vulnerable to changes in lipid metabolism suggesting its importance in survival. Selection for this subpopulation appears specific to EGFR inhibition, as it is not conferred by inhibition of pathways downstream of EGFR, including Src, PI3K/Akt, and MAPK. In certain human tumors and GBM PDX, expression levels of lipid metabolic enzymes is high in the absence of EGFR inhibition. In these tumors enzyme inhibition conferred decreased tumor cell survival and invasion. Preclinical studies will evaluate the benefit of inhibiting lipid metabolic enzymes in PDX. These data identify specific tumor cell vulnerabilities and suggest possible strategies to target EGFR resistance mechanisms.
The Use of IVIG for Solid Organ Transplantation: An Evidence Based Practice Guideline
Authors: Nadine Shehata, Heather Ann Hume, Valerie Palda, Ralph Meyer, Patricia Campbell, Peter Nickerson, Tom D Blydt-Hansen, Lori West, Heather Ross, Steven Martin, Tom Waddell, Carl Cardella, Davi d Anderson, John Freedman, Kevork Peltekian
Journal: Blood (2008)
127. Detection of Vector Integration Sites by Targeted Sequencing
Authors: Stefan Wilkening, Saira Afzal, Raffaele Fronza, Christof von Kalle, Manfred Schmidt
Journal: Molecular Therapy (2015)

For biosafety assessment and the understanding of viral integration mechanisms the determination of the exact position and distribution of viral integration sites in the host genome is crucial. Current methods for mapping of vector insertion sites are based on primer binding within the vector genome, its elongation into the host genome, ligation of a common adapter on the host part, and subsequent PCRs. Thus, these methods depend on the presence of the primer binding site in the viral genome and biases are introduced during restriction digest (if applied), ligation, and PCR.
Clinical characteristics and prognostic factors of plasmablastic lymphoma patients: analysis of 135 patients from the LYSA group
Authors: E. Tchernonog, P. Faurie, P. Coppo, H. Monjanel, A. Bonnet, M. Algarte Génin, M. Mercier, J. Dupuis, F. Bijou, C. Herbaux, A. Delmer, B. Fabiani, C. Besson, S. Le Gouill, E. Gyan, C. Laurent, H. Ghesquieres, G. Cartron
Journal: Annals of Oncology (2016)
Abstract 4873: Epicopy: Measuring DNA copy number variation using high-density methylation microarrays
Authors: Soonweng Cho, Hyun-seok Kim, Leslie M. Cope, Christopher B. Umbricht
Journal: Cancer Research (2015)

Abstract Background: Cancers exploit changes in both genomic copy number and DNA methylation to promote growth and escape tumor-suppressor pathways. Under the 2-hit hypothesis, a single gene is likely to be altered by multiple mechanisms at the same time and integrated analysis can sharpen the focus on the most likely drivers. Requiring larger amounts of input material and imposing additional costs may limit multiplatform analysis, especially in studies using archival tissues with long clinical follow-up information where the nucleic acids are degraded and yields are generally lower than are obtained from fresh tissues. Taking advantage of similarities between methylation arrays and SNP arrays, we developed Epicopy, a robust computational method to identify DNA copy number variation (CNV) using high-density Illumina Human Methylation 450K methylation microarrays, thereby delivering two complementary genetic and epigenetic profiles from a single chip. Methods: Epicopy was developed using data from thyroid carcinoma samples arrayed by The Cancer Genome Atlas (TCGA) and subsequently validated on breast and lung small cell carcinoma TCGA datasets. Using Epicopy, we identified circumstances where CNV information can be reliably measured by methylation microarrays. Results: Using TCGA SNP microarrays as the gold standard to assess the performance of methylation derived CNV data from the thyroid, breast, and lung small cell carcinoma datasets, we showed that Epicopy is able to detect CNVs identified by SNP arrays at a sensitivity of 0.69 and specificity of 0.90. Frequently occurring CNVs identified using Genomic Identification of Significant Targets in Cancer (GISTIC), were identified with even higher accuracy. Conclusion: Epicopy provides a robust method to obtain both copy number and methylation information from a single methylation microarray experiment and will add value to methylation microarrays at no additional cost to the user. Tools to highlight regions of high sensitivity and specificity will also be provided to help users decide on the feasibility of using Epicopy to identify CNVs in regions of interest. Epicopy is implemented in the R statistical language and will be made available as a freestanding package as part of the Bioconductor bioinformatics software project. Citation Format: Soonweng Cho, Hyun-seok Kim, Leslie M. Cope, Christopher B. Umbricht. Epicopy: Measuring DNA copy number variation using high-density methylation microarrays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4873. doi:10.1158/1538-7445.AM2015-4873
Abstract 1953: Group I Paks as therapeutic targets in NF2-deficient meningioma
Authors: Hoi Yee Chow
Journal: Cancer Research (2015)

