tbuckley/cabot-search huggingface dataset:
445. A Delectable Lentiviral Vector System for Testing Oncogene Addiction in Hematological Malignancies
Authors: Jamie L. Maciaszek, Louise M. Treanor, Brian P. Sorrentino
Journal: Molecular Therapy (2015)

Mouse models of hematological malignancies can be established by overexpressing oncogenes in hematopoietic cells followed by transplantation. It is often unclear whether the oncogene is only necessary for initiating the malignancies or if it is also required for maintenance, known as oncogene addiction. An addicted oncogene could then serve as target for therapy. We have developed a dual lentiviral vector system to distinguish these possibilities. We chose the oncogene LMO2 as our model because it is involved in a number of leukemias caused by gamma-retroviral vector insertion in gene therapy of SCID-X1 and Wiskott-Aldrich syndrome. Our previous studies showed that overexpression of LMO2 using a gamma-retroviral vector in early thymic progenitors (ETP) caused a differentiation block at the DN2 stage of development and subsequent transplant of these cells gave rise to leukemia with 100% penetrance in mice. We inserted the LoxP sequence into the 3' U3 region of a self-inactivating CL20 lentiviral backbone and subcloned a MSCV-LMO2-i-GFP expression cassette into the vector (Fig 1A) to make a CL20-tLMO2-i-GFP vector. To deliver Cre recombinase in an inducible fashion, we constructed a second lentiviral vector in which a MSCV-CreERT2-i-mCherry expression cassette is inserted. Vectors were made by transiently transfecting 293T cells and the unconcentrated titer of these vectors were 2E6 and 3E6 TU/ml, respectively. We first tested these vectors in NIH3T3 cells. NIH3T3 cells transduced with these two vectors were subsequently sorted for GFP+mCherry+ double positive cells. We then treated the cells with various concentrations of 4-hydroxytamoxifen (4-OHT) to induce nuclear entry of Cre recombinase in order to delete the MSCV-LMO2-i-GFP expression cassette. Seven days later, 79.3% of the cells lost GFP expression in the group that was treated with 100nM 4-OHT (Fig 1B), indicating efficient cassette deletion. The loss of LMO2 protein is also confirmed by Western blot (Fig 1C). We then transduced ETP cells with the CL20-tLMO2-i-GFP vector and cultured the cells on an OP9-DL1 stroma expressing the Delta-like ligand DL1 to induce differentiation. At day 14, 90.5% of the transduced cells were blocked at the DN2 stage, demonstrating that this deletable lentiviral vector was able to express sufficient levels of LMO2 to induce the DN2 block (Fig 1D). These cells have been transplanted into sublethally irradiated Rag2-/-IL2rg-/- mice to establish the leukemia. One leukemia has been established with a GFP+ tumor, enlarged spleen of 0.534g and an erythroid phenotype as analyzed via flow cytometry. Tumor cells have been transduced with CreERT2 vector for secondary transplant and treatment with tamoxifen to establish whether LMO2 is required for tumor maintainence. In summary, we have established a dual lentiviral vector system that can be used conveniently to study oncogene addiction in hematological malignancies.
PWE-083 Relationship between BMI and the function of the lower oesophageal sphincter in patients with normal upper gastrointestinal endoscopy
Authors: J Fletcher, G R Jones, L S Murray, K E L McColl
Journal: Gut (2010)

