tbuckley/cabot-search huggingface dataset:
Abstract 3565: Gli2 induces melanoma tumor growth and progression: A critical role of c-Myc
Authors: Neel Manoj Fofaria, Sanjay K. Srivastava
Journal: Cancer Research (2015)

Abstract Gli2 is one of the key transcription factors in sonic hedgehog (Shh) pathway. Aberrant activation of Gli2 has been reported in several malignancies. However, the role of Gli2 in melanoma progression is unclear. Our results showed that knock down of Gli2 in melanoma cells inhibited the proliferation as well as induced apoptosis in melanoma cells in vitro, which was associated with down-regulation of c-Myc. Melanoma cells with stable Gli2 knockdown demonstrated diminished tumor growth when injected subcutaneously in athymic nude mice. In addition, Gli2 inhibitors GANT58 and GANT61 significantly inhibited the growth of melanoma cell lines. Furthermore, oral administration of 5mg/kg piplartine (PL), an alkaloid inhibited the growth of melanoma tumor xenograft by 84% as compared to control. The tumor suppression by PL was associated with inhibition of Gli2 and c-Myc as observed by western blot and immunohistochemistry analysis. The concentration of PL achieved in plasma was 8.5μM whereas in tumor was 6μmol/gm as analyzed by LC-MS/MS. Interestingly, the IC50 of PL at 48 hours was around 3-4μM in a panel of 15 melanoma cells lines, correlating well with the concentrations achieved in vivo. Melanoma cells treated with 2.5, 5 and 7.5μM PL for 48 hours induced significant apoptosis, with concomitant inhibition of Gli2 as well as c-Myc. Gli2 overexpression and treatment with Shh ligand significantly blocked PL mediated inhibition of cell proliferation and induction of apoptosis, establishing the role of Gli2 in PL-mediated growth suppression of melanoma cells. PL inhibited nuclear translocation as well as DNA binding of Gli2 as observed by analysis of Gli2 in nuclear fraction and Chromatin Immunoprecipitation (ChIP) assay, indicating the importance of Gli2 transcriptional activity in melanoma cell proliferation. In conclusion, our results provide convincing evidence that Gli2 mediated induction of c-Myc plays an important in melanoma tumor growth and subsequently establishes that PL mediated inhibition of melanoma cells in vitro and in vivo is associated with inhibition of Gli2. [Supported in part by R01 grant CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: Neel Manoj Fofaria, Sanjay K. Srivastava. Gli2 induces melanoma tumor growth and progression: A critical role of c-Myc. [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 3565. doi:10.1158/1538-7445.AM2015-3565
Abstract 2746: Significant evidence for linkage for lethal prostate cancer on chromosome arm 4q in Utah high-risk pedigrees
Authors: Lisa A. Cannon-Albright, craig C. TEERLINK, Robert A. Stephenson, Neeraj Agarwal
Journal: Cancer Research (2015)

Abstract Background: Using the unique Utah genealogical resource that links 12 generations of genealogy data to a statewide cancer registry from 1966 and statewide death certificates from 1904 we have identified a set of high-risk lethal prostate cancer pedigrees with a significant excess of prostate cancer cases having died from prostate cancer. Methods: Clusters of prostate cancer cases descended from a common ancestor, among whose descendants is observed a statistical excess of prostate cancer (high-risk prostate cancer pedigrees) were recruited and sampled over the past 25 years. Pedigrees including 4 or more cases who have subsequently been reported to have died from prostate cancer (as evidenced by inclusion as a cause of death on a Utah death certificate) were genotyped with 720k high-density SNPs across the genome. Linkage analysis with markers not in linkage disequilibrium was performed to identify regions hypothesized to contain a lethal prostate cancer predisposition gene. Results: A single extended Utah high-risk prostate cancer pedigree (p&amp;lt;0.05 for significant excess of deceased prostate cancer cases) including 6 distantly related sampled prostate cancer cases who went on to die as a result of their prostate cancer showed significant evidence for linkage at chromosome arm 4q24 (LOD score = +3.28), with 5 of the 6 cases having inherited the same region of chromosome 4 from a common ancestor. Conclusions: The inability of association studies to identify prostate cancer predisposition genes has returned focus to linkage studies of highly informative high-risk pedigrees, which provide power for identifying and localizing regions of interest for predisposition genes. A focus on only