Abstract Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40-60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2-/- meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas. Citation Format: Hoi Yee Chow. Group I Paks as therapeutic targets in NF2-deficient meningioma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1953. doi:10.1158/1538-7445.AM2015-1953
Abstract 5394: First-in-class dual PIM/FLT3 kinase inhibitor SEL24-B489 for the treatment of hematological malignancies
Authors: Krzysztof Brzózka, Wojciech Czardybon, Aniela Gołas, Renata Windak, Michał Gałęzowski, Ewelina Gabor-Worwa, Bożena Winnik, Agnieszka Przybyłowicz, Maciej Szydłowski, Emilia Białopiotrowicz, Tomasz Sewastianik, Elżbieta Mądro, Ewa Lech-Marańda, Krzysztof Warzocha, Przemysław Juszczyński
Journal: Cancer Research (2015)

Abstract Despite huge effort spent on understanding acute myeloid leukemia (AML), current standards of care are still based on the same chemotherapy agents as two decades ago - typically based on cytarabine chemotherapy with an anthracycline. Although patients aged &amp;lt;60 years may achieve remission to induction therapy, most patients will relapse. One of primary reasons for that is high heterogeneity of the disease. Recently one of the most extensively investigated approaches to the treatment of AML, are targeted therapies, especially inhibition of certain kinases. Probably mostly investigated up to date are inhibitors of FLT3 with most advanced clinical compound - AC220 (Quizartinib). FLT3 inhibitors are very effective in killing cancer lines with a major drawback of the therapy being fast development of resistance. PIM kinases are expressed in various cancers including AML but also other liquid tumors as well as in some solid tumors. Inhibition of PIM kinases which are downstream in the FLT3 signaling cascade have already shown influence on cancer cell survival. In addition there are great hopes related to the fact that PIM kinases were shown to contribute in resistance to FLT3 inhibitors. This leads to the conclusion that combined inhibition of PIM and FLT3 may be a rational strategy. Selvita has developed series of inhibitors combining activity against PIM and FLT3 kinases. Selected clinical candidate SEL24-B489 - has shown excellent anticancer efficacy. It is active against broad panel of AML cell lines and primary blasts, but also against other hematological cancers: DLBCL, CLL, HL - both in vitro on cell lines, patient samples and in vivo. Head to head comparison of SEL24-B489 with PIM (AZD1208) and FLT3 (AC220) inhibitors currently in clinical development will be presented. Comparison shows strong activity of SEL24-B489 against broader panel of cell lines in vitro and in vivo (in xenograft models) than AZD1208 or AC220. SEL24-B489 is currently in preclinical development and details of toxicology profile will also be discussed. Citation Format: Krzysztof Brzózka, Wojciech Czardybon, Aniela Gołas, Renata Windak, Michał Gałęzowski, Ewelina Gabor-Worwa, Bożena Winnik, Agnieszka Przybyłowicz, Maciej Szydłowski, Emilia Białopiotrowicz, Tomasz Sewastianik, Elżbieta Mądro, Ewa Lech-Marańda, Krzysztof Warzocha, Przemysław Juszczyński. First-in-class dual PIM/FLT3 kinase inhibitor SEL24-B489 for the treatment of hematological malignancies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5394. doi:10.1158/1538-7445.AM2015-5394
Depletion of L3MBTL1, a PcG Gene Deleted in Patients with 20q-Associated with Hematologic Malignancies, Accelerates Erythroid Differentiation of Hematopoietic Progenitor Cells
Authors: Fabiana Perna, Nadia Gurvich, Ruben Hoya-Arias, Francesca Voza, Vladimir Jankovic, Nagesh Kalakonda, Stephen D. Nimer
Journal: Blood (2008)
Prognostic Effect of Mutations in the Splicing Gene Machinery in 339 Patients with MDS or Secondary AML Following MDS After Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Felicitas Thol, Christian Koenecke, Sofia Kade, Liu Huang, Uwe Platzbecker, Christian Thiede, Thomas Schroeder, Guido Kobbe, Martin Gehlhaar, Robin Bollin, Stefanie Buchholz, Michael Stadler, Gudrun Göhring, Elke Dammann, Moritz Kleine, Wiebke Brauns, Michael Hallensleben, Brigitte Schlegelberger, Jürgen Krauter, Arnold Ganser, Nicolaus Kröger, Michael Heuser
Journal: Blood (2012)
39. Modulation of Histone Dosage and Chromatin Dynamics Regulates AAV Transduction
Authors: Lorena Zentilin, Rudy Ippodrino, Miguel Mano, Mauro Giacca
Journal: Molecular Therapy (2015)