<h3>Introduction</h3> Western populations have recently experienced a substantial rise in both obesity and gastro-oesophageal reflux disease (GORD). There is growing evidence of a link between both conditions with higher BMI associated with greater prevalence of GORD symptoms, Barrett9s oesophagus and oesophageal adenocarcinoma. Currently, the most common dyspeptic patients seen in clinical practice are <i>H pylori</i> negative with a normal endoscopy. It is unclear if BMI has any effect on oesophageal physiology in these patients. <h3>Aims</h3> To examine the association between BMI and the function of the lower oesophageal sphincter (LOS) in dyspeptic patients with a normal endoscopy. <h3>Methods</h3> Patients with dyspepsia, a normal endoscopy and negative for <i>H pylori</i> had their BMI measured followed by assessment with water perfused oesophageal manometry and 24-h oesophageal pH monitoring. The LOS pressure, LOS length and LOS intra-abdominal length (high pressure zone distal to respiratory inversion point) were measured by station pull through. This involved withdrawing the catheter at 1 cm increments every minute with the patients sitting. Pressures were expressed using intragastric pressure as baseline. 24-h oesophageal acid exposure was measured as the per cent time pH &lt;4 for the total, upright and supine period. Association between BMI and each of the above parameters was assessed using Spearman Rank Correlation (SR). <h3>Results</h3> 105 patients (46 males) were studied (mean age 44 years range 20–74). The median BMI was 26 (range 17.6–40.4) with 39% overweight and 20% obese. Higher BMI was associated with higher oesophageal per cent time pH &lt;4 for total (SR=0. 43, p≤0.001), upright (SR=0.33, p=0.001) and supine (SR=0.37, p≤0.001,) periods and was also associated with a lower resting LOS pressure (SR=−0.32, p=0.002). LOS length (SR=−0.02, p=0.82) and LOS intra-abdominal length (SR=−0.18, p=0.09) were not significantly associated with BMI. <h3>Conclusion</h3> In patients with normal endoscopy there is a strong association between BMI and impaired function of the gastro-oesophageal barrier. The mechanism of this association requires to be investigated.
Prophylactic Use of Voriconazole for Invasive Fungal Infection in Children and Adolescents with Acute Myeloid Leukemia
Authors: Hirozumi Sano, Ryoji Kobayashi, Daiki Hori, Kenji Kishimoto, Daisuke Suzuki, Kazue Yasuda, Kunihiko Kobayashi
Journal: Blood (2015)
Functional Polymorphisms of Notch 4 and the Risk of Aplastic Anemia.
Authors: Hee Nam Kim, Yeo-Kyeoung Kim, II-Kwon Lee, Deok-Hwan Yang, Myung Geun Shin, Hoon Kook, Tai Ju Hwang, Moo Rim Park, Deog Yeon Jo, Jong Ho Won, HyeoungJoon Kim
Journal: Blood (2007)
Abstract 1937: In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers
Authors: Yaomin Xu, Xingyi Guo, Shilin Zhao, Eric Torstenson, Todd Edwards, Yu Shyr
Journal: Cancer Research (2015)

Abstract Understanding the extensive functional consequences of molecular drivers of a cancer is challenging. We developed an in-depth genomic analytical framework to identify the gene and pathway targets dysregulated by somatic driver mutations. Using The Cancer Genome Atlas (TCGA) breast cancer data, we systemically analyzed all high frequent mutation events including amplification, deletion and point mutation across tumor tissues. Those include the known molecular driver genes such as PIK3CA, GATA3, PTEN and TP53. Utilizing bagging with distance-based regression for differential gene expression analysis, we identified several thousands gene targets associated with the somatic mutations. Integrating gene co-expression regulatory network and the association dependence structure among the somatic mutations, we explored a complex association network of molecular pathway modules or sub-modules that are specific to a mutational event or common to a set of events. Interestingly, we found those modules commonly associated with sets of mutation events were significantly enriched in well-known breast cancer related pathways such as ERBB2, PI3AK and TGFB1. Combined with the publicly available data of a genome-wide RNA-mediated interference screen in breast cancer, we further demonstrated that those modules enriched with cell proliferation essential genes. Our analysis strategy provides a novel view of complex functional mechanism driven by the driver mutation events and it has high potential to provide novel insights to the understanding of the tumorigenesis or the development of therapeutic targets. Citation Format: Yaomin Xu, Xingyi Guo, Shilin Zhao, Eric Torstenson, Todd Edwards, Yu Shyr. In-depth genomic analysis reveals complex functional consequence of driver mutations in breast cancers. [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 1937. doi:10.1158/1538-7445.AM2015-1937
158. Chemically Modified Messenger RNA Furnished With Cellular UTRs Increases the Functional mRNA Productivity
Authors: Mehrije Ferizi, Manish K. Aneja, Carsten Rudolph, Christian Plank
Journal: Molecular Therapy (2015)