those prostate cancer cases who are members of high-risk lethal prostate cancer pedigrees, who also went on to die as a result of their prostate cancer, has resulted in the identification of evidence for a prostate cancer predisposition gene on chromosome arm 4q24, confirming a previous GWAS that reported association with prostate-cancer-specific-survival (Pomerantz MM et al., 2011) in this region harboring TET2 (a tumor suppressor gene involved in pathogenesis of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms), and PP2A (implicated in androgen receptor regulation in prostate cancer cell lines). Citation Format: Lisa A. Cannon-Albright, craig C. TEERLINK, Robert A. Stephenson, Neeraj Agarwal. Significant evidence for linkage for lethal prostate cancer on chromosome arm 4q in Utah high-risk pedigrees. [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 2746. doi:10.1158/1538-7445.AM2015-2746
A Phase II Trial of Alemtuzumab (Campath) with DA-EPOCH-R in Relapsed or Refractory Diffuse Large B-Cell Lymphoma and Hodgkin Lymphoma
Authors: Cliona Grant, Kieron Dunleavy, Julieanne Hessler, Seth M. Steinberg, Stefania Pittaluga, Elaine S. Jaffe, Wyndham H. Wilson
Journal: Blood (2012)
727. Characterizing the Adeno-Associated Virus 1 Sialic Receptor Binding Site and Its Overlap with Antigenic Epitopes
Authors: Lin-Ya Huang, Ami Patel, Robert Ng, Edward B. Miller, Sujata Halder, Robert McKenna, Aravind Asokan, Mavis Agbandje-McKenna
Journal: Molecular Therapy (2016)

Adeno-associated viruses (AAVs) are being development as gene delivery vectors and have shown promise in several clinical trials. And an AAV1-based vector has been approved by the European Commission for the treatment of lipoprotein lipase deficiency disease. However, limitations in tissue transduction specificity as well as neutralization by pre-existing antibodies remain are two major obstacles. To overcome these problems, it is important to characterize functional capsid regions that dictate virus binding to cellular receptors during infection and the potential overlap(s) of these regions with capsid antigenic epitopes. In this study, the sialic acid (SIA) binding site on AAV1 was determined by solving the structure of the AAV1-SIA complex using X-ray crystallography. Residues that form the SIA binding pocket are identical between AAV1 and AAV6; hence, structurally predicted SIA binding sites were mutated on both serotypes to confirm their role in the SIA interaction. Binding and transduction assays with these mutants in CHO cell lines Pro5, Lec2, Lec8, and Lec1, which display different terminal glycans, confirmed the structurally mapped binding pocket. Furthermore, native dot blot showed that several of the AAV1 SIA binding mutants can escape from antibody recognition. This finding is consistent with the overlap between the SIA binding site and the previously mapped AAV1 epitopes. Significantly, a glycan binding mutant with slightly reduced transduction ability is able to escape from antibody recognition. This study identifies an overlap between receptor recognition and antibody reactivity and provides amino acid level information for rational capsid engineering of AAV vectors for improved therapeutic efficacy.
Abstract 3680: Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy
Authors: Rakesh K. Tekade, Susanne R. Youngren-Ortiz, Haining Yang, Rahul Haware, Mahavir B. Chougule
Journal: Cancer Research (2015)

Abstract Onconase (ONC) is a member of a ribonuclease superfamily that has potent cytostatic activity against malignant mesothelioma (MM). However, the recent clinical trials have failed due to unfavorable biopharmaceutical characteristics. The objective of this investigation was to develop BSA-chitosan based hybrid nanoformulations for the efficient delivery of ONC to MM while minimizing the exposure to normal tissues. Taguchi Orthogonal Array L9 type design was used to formulate ONC loaded albumin nanocarriers (ONC-ANC). The ONC-ANC surface was hybridized using varying chitosan concentrations ranging between 0.100-0.175%w/v to form various ONC loaded hybrid nanocarriers (ONC-HNC). The obtained data set was analyzed by principal component analysis (PCA) and principal component regressions (PCR) to decode the effects of investigated design variables. ONC-ANC were found to have a mean particle size of 15.78 ± 0.24 nm (ζ = -21.89 ± 0.11 mV). PCA showed positive correlations between investigated design variables like the bovine serum albumin (BSA) concentration, ethanol dilution, and total ethanol with formulated nanocarrier particle size and entrapment