tbuckley/cabot-search huggingface dataset:
Platelet-Targeted, Thrombin-Activatable Fibrinolytic Pro-Drugs As Novel Therapies: Application to the Prothrombotic Disorder of Heparin-Induced Thrombocytopenia (HIT)
Authors: Rudy Fuentes, Hyun Sook Ahn, Vincent M. Hayes, Valerie Tutwiler, Yuhuan Wang, Daniel W. Bougie, M. Anna Kowalska, Lubica Rauova, Richard H. Aster, Douglas B. Cines, Vladimir R Muzykantov, Mortimer Poncz, Sergei Zaitsev
Journal: Blood (2012)
Abnormalities in Glucose Uptake and Metabolism in Imatinib-Resistant Bcr-Abl Positive Cells.
Authors: Natalie J. Serkova, Douglas J. Kominsky, Jaimi L. Brown, Jelena Miljus, Laszlo G. Boros, Gail S. Eckhardt, Junia V. Melo
Journal: Blood (2006)
Abstract 2710: Tumorigenic activity of a novel KIF5B-RET fusion gene
Authors: Jung-Young Shin, Min-Young Kim, Kyoung-Hwa Son, Jeong-Oh Kim, Jin-Hyoung Kang
Journal: Cancer Research (2015)

Abstract The KIF5B-RET gene is a novel fusion gene resulting from pericentric inversion between the kinesin family member 5B (KIF5B) and the rearranged during transfection (RET) gene, which recently isolated as an oncogene in non-small cell lung cancers. In the present study, we investigated the mechanisms associated with tumorigenic activity of KIF5B-RET fusion gene. We used a HEK-293T cell line stably expressing the KIF5B-RET fusion gene in pLOC lenti-viral vector. We investigated the tumor formation in a xenograft mouse models after subcutaneous injection and confirmed the expression of KIF5B-RET by PCR and western blot analysis. We also explored the mechanism of KIF5B-RET fusion gene in stable cell line. The KIF5B-RET stable cells showed upregulation of the cell growth, migration and colony formation. Furthermore, the KIF5B-RET stable cells induced the activation of BRAF, AKT and ERK compared with the parental cells. These results suggest that the KIF5B-RET fusion gene promotes the cell proliferation and tumorigenic activity though BRAF, AKT and ERK activation. These findings may also provide the possible that KIF5B-RET fusion gene as a ‘driver’ in some subgroups of lung cancers. Citation Format: Jung-Young Shin, Min-Young Kim, Kyoung-Hwa Son, Jeong-Oh Kim, Jin-Hyoung Kang. Tumorigenic activity of a novel KIF5B-RET fusion gene. [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 2710. doi:10.1158/1538-7445.AM2015-2710
56. AAV Vector-Mediated CRISPR Attacks on Proviral HIV-1 DNA for Purging of Cellular Reservoirs
Authors: Kathleen Boerner, Manuela Nickl, Florian Schmidt, Ann-Christin Gnirck, Philipp Bayer, Hans-Georg Kräusslich, Dirk Grimm
Journal: Molecular Therapy (2015)