Over the last decade, transcript therapy has emerged as a promising disease preventive and therapeutic approach. Messenger RNA successfully transfects slowly dividing primary cells without the risk of insertional mutagenesis. Hence, strategies like incorporation of chemically modified nucleotides within the mRNA and insertion of untranslated regions (UTRs) into the mRNA sequence, have been developed to increase stability and enhance translational efficiency of exogenous mRNA. The aim of the current project is to investigate a set of UTR sequences as "stability" and/or "translational enhancers". To achieve this, various cellular UTRs were selected based on published mRNA stability and screened via different reporter assays both in immortalized cell lines and primary cells. We could observe longer expression with some of the tested UTR combinations compared to control mRNA without UTRs. Interestingly, the mRNA itself was neither stabilized nor differentially translated. Nonetheless, for some UTR containing constructs, higher protein expression normalized to the amount of delivered mRNA could be observed. The best working combination of UTRs is currently being incorporated into a vector coding for hBMP-2 and the resulting mRNAs would then be transfected in mesenchymal stem cells (rAMSCs) to induce osteogenic differentiation.
PTU-043 Genetic polymorphism in the multidrug resistance-5 gene is associated with non-response to azathioprine treatment in inflammatory bowel disease: Abstract PTU-043
Authors: M A Smith, A M Marinaki, J D Sanderson
Journal: Gut (2010)

<h3>Introduction</h3> Multidrug resistance (MDR) genes encode transmembrane ATP-dependent pumps, otherwise known as the ATP-binding cassette subfamily-b (ABCB) transporters responsible for removing xenobiotics, particularly drugs, from cells. Thiopurine metabolites are exported from cells by MDR-4 and MDR-5. Altered ABCB pump activity has been linked to treatment resistance in other contexts. <h3>Methods</h3> Using Taqman® real-time PCR genotyping assays, a prospective cohort of 192 patients receiving azathioprine for IBD was genotyped for three coding region SNPs in MDR4 and three in MDR5, (all of which occur commonly in the Caucasian population). The SNPs tested were in MDR4: 175C→T, 711A→T and 1954A→G and in MDR5: 2T→C, 343A→G and 1573G→A. Association between genotype and clinical outcome on azathioprine treatment (complete response, non-response or withdrawal due to side-effects) was sought. Association tests were performed under a dominant model, using Fisher9s Exact test. No correction for multiple testing has been applied. <h3>Results</h3> The SNP MDR-5 c.343A→G was associated with a lack of clinical response to thiopurine treatment p=0.02, OR 2.43, 95%CI 1.14 to 5.17. Moreover, when analysed alongside other known markers of non-response to thiopurine treatment, (TPMT activity &gt;35 pmol/h/mgHb and AOX 3404A→G) increasing numbers of markers increased their chance of non-response, p=0.0001 (χ<sup>2</sup> for trend). No other SNP had a significant effect on clinical response and no SNP was associated with ADRs. <h3>Conclusion</h3> This study raises the possibility that MDR polymorphism could be important in thiopurine pharmacogenetics and warrants further study in other cohorts. Reliable markers of non-response to thiopurines could be incorporated into a panel of pharmacogenetic markers to inform the selection and dosing of immunomodulatory drugs, offering each individual the best chance of achieving early effective disease control Abstract 043.
Trends in U.S. Cardiovascular Care
Authors: Frederick A. Masoudi, Angelo Ponirakis, James A. de Lemos, James G. Jollis, Mark Kremers, John C. Messenger, John W.M. Moore, Issam Moussa, William J. Oetgen, Paul D. Varosy, Robert N. Vincent, Jessica Wei, Jeptha P. Curtis, Matthew T. Roe, John A. Spertus
Journal: Journal of the American College of Cardiology (2016)
Abstract 2910: The dual role of autophagy in cadmium induced prostate carcinogenesis
Authors: Trinath P. Das, Arokya MS John, Suman Suman, Murali Ankem, Chendil Damodaran
Journal: Cancer Research (2015)