efficiency (EE). PCR showed that the particle size depends on BSA, ethanol dilution, and total ethanol content, while EE was only influenced by BSA content. Further analysis of chitosan and TPP effects used for coating of ONC-ANC by PCR confirmed their positive impacts on the particle size, zeta potential, and prolongation of ONC release compared to uncoated ONC-ANC. PCR analysis of preliminary stability studies showed increase in the particle size and zeta potential at lower pH. However, particle size, zeta potential, and EE of developed HNC were below 63 nm, 31 mV, and 96%, respectively, indicating their stability under subjected buffer conditions. Out of the developed formulations, HNC showed enhanced inhibition of cell viability with lower IC50 against human MM-REN cells compared to ONC and ONC-ANC. This might be attributed to the better cell uptake of HNC, which was confirmed in the cell uptake fluorescence studies. These studies indicated that a developed nanotherapeutic approach might prove beneficial in reducing the therapeutic dose of ONC, minimizing adverse side effects by limiting the exposure of ONC to normal tissues, and help in the development of new therapeutic formulations and routes of administration. Citation Format: Rakesh K. Tekade, Susanne R. Youngren-Ortiz, Haining Yang, Rahul Haware, Mahavir B. Chougule. Albumin-chitosan hybrid onconase nanocarriers for mesothelioma therapy. [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 3680. doi:10.1158/1538-7445.AM2015-3680
Ticagrelor Versus Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest Undergoing Percutaneous Coronary Intervention and Hypothermia
Authors: Klemen Steblovnik, Ales Blinc, Mojca Bozic Mijovski, Misa Fister, Ursa Mikuz, Marko Noc
Journal: Circulation (2016)

Comatose survivors of out-of-hospital cardiac arrest increasingly undergo immediate percutaneous coronary intervention (PCI) and stenting, which is associated with the need for administration of P2Y12 inhibitor. 1Because these patients remain intubated and mechanically ventilated after reestablishment of spontaneous circulation, administration of crushed and dissolved tablets by nasogastric tube remains the only option.Because the antiplatelet effect of clopidogrel is significantly decreased during the first 48 hours after reestablishment of spontaneous circulation, 2 we hypothesized that a novel P2Y12 inhibitor, ticagrelor, which does not require metabolic activation in the liver, might result in faster and stronger platelet inhibition.Consecutive comatose survivors of out-of-hospital cardiac arrest with reestablishment of spontaneous circulation undergoing immediate PCI receiving a periprocedural bolus of 250 to 500 mg acetylsalicylic acid (Aspegic, Sanofi-Aventis) and unfractionated heparin to target activated clotting time between 250 and 300 seconds were randomized to ticagrelor (Brilique, AstraZeneca) or clopidogrel (Plavix, Bristol-Myers Squibb) with a random table and sealed envelope system.The tablets were crushed, dissolved into 15 to 20 mL of distilled water, and injected using a nasogastric tube.Ticagrelor was administered as 180 mg loading and then 90 mg every 12 hours.Clopidogrel was given as 600 mg loading and then 75 mg per day together with a 100-mg daily dose of acetylsalicylic acid.Patients were cooled to 32 o C to 34 o C for 24 hours and then were subject to spontaneous rewarming.Before PCI and 2, 4, 12, 22, and 48 hours after P2Y12 loading, platelet function was measured by VerifyNow P2Y12 Test (Accriva Diagnostics,) and Multiplate (Roche, Switzerland).For VerifyNow, platelet reactivity was expressed in P2Y12 reaction units (PRUs), and in % inhibition, it was calculated as [(1-(P2Y12 receptor blockade/Basal platelet reactivity) x 100].For Multiplate, arbitrary aggregation units were used.High on-treatment platelet reactivity was defined as >208 PRU, <11% inhibition, and >46 U. 3 In-hospital incidence of definite stent thrombosis, bleeding defined as BARC 3a and 5, 4 and survival with good neurological outcome were documented.Differences between the groups were analyzed using the χ2 test or Fischer exact test for categorical variables, and Student t test or Mann-Whitney U test was used for numeric variables.Linear mixed modeling was used to assess the significance at the various time points.P<0.05 was considered significant.The study (Clinical Trial Registration: URL: https://clinicaltrials. gov.Unique identifier: NCT02224274) was
Telomerase Inhibitor BIBR1532 Induces Telomere Shortening and Growth Inhibition in Extra-Germinal Center (GC)-Derived Lymphoid Cell Lines.