Recombinant adeno-associated vectors (AAVs) have gained momentum due to their combined characteristics of safety and efficiency. Nonetheless, the identity of the host functions intercepting the AAV transduction pathway still needs to be thoroughly understood. To address this issue on a genome-wide scale, we previously performed an unbiased RNAi high throughput screening (HTS; 18,120 human target genes) and identified 710 negative and 414 positive regulators of AAV efficiency. Based on the results obtained and with the purpose to identify factors involved in single-stranded (ss) AAV genome processing, we compared, again in an HTS format, siRNAs affecting ssAAV, but dispensable for scAAV transduction. One of the genes identified was ERI-1. While the effects of this protein were negligible on scAAV transduction, its knock down or overexpression lead to a 5 fold decrease or 2-7 fold increase of ssAAV efficiency, respectively. ERI-1 is a 3'-exoribonuclease known to degrade endogenous miRNAs and histone mRNAs. Indeed, we observed that AAV transduction negatively correlated with histone mRNA levels. Chromatin immunoprecipitation (ChIP) studies aimed at assessing the extent of chromatinization of the AAV genome revealed that the overexpression of ERI-1 determined an over 10-fold, selective reduction on ssAAV genome association with H3 and H4, while changes were negligible for scAAV DNA and for control cellular genes. Consistent with chromatin exerting a repressive role on ssAAV transduction, we also noticed that the downregulation of the main replication-dependent histone chaperone CAF-1 induced an over 20-fold increase in transduction. Increase of ssAAV2 transduction by ERI-1 also decreased the association, with the viral DNA, of proteins of the cellular DNA damage response (DDR; e.g. Nbs1 and Mre11), which our previous work had indicated as inhibitory of AAV transduction. Interestingly, DNA damage per se induced downregulation of histone gene expression. In particular, hydroxyurea, a drug markedly increasing AAV transduction, also determined histone mRNA degradation, an effect that required integrity of ERI-1. These results underline the importance of chromatin and its dynamic regulation in determining the fate of productive AAV transduction. These findings can be exploited for the development of more effective AAV-mediated gene delivery strategies.
A Specific Gene Expression Signature Affecting the Beta-Catenin and Notch Signaling Pathways and the Downregulation of MALAT1 Prove Acute Myeloid Leukemia with Limited Differentiation (AML-LD) as a Distinct Entity with NPM1 Mutation.
Authors: Wolfgang Kern, Vera Grossmann, Alexander Kohlmann, Susanne Schnittger, Claudia Haferlach, Torsten Haferlach
Journal: Blood (2009)
Abstract 4387: Anti-tumor activity of TNF-gold nanodrugs tagged with tumor vasculature-homing peptides containing the NGR or isoDGR motives
Authors: Flavio Curnis, AnnaMaria Gasparri, Angelina Sacchi, Martina Fiocchi, Angelo Corti
Journal: Cancer Research (2015)