Abstract Cadmium chloride (Cd) and cadmium products cause both acute and chronic cytotoxicity and Cd exposure correlates with the risk of cancer, especially prostate cancer in humans. On the cellular and molecular level, Cd compounds may promote transformation of healthy cells to a malignant state by inducing expression of pro-survival signaling molecules. However, the precise molecular mechanism by which Cd affects cellular transformation in different tissue types, especially in prostate, is yet to be delineated. Autophagy is an intracellular lysosomal degradation process by which cells remove damaged organelles and maintain the integrity of intracellular components. In cancer cells, autophagy promotes cancer cell survival as well as cell death. It is unclear of how, and under what circumstances, these dual and opposite roles of autophagy affect both anti-oncogenic and oncogenic functions. It is possible that uncharacterized molecular switch that influences the anti-oncogenic function of autophagy in healthy cells to become oncogenic. In our studies, we found that exposure of normal prostate epithelial cells (RWPE-2) in culture to Cd (10μM) results in growth inhibition. By contrast, the growth of Cd-transformed prostate epithelial (CTPE) cells was not inhibited by the same Cd treatment. While analyzing the molecular link between Cd induced toxicity and generation of reactive oxygen species (ROS) generation in RWPE-2 and CTPE cells; we found there was no significant change in the ROS induction in both cell types. In addition, no changes in the expression of autophagy targeted genes (Atg family proteins) were seen in Cd treated in both non-transformed and transformed cells. However, microtubule-associated protein 1A/1B-light chain 3B (LC-3B), which is directly involved in autophagy initiation was upregulated in Cd-treated non-transformed cells, but not in Cd-treated transformed cells. LC-3B activation also correlated with growth inhibition in non-transformed cells, while impairing LC-3B activation in RWPE-2 cells causes resistance to CD induced growth inhibition. Our ongoing study will determine whether induction of autophagy via LC-3B is a key event that facilitates Cd-mediated conversion of non-transformed prostate epithelial cells to a malignant state. We strongly believe our studies will define a new concept of LC-3B mediated autophagy in Cd-induced prostate carcinogenesis. Citation Format: Trinath P. Das, Arokya MS John, Suman Suman, Murali Ankem, Chendil Damodaran. The dual role of autophagy in cadmium induced prostate carcinogenesis. [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 2910. doi:10.1158/1538-7445.AM2015-2910
Abstract 2031: RRD-251 enhances retinoic acid induced differentiation of myeloblastic leukemic cells
Authors: Aaron S. Wallace, Wendy M. Geil, Andrew Yen
Journal: Cancer Research (2015)

Abstract All-trans-retinoic acid (RA) is known to induce terminal granulocytic differentiation and cell cycle arrest in HL-60 cells. This is driven by sustained activation of the MAPK pathway, where Raf-1 (MAPKKK) acts as a critical signaling molecule. RRD-251 is a small molecule that binds to the Rb protein and prevents its interaction with Raf-1. Hyperphosphorylation of Rb leads to a conformational change, inhibiting its ability to sequester the E2F family of transcription factors. To determine the effect of RRD-251 on RA-induced differentiation, cells were treated with RA and/or RRD-251 and then analyzed for proliferation, expression of key markers of differentiation, cell cycle arrest, and modifications in protein levels. RRD-251 by itself significantly inhibited proliferation, but cells treated with both RA and RRD-251 showed even further reduction in cellular growth. Similarly, both RA and RRD-251 induce cell cycle arrest, but cells treated with both show higher levels of G0/G1 than singly treated cells. Expression of CD11b is used a late classical marker for differentiation in HL-60. RRD-251 does not induce expression of CD11b, but cultures treated with RRD-251 and RA have nearly double the amount of cells expressing CD11b as compared to RA treated cells alone 72 hours after treatment. Additionally, we had wanted to see the relationship between specific Rb phosphorylation, the cell cycle, and treatment of RA and RRD-251. At 72 hours after treatment, RA induces the formation of a population of cells with no phosphorylation at serine 608 of Rb, which was 99.9% in G0/G1. The appearance of two populations for Rb phosphorylation was unique to serine 608 out of the four phospho-sites that we studied: serine 608, serine 780, serine 795, serine 807/811. Cells treated with both RA and RRD-251 had more cells in the no-phosphorylation population at 72 hours, as well as the appearance of this population at 48 hours. Finally, we observed the changes in protein amounts and localizations by western blotting. RA is known to cause the phosphorylation of Raf-1 at serine 621 and its translocation to the nucleus at 48 hours. This was observed on our blots and that cells treated with both RA and RRD-251 had increased amounts of total nuclear Raf-1 and of pS621 Raf-1 at 48 and 72 hours. The results reported here further support the usefulness of RRD-251 as an anti-cancer drug, from reducing tumor size and preventing angiogenesis in drug-resistant melanoma, to enhancing retinoic acid-induced differentiation in myeloblastic leukemic cells. Citation Format: Aaron S. Wallace, Wendy M. Geil, Andrew Yen. RRD-251 enhances retinoic acid induced differentiation of myeloblastic leukemic 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 2031. doi:10.1158/1538-7445.AM2015-2031
Abstract 5521: Interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in colorectal cancer
Authors: Chih-Yung Yang, Chi-Hong Lin, Jeng-Kai Jiang
Journal: Cancer Research (2015)