Authors: Marco Ladetto, Irene Ricca, Mara Compagno, Dario Ferrero, Alberto Rocci, Maria Dell’Aquila, Paola Omedè, Roberto Francese, Federica De Marco, Sonia Vallet, Loredana Santo, Daniela Drandi, Monica Astolfi, Mario Boccadoro, Corrado Tarella
Journal: Blood (2004)
Elotuzumab (HuLuc63) Activates CD56dim Natural Killer Cells and Monocytes Resulting in the Release of IP-10 and MCP-1
Authors: Balaji Balasa, Mahrukh Huseni, Jyothi Cherukuri, Roxanne Steinle, Amulya Nanisetti, Daniel Afar, Eric Hsi, Vladimir Vexler
Journal: Blood (2008)
Abstract 316: Development of a novel 3D cancer model by cultivation of malignant effusions in a 3D cell culture system
Authors: Arno Amann, Marit Zwierzina, Julia M. Huber, Gabriele Gamerith, Stefan Koeck, Mario Bitsche, Edith Lorenz, Heinz Zwierzina
Journal: Cancer Research (2015)

Abstract Introduction: Metastatic spread and the occurrence of tumour cell resistance to therapeutic interventions can be induced by different molecular processes. Among those, tumour stroma interactions play a crucial role. So far only few cell culture models exist to study these cell processes. Therefore, we describe the development of a hanging drop technology for 3D culture of primary cells isolated from malignant effusion obtained from cancer patients. Methods: A 96-well hanging drop microtiter plate (InSphero AG, Zürich, Switzerland) was applied for the 3D cultivation of cells. Primary cells were isolated either from malignant ascites or pleura effusion of cancer patients. Cells were seeded either into 2D cell culture plates or into hanging drops for an incubation period of ten days. Apart from conventional histology (H&amp;E), protein expression was displayed immunohistochemically (IHC) and by flow cytometry. The applied antibodies displayed the expression of e-cadherin, vimentin, Ki67, CD31, CD45, Epcam, Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) and α-smooth muscle actin (α-SMA). In addition, viability of all samples was determined by an AnnexinV/Propidium Iodide staining using flow cytometry. Results: Microtissue aggregation differed significantly depending on whether the malignant cell effusions displayed expression of Epcam. Effusions consisting of a high number of Epcam positive cells formed solid and viable microtissues. The viability of microtissues remained high (&amp;gt;80%) similar to cells cultivated in 2D cell culture plates. Tumour cells, defined as e-cadherin and Epcam positive by flow cytometry were still detected in microtissues after ten days of incubation in 3D. Furthermore, endothelial cells, defined as CD31 and Lgr5 positive could also be discriminated in microtissues. Conclusion: We demonstrate that our method is a promising tool for the generation of tumour microtissues consisting of primary isolated cells from malignant effusions. Therefore, our technology represents a promising method to investigate tumour stroma interactions in an in vitro system that reflects more closely the in vivo environment. Citation Format: Arno Amann, Marit Zwierzina, Julia M. Huber, Gabriele Gamerith, Stefan Koeck, Mario Bitsche, Edith Lorenz, Heinz Zwierzina. Development of a novel 3D cancer model by cultivation of malignant effusions in a 3D cell culture system. [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 316. doi:10.1158/1538-7445.AM2015-316
Treatment of Advanced CMML by Azacitidine (AZA) In a Compassionate Program. the GFM Experience In 38 Patients (pts)
Authors: Alice Wolfromm, Francois Dreyfus, Norbert Vey, Jacques Delaunay, Aspasia Stamatoullas, Anne Banos, Anne Marfaing-Koka, Stephane de Botton, Dominique Bordessoule, Laurence Legros, Odile Beyne Rauzy, Emmanuel Gyan, Pascale Cony Makhoul, Sylvain Thepot, Raphael Itzykson, Pierre Fenaux, Lionel Ades
Journal: Blood (2010)
Prognostic Impact of Aberrant RUNX1 Expression in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Maria Knyrim, Madlen Jentzsch, Marius Bill, Juliane Grimm, Karoline Schubert, Michael Cross, Georg-Nikolaus Franke, Wolfram Poenisch, Vladan Vucinic, Gerhard Behre, Dietger Niederwieser, Sebastian Schwind
Journal: Blood (2015)
Abstract 3384: Cancer Core 125 Panel for quantitative expression and mutation profiling
Authors: Alex Chenchik, Mikhail Makhanov, Gregory Dolganov, Stefanie Jeffrey
Journal: Cancer Research (2015)