HIV, the human immunodeficiency virus, is highly successful as a viral pathogen due to its ability to persist in the infected host as an integrated proviral DNA within cellular reservoirs, particularly in resting CD4+ T cells and macrophages. Current antiretroviral combination therapy can control viral spread and viremia but cannot eradicate latent HIV genomes, raising an urgent need for alternative strategies for long-term remission or cure. We combined two powerful technologies, synthetic AAV vectors and CRISPR-mediated gene engineering, with the ultimate aim to eliminate integrated HIV from latently infected human cells. Therefore, we first screened a library of peptide display mutants based on 12 different AAV serotypes and identified novel capsids that mediate potent transduction of relevant HIV target cells, including primary human T-lymphocytes and macrophages. Our lead candidates – two peptide-modified variants of AAV9 or AAVrh.10 – were capable of transducing >65% of primary humanCD4+ T cells and were superior to all 12 wildtype AAV isolates. Concurrently, we created AAV vector genomes that express – alone or in combination – the two essential CRISPR components, i.e., the Cas9 protein and a g(uide)RNA directed against either the HIV-1 long terminal repeats (LTRs), or against viral structural genes. AAV/CRISPR vector efficiency and specificity were validated using a T7 endonuclease assay, showing successful Cas9-mediated induction of double-stranded DNA breaks at the specific HIV-1 target regions and subsequent error-prone repair in HeLaP4 cells with a stably integrated HIV-1 genome. To further potentiate the approach, we exploited a highly customizable self-complementary AAV vector backbone recently developed in our lab that permits multiplexing up to three gRNAs under control of the U6, H1 and 7SK promoters in a single vector particle. We engineered this template to co-express our best gRNAs against the two HIV-1 LTRs and the viral gag gene, and compared its potency with our different first-generation single gRNA vectors. In reporter cells carrying a GFP-encoding HIV-1 genome, simultaneous cleavage was indeed detected at three different sites (5'LTR, 3'LTR and gag), reaching an impressive 63.5% cutting efficiency (versus 36.6-50% for the single gRNA vectors) and demonstrating the power of these vectors to cleave HIV-1 proviral DNA. Finally, we will present results from our ongoing validation of proviral cleavage in human T-cell lines that are latently infected with HIV-1 as a physiologically relevant model of HIV-1 latency. The described experiments prove the possibility to target, cut and destroy integrated HIV-1 proviral DNA with AAV/CRISPR vectors in human cells, and therefore support the further development of our tools and approach into a novel clinical modality for purging of latent HIV-1 reservoirs.
Childhood, adolescents, and young adults (age 25 and younger) colorectal cancer: A multicenter study.
Authors: M. A. Kaplan, A. Isikdogan, M. Gumus, Ü. Yalçintas Arslan, C. Geredeli, N. Ozdemir, D. Koca, F. Dane, A. Suner, E. T. Elkiran, M. Kucukoner, M. Seker, K. Helvaci, T. Guler, D. Uncu, A. Inal, R. Yildiz
Journal: Journal of Clinical Oncology (2011)

e14127 Background: Colorectal cancer (CRC) is one of the most common tumors in adults, also can occur rarely in children and young adults. Compared to adults contains significant differences in terms of symptoms, presentation, histological subgroups, localization, stage and prognosis. The aim of this study to evaluate clinicopathologic and treatment outcomes of young CRC patients. Methods: Between May 2003 to June 2010, 76 patients included in the study. The medical records studied to analyze the age, sex, presenting symptoms, presentation, family history, presence or absence of polyps, histological features, localization, stage, treatment outcomes, recurrence time and site, metastatic sites and survival outcomes. Patients were divided into two groups as; child-adolescent (0 to 19 years of age) and young adult (20 to 25 years of age). Results: A total of 76 patients (42 male, 34 female) were identified. Median age was 23 (10 to 25). Twenty two percent of patients had family history and 6.8% had presences of polyps, 24% had acute presentation, 47.4% had mucinous adenocarcinoma and 26.3% had metastatic disease. Most common symptom was abdominal pain (53.5%) and most common localization was left colon (64.5%). Statistically significant differences between the two groups in terms of sex and symptoms (p<0.05). Although there was numerically difference between the two groups no statistically significant difference for acute presentation (35.0% vs. 20.0%, p= 0.179). Patients who undergoing curative surgery shows a significant increase in survival (19.6 months vs. 3.7 months, p<0.001). Dukes B, C and D patients shows 24.5, 19.4 and 11.7 months survival, respectively (p=0.004). Patients who accepted chemotherapy after surgery (n= 52) and who rejected (n=6) shows 20.4 months and 13.0 months survival, respectively. (p=0.28). Other parameter affected survival is response to palliative chemotherapy (18.8 months vs. 11.4 months, p=0.06). Conclusions: CRC should not be excluded only on the bases of the age. Young-adult patients more similar to adults compared with child-adolescent patients. Surgery, adjuvant chemotherapy and palliative chemotherapy should be considered for appropriate patients.
Abstract 715: Regulation of the ABCG2 drug efflux transporter in breast cancer cells
Authors: Vivian YL Chua, Jennet Harvey, Jacqueline Bentel
Journal: Cancer Research (2015)