Abstract Previously and our studies have observed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We use human atherosclerotic plaque-specific peptide-1 (AP1) that specifically target to IL-4Rα. This study investigated the in vitro binding and internalization of AP1, specific targeting to IL-4Rα, therapeutic efficacy and systemic toxicity in vivo of AP1-conjuagted liposomal doxorubicin. In vitro, The AP1 strongly bound to and was efficiently internalized into IL-4Rα-overexpressed CT26 cells than CT26 control cells, while little binding and internalizing of a control peptide was seen. Selective cytotoxicity experiment revealed AP1-conjugated liposomal doxorubicin preferentially killed the IL-4Rα-overexpressed CT26 cells compared to control CT26 cells. In addition, AP1-conjugated liposomal doxorubicin administered intravenously significantly inhibited tumor growth and decreased cardiotoxicity of doxorubicin in subcutaneously tumor-bearing mouse model. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressed colorectal cancers. Citation Format: Chih-Yung Yang, Chi-Hong Lin, Jeng-Kai Jiang. Interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in colorectal cancer. [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 5521. doi:10.1158/1538-7445.AM2015-5521
Can teenagers control a 3D racing game using motion-onset visual evoked potentials?
Authors: Ryan Beveridge, Shane Wilson, Damien Coyle
Journal: Brain-Computer Interfaces (2016)

Motion-onset visual evoked potentials (mVEPs) are time- and phase-locked brain responses to motion-related stimuli. An mVEP response provides robust features for brain-computer interface (BCI) applications and has the added benefit of being less visually fatiguing than other visual evoked potentials (VEPs). In this study an mVEP BCI that enables control of a visually rich, three-dimensional (3D) car-racing video game is evaluated. A group of 15 teenage schoolchildren (13–16 years old) participated in a single session while they attended a summer school. Participants were asked to control the direction of a car within a realistic racing circuit, where the position of the car was controlled by focusing on one of five motion-related stimuli. Classification accuracy (%) and information transfer rate (ITR) (bits per minute (bpm)) results were encouraging, with participants achieving an average online accuracy of 72% (12 bpm) in the first lap, 67% (10 bpm) in the second lap and 65% (10 bpm) in the third lap (chance accuracy and ITR is 20% and zero bpm). The study shows for the first time the feasibility of using the mVEP paradigm in a commercial-grade car-racing video game. It is also one of the first reports on the performance of a group of teenagers using a BCI.
The Outcome of Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Outside of a Clinical Trial or On a Clinical Trial At a Single Institution
Authors: Musa Yilmaz, Hagop M. Kantarjian, Elias J. Jabbour, Susan M. O'Brien, Gautam Borthakur, Srdan Verstovsek, Guillermo Garcia-Manero, Farhad Ravandi, Jan A. Burger, Sherry A. Pierce, Alfonso Quintás-Cardama, Jorge E. Cortes
Journal: Blood (2012)