Abstract Molecular profiling of heterogeneous circulating tumor cells (CTCs) and tumor biopsy samples at the single-cell level is critical for identifying different cancer cell subpopulations and understanding their value in predicting metastatic cancer progression and responses to treatment. Unfortunately, the isolation and comprehensive characterization of hundreds to thousands of individual cancer cells present formidable analytical and technical challenges. To this end, we developed a high-throughput (HT) HiCellex technology to obtain the genome-wide expression and mutation profiles of hundreds to thousands of epithelial cancer cells at the single cell level. Importantly, HiCellex allows selective molecular profiling of a complete set of viable cells at the single-cell level in the presence of contaminating leukocytes without physical separation of individual cells. The genetic profiling technology uses unique cell-specific molecular barcodes to label mRNAs in individual viable cancer cells by a spliceosome-mediated trans-splicing mechanism. Barcoded trans-splicing constructs, necessary for the labeling of the entire population of pre-mRNAs, are delivered and expressed in a pool of target cancer cells with lentiviral vectors. Digital expression data are generated by HT sequencing of barcoded amplified cDNAs and easily cluster to each cell in silico using cell-specific barcodes. This presentation will provide results of development and validation of genome-wide and multiplex RT-PCR profiling assay of the 500 most informative subtyping and metastatic signature genes (MGS) in model cancer cell lines, CTC and tumor samples. The developed HiCellex 500 MGS profiling assay is a cost-effective approach to effectively characterize, subtype and identify prognostic and diagnostic biomarkers in heterogeneous cancer cells at the single-cell level. Citation Format: Alex Chenchik, Mikhail Makhanov, Gregory Dolganov, Stefanie Jeffrey. Cancer Core 125 Panel for quantitative expression and mutation profiling. [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 3384. doi:10.1158/1538-7445.AM2015-3384
A circulating microvesicle-based biosignature for the detection of colorectal cancer.
Authors: D. Spetzler, T. Tinder, S. Kankipati, M. Maheshwari, C. D. Kuslich
Journal: Journal of Clinical Oncology (2011)

373 Background: Microvesicles are principally derived either from the endosomal pathway (as exosomes) or shed directly from the plasma membrane. They are between 40-500 nm in diameter and are secreted by most cell types, including tumor cells. In circulation, microvesicles appear to participate in cellular communication by transporting mRNAs, miRs and proteins from their cell of origin to target cells where they can elicit biological responses. The quantity and protein topography of microvesicles shed from cancer cells varies considerably compared to those shed from normal cells. Thus, the concentration of circulating plasma microvesicles with molecular markers indicative of the disease state can be used as a robust and informative blood-based biosignature. In this study we report the results of the application of a novel multiplexed method for quantifying and profiling microvesicles in plasma for the detection of colorectal cancer. Methods: We have developed a versatile mulitplexed microvesicle-based discovery panel with 73 different antibodies that target surface proteins of various microvesicle subpopulations. This system was used to develop a microvesicle-derived biosignature composed of 2 different surface membrane protein biomarkers. Results: In this study, we demonstrate that a combination of TMEM211 and CD24 provide a robust signature for the detection of colorectal cancer (CRC). We isolated microvesicles from plasma of 257 patients with CRC, 57 stage I, 104 stage II, 80 stage 3, 6 stage IV, and 11 of unknown stage; 327 self-described, age-range matched normal plasma specimens were used for the control population. The level of TMEM211 and CD24 containing microvesicles for these samples was determined using a multiplexed immunoassay. Thresholds were empirically determined to maximize the sensitivity and specificity of CRC detection, resulting in a sensitivity of 90% with a specificity of 85% with an AUC of .91. Conclusions: This study demonstrates that it is possible to use circulating microvesicles for the development of a highly sensitive and specific blood-based assay to detect CRC. [Table: see text]
Characterisation of the Novel, High Purity, Double Virus Inactivated Von Willebrand Factor and Factor VIII Concentrate Wilate®.
Authors: Monika Stadler, Gerhard Gruber, Christoph Kannicht, Lothar Biesert, Kai-Uwe Radomski, Haryadi Suhartono, Katharina Pock, Andrea Neisser-Svae, Josef Weinberger, Juergen Roemisch, Tor-Einar Svae
Journal: Blood (2005)