Abstract The ABC transporters, including ABCG2 or breast cancer resistance protein (BCRP) are drug efflux transporters. Their overexpression in cancers including breast cancer has been associated with the development of multidrug resistance (MDR) due to ABC transporter-mediated export from tumour cells of therapeutic drugs such as chemotherapeutic (eg. mitoxantrone, doxorubicin) and targeted agents (eg. tyrosine kinase inhibitors). PCR microarray analysis identified that ABCG2 expression was downregulated in the breast cancer cell lines, MCF-7 and T-47D following treatment of cells with the androgen, 5α-dihydrotestosterone (DHT), the Hedgehog pathway inhibitor, cyclopamine, or a combination of 10-8M DHT and 2μM cyclopamine. RT-qPCR analysis confirmed that DHT and cyclopamine treatments of MCF-7 cells rapidly downregulated ABCG2 mRNA levels by 24 hours. ABCG2 protein levels were also progressively decreased over 8 days of treatment, with earlier reductions in ABCG2 levels observed in cells co-treated with DHT and cyclopamine. As the ABC transporters are primarily active on membrane surfaces as drug exporters, the intracellular localisation of ABCG2 was investigated by immunofluorescence microscopy. In MCF-7 cells, DHT and/or cyclopamine decreased ABCG2 accumulation in cell-to-cell membrane junction complexes and interestingly, accumulation of ABCG2 into cytoplasmic vesicles which resembled aggresomes was observed in cells exposed to cyclopamine. Consistent with the reduced levels of membrane-bound ABCG2, export of the fluorescent ABCG2-specific substrate, mitoxantrone from MCF-7 cells was delayed following treatment of cultures with DHT and cyclopamine, thereby indicating diminished ABCG2 efflux activities. Moreover, these DHT- and cyclopamine-treated cells were also more responsive to the cytotoxic effects of mitoxantrone as the IC50 for mitoxantrone was decreased by ∼80% in treated cells compared to controls. Resistance to drug therapies, which is often facilitated by the ABC transporters, is a major cause of treatment failure and recurrence of breast cancer. As such, development and implementation of adjuvant compounds such as androgens and Hedgehog inhibitors, which inhibit expression and function of ABCG2 and other efflux transporters in breast cancer cells, may improve treatment outcomes and prolong recurrence-free survival of patients. Citation Format: Vivian YL Chua, Jennet Harvey, Jacqueline Bentel. Regulation of the ABCG2 drug efflux transporter in breast cancer cells. [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 715. doi:10.1158/1538-7445.AM2015-715
588. Effective Prevention of Liver Fibrosis by Liver-Targeted Hydrodynamic Gene Delivery of Matrix Metalloproteinase-13 in Rat Liver Fibrosis Model
Authors: Hiroyuki Abe, Kenya Kamimura, Yuji Kobayashi, Masato Ohtsuka, Hiromi Miura, Riuko Ohashi, Takeshi Yokoo, Tsutomu Kanefuji, Takeshi Suda, Masanori Tsuchida, Yutaka Aoyagi, Guisheng Zhang, Dexi Liu, Shuji Terai
Journal: Molecular Therapy (2015)

Liver fibrosis is final stage of chronic liver diseases which may cause liver failure and liver cancer. While various diagnostic methods, including serum marker have been established, no standard therapy has developed. The objective of this study is to assess the approach of overexpressing matrix metalloproteinase-13 gene (MMP13) in rat liver to block liver fibrosis. The rat liver fibrosis model was developed by the bile duct ligation (BDL). And the liver-targeted hydrodynamic gene delivery procedure involves catheter insertion via the inferior vena cava (IVC) to the junction of the IVC and the hepatic veins followed by the hydrodynamic injection of MMP13 expression vector, containing CAG promoter-MMP13-IRES-tdTomato-polyA cassette with temporal blood flow occlusions at the supra- and infra-hepatic IVC. Three groups (n=5 in each group) of animals, BDL alone (non-treated), BDL simultaneously followed by hydrodynamic delivery of pBGI-MMP13 (treated group), and hydrodynamic delivery of pBGI-MMP13 (control) were analyzed for: 1) MMP13 expression in serum and cells in the liver by ELISA, western blotting, immunohistochemical staining, and fluorescent detection; and 2) therapeutic effect on liver fibrosis by analysis of serum fibrotic markers of hyaluronic acid and collagen type IV, and histological analysis including silver staining. Serum concentration of MMP13 in pBGI-MMP13 treated group reached 71.±5.1 pg/ml (p<0.001) compared to ≈5 pg/ml in non-treated group in 2 weeks after the procedure which sustained for following 8 weeks and slowly declined to 37.±5.9 pg/ml in 20 weeks. The protein expression in the liver was also confirmed by western blotting and immunohistochemical staining of the liver samples. The expression of MMP13 contributed on the therapeutic effect which was evidenced by the statistically lower level of the hyaluronic acids of 50.±7.0 ng/ml in treated group than that of 20 ± 19 ng/ml in non-treated group (p<0.5) 2 weeks after the BDL, which sustained for 8 weeks. The serum level of collagen type IV showed similar pattern although no statistical difference was marked. Silver staining showed a significantly lower volume of the fibrotic tissue in treated group than that of non-treated. These results suggest that the liver-targeted hydrodynamic injection of pBGI-MMP13 could achieve long-term gene expression in rat liver and prevent the fibrotic development in the liver.
Abstract 2122: RNA editing reveals new regulatory functions in tumorigenesis
Authors: Landian Hu
Journal: Cancer Research (2015)