Abstract Colloidal gold (Au) is a well-tolerated nanomaterial currently exploited for several applications in the field of nanomedicine. In particular, gold nanoparticles loaded with tumor necrosis factor-alpha (TNF), a cytokine endowed with anti tumor activity, have a therapeutic index higher than that of TNF. For this reason TNF-gold nanoparticles are currently tested in cancer patients. We have addressed the hypothesis that TNF-gold nanoparticles tagged with tumor vasculature homing peptides have improved therapeutic properties. To this aim we have tagged TNF-gold nanoparticles with albumin-peptide conjugates containing the NGR (Asn-Gly-Arg) or isoDGR (isoAsp-Gly-Arg) motives, i.e. with ligands of CD13 and integrin alphavbeta3, respectively, expressed by the tumor neovasculature. The therapeutic properties of the resulting nanodrugs (called NGR-HSA/Au/TNF and isoDGR-HSA/Au/TNF) were then investigated in fibrosarcoma- or lymphoma-bearing mice and compared with those a nanodrug lacking the targeting peptide (called HSA/Au/TNF). The results showed that intravenous administration of extremely low doses of NGR-HSA/Au/TNF or isoDGR-HSA/Au/TNF (equivalent to 5 pg of bioactive TNF/mouse) were sufficient to induce anti-tumor effects, whereas similar doses of HSA/Au/TNF were minimally active. Low-dose NGR-HSA/Au/TNF and isoDGR-HSA/Au/TNF, but not HSA/Au/TNF, could also exert synergistic anti-tumor effects with melphalan, a chemotherapeutic drug. These findings support the concept that tagging TNF-gold nanoparticles with tumor vasculature homing peptides have an improved antitumor activity, likely because of an active targeting mechanism. Citation Format: Flavio Curnis, AnnaMaria Gasparri, Angelina Sacchi, Martina Fiocchi, Angelo Corti. Anti-tumor activity of TNF-gold nanodrugs tagged with tumor vasculature-homing peptides containing the NGR or isoDGR motives. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4387. doi:10.1158/1538-7445.AM2015-4387
Survival of AIDS-associated non-Hodgkin lymphoma in the pre- and post-HAART era at the Instituto Nacional de Enfermedades Neoplásicas: 1988-2010.
Authors: L. E. Cuéllar Ponce De León, L. M. Miranda Rosales, F. Aquino Robles, C. J. Flores, C. Samanez Figari, C. Vallejos Sologuren
Journal: Journal of Clinical Oncology (2011)

e18523 Background: Despite the introduction of HAART, which has reduced malignancies associated with AIDS, there has been an increase of non-Hodgkin lymphomas associated with AIDS (ARLs). The aim of this study was to describe the survival of patients with ARLs at the Instituto Nacional de Enfermedades Neoplásicas (INEN): 1988-2010. Methods: Cross-sectional observational study. Pre-HAART period was 1988-2004 and post-HAART 2005-2010. CD4 counts and HAART and chemotherapy were performed on a regular basis from January 2005. The regimens used were CHOP and CHOEP for diffuse large B cell lymphoma (DLCL) and Hyper C-VAD for Burkitt's Lymphoma (BL). Comparisons were made using the method of X2 and survival with the Kaplan-Meier test. Results: 115 cases of ARLs were included, 61 cases (53.1%) in the pre-HAART and 54 cases (46.9%) in the post-HAART period. The median age was 37.5 (18-86) years. Median CD4 at diagnosis in the post HAART period was 105.5 (1-538) cells/uL. There were no significant differences between characteristics of both groups (p<0.05). Overall survival (OS) for both subtypes of lymphomas was increased, non-Hodgkin lymphoma diffuse large B cell (DLCL) from 8.4 to 20.3 months (p<0.01) and Burkiitt's lymphoma (BL) from 11.6 to 33 months (p<0.01). OS at 1 and 2 years were 15% and 5% in the pre-HAART and 60% and 50% in the post-HAART era respectively. The OS at 5 years in the post-HAART period was 42.64%. Conclusions: The survival of patients with ARLs showed a significant improvement in the post-HAART period in comparison with the pre-HAART period, with the same tendency in DLCL and BL patients Characteristics Pre-HAART 1988-2004 Post-HAART 2005-2010 P value N 61 54 Age 39 y (23-86) 37 y (18-71) 0.48 DLCL 73.8% (45) 83.3% (45) 0.30 OS - 5 years (median) DLCL 8.4 m (4.7-30.2) 20.3 m (4.5-36.1) <0.01 BL 11.6 m (7.8-13.2) 33 m (16.7-49.3) <0.01 OS - 1 year (total) 15% 60% <0.01 OS - 2 years (total) 5% 50% <0.01 Abbreviations: DLCL, non-Hodgkin lymphoma diffuse large B cell; LB, Burkitt's lymphoma; OS, overall survival.