Abstract RNA Editing is a widespread post-transcriptional event that could increase the diversity of transcriptome. In humans, the most common type of RNA editing is adenosine-to-inosine (A-to-I) editing which is catalyzed by a family of enzymes called adenosine deaminase acting on RNA (ADARs). Over 90% A-to-I RNA editing sites locate in Alu elements, the most abundant transposable elements in human genome. We picked up 83 CEU individuals and 89 YRI individuals for RNA editing analysis. 94,315 credible sites are obtained after series of strict computational procedures. Those genes whose transcripts harbor numerous RNA sites are found to be enriched in several cancer-related pathways such as small cell lung cancer pathway, p53 signaling pathway and apoptosis pathway. Our work provides new insight into the regulation mechanism of RNA editing acting on tumorigenesis. Citation Format: Landian Hu. RNA editing reveals new regulatory functions in tumorigenesis. [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 2122. doi:10.1158/1538-7445.AM2015-2122
Pharmacology of Modulators of Alternative Splicing
Authors: David O. Bates, Jonathan C. Morris, Sebastian Oltean, Lucy F. Donaldson
Journal: Pharmacological Reviews (2016)

More than 95% of genes in the human genome are alternatively spliced to form multiple transcripts, often encoding proteins with differing or opposing function. The control of alternative splicing is now being elucidated, and with this comes the opportunity to develop modulators of alternative splicing that can control cellular function. A number of approaches have been taken to develop compounds that can experimentally, and sometimes clinically, affect splicing control, resulting in potential novel therapeutics. Here we develop the concepts that targeting alternative splicing can result in relatively specific pathway inhibitors/activators that result in dampening down of physiologic or pathologic processes, from changes in muscle physiology to altering angiogenesis or pain. The targets and pharmacology of some of the current inhibitors/activators of alternative splicing are demonstrated and future directions discussed.
Improved Outcome with Busulfan, Melphalan, and Thiotepa Conditioning (BuMelTt) in Autologous Hematopoietic Stem Cell Transplantation for Relapsed/Refractory Hodgkin Lymphoma
Authors: Tarunpreet Bains, Andy I Chen, Andrew Lemieux, Brandon Hayes-Lattin, Jose F. Leis, Richard T Maziarz
Journal: Blood (2011)
The Plk-1 Inhibitor BI 2536 Counteracts Proliferation and Viability of CML Cells and Synergizes with Imatinib and Nilotinib (AMN107) in Producing Growth Inhibition.
Authors: Karoline V. Gleixner, Veronika Ferenc, Alexander Gruze, Michael Kneidinger, Christian Baumgartner, Matthias Mayerhofer, Winfried F. Pickl, Christian Sillaber, Peter Valent
Journal: Blood (2007)
Abstract 493: Drug response profiling to inform individualized treatment approaches in high risk leukemia
Authors: Viktoras Frismantas, Anna Rinaldi, Maria Pamela Dobay, Salome Higi, Sabrina Eugster, Blerim Marovca, Peter Horvath, Mauzro Delorenzi, Joachim Kunz, Obul R. Bandapalli, Gunnar Cario, Martin Stanulla, Andreas E. Kulozik, Martina Muckenthaler, Cornelia Eckert, Thomas Radimerski, Jean-Pierre Bourquin, Beat C. Bornhauser
Journal: Cancer Research (2015)

Abstract Novel treatment approaches are needed for patients with acute lymphoblastic leukemia (ALL) who respond poorly to current therapies. The genotypic diversity identified recently by next generation sequencing technologies within ALL calls for individualized novel strategies. However, functional correlations of oncogenic lesions with drug response profiles are ill defined for ALL. We have established an imaging-based cell viability analysis platform to generate drug response profiles for primary patient-derived ALL samples co-cultured with mesenchymal stroma cells, expecting to derive functional information directly from individual patient samples. Such response profiles may mirror perturbations in relevant cellular programs that could be exploited therapeutically. Our pipeline integrates high-content screening, newly developed bioinformatics tools and biochemical approaches. We screened a library of 65 compounds for activity in 37 precursor B-ALL and 23 T-ALL samples including refractory cases. Cross-sample comparisons revealed that cells from relapsed refractory patients showed a more resistant phenotype for most of the drugs. While only a few agents including genotoxic drugs showed activity across all samples, we detected selective activity of given drugs that distinguish patient sample groups. MLL-rearranged and TCF3-HLF-positive ALL samples as well as a subgroup of T-ALL cases were highly sensitive to the BCL-2 specific BH3-mimetic ABT-199 suggesting BCL-2 dependency for these cases. Multiparametric analyses of in vitro responses predicted in vivo activity of ABT-199 in xenografted mice. Moreover, we could identify synergistic activity of ABT-199 with clinical and preclinical compounds, such as topotecan or epigenetic modifiers. Our drug response profiling pipeline contributes to the identification of distinct vulnerabilities in leukemia and may facilitate the selection of candidate drugs for further development into clinical application. Citation Format: Viktoras Frismantas, Anna Rinaldi, Maria Pamela Dobay, Salome Higi, Sabrina Eugster, Blerim Marovca, Peter Horvath, Mauzro Delorenzi, Joachim Kunz, Obul R. Bandapalli, Gunnar Cario, Martin Stanulla, Andreas E. Kulozik, Martina Muckenthaler, Cornelia Eckert, Thomas Radimerski, Jean-Pierre Bourquin, Beat C. Bornhauser. Drug response profiling to inform individualized treatment approaches in high risk leukemia. [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 493. doi:10.1158/1538-7445.AM2015-493
Abstract A72: Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A
Authors: Howard S. Hochster, Zev A. Wainberg, Martin Gutierrez, David Waterhouse, E Gabriela Chiorean, Ben George, Amy Ko, Victoria Manax, Sotirios Stergiopoulos, Peter O'Dwyer
Journal: Cancer Research (2016)

Abstract Background: Cytotoxic chemotherapy activates the immune system through multiple mechanisms, including stress signaling, antigen release by dying tumor cells, and modulation of immune cell populations. Nivo, an anti–PD-1 antibody, has demonstrated activity in other solid tumors but has not yet demonstrated activity in PC. The combination of nab-P + G is approved by the US Food and Drug Administration as first-line therapy for metastatic PC (MPC). nab-P does not require corticosteroid pretreatment, which makes it a suitable combination partner with nivo to test for safety and efficacy in PC. Here we report interim results from the first of 2 PC cohorts of a Phase 1 study of nivo + the standard dose and schedule of nab-P. Methods: The 2 PC cohorts (arms A and B) were to be initiated sequentially. In arm A, patients with locally advanced PC (LAPC) or MPC who had received 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) in combination with nivo 3 mg/kg on days 1 and 15 of the 28-day cycle starting with cycle 1. The primary objective of part 1 was to identify dose-limiting toxicities (DLTs). Patients treated with ≥ 2 cycles of nivo + nab-P or who discontinued due to a DLT prior to completing 2 cycles of nivo + nab-P were considered DLT evaluable. If arm A is deemed safe per DLT evaluation, arm B will enroll chemotherapy-naive patients, who will receive G 1000 mg/m2 qw 3/4 in addition to nivo + nab-P. Results: Between February 24 and December 3, 2015, 11 patients were enrolled in arm A. Most patients were &amp;lt; 75 years of age (82%) and male (55%). No DLTs were observed, and no grade 3/4 AEs occurred in &amp;gt; 1 patient. Among 8 response-evaluable patients, 1 had a partial response and 4 achieved stable disease. Eight patients discontinued treatment due to disease progression. Conclusions: In arm A of the PC cohort, the addition of nivo to nab-P did not appear to increase safety/tolerability concerns. Based on safety observed in arm A, arm B will enroll patients with MPC for first-line treatment with nivo + nab-P + G. ClinicalTrials.gov: NCT02309177. Citation Format: Howard S. Hochster, Zev A. Wainberg, Martin Gutierrez, David Waterhouse, E Gabriela Chiorean, Ben George, Amy Ko, Victoria Manax, Sotirios Stergiopoulos, Peter O’Dwyer.{Authors}. Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A72.