tbuckley/cabot-search huggingface dataset:
Kinetics of Human VWF Cleavage by Human ADAMTS13: Comparison of Recombinant and Plasma-Derived VWF
Authors: Hanspeter Rottensteiner, Katalin Varadi, Susanne Vejda, Jutta Schreiner, Herbert Gritsch, Peter L. Turecek, Hartmut J Ehrlich, Hans Peter Schwarz
Journal: Blood (2008)
Abstract 340: Identification of p62/IMP2 novel targets in breast cancer metastasis
Authors: Yang Li, Bo Peng, Ningjing Lei, Wei Qian, Giulio Francia, Jianying Zhang
Journal: Cancer Research (2015)

Abstract As one of the most common types of cancer in women, breast cancer is far from being well controlled, especially when the cancer spreads to other organs in the body. Therefore, it is important to understand the molecular and cellular mechanism of metastatic breast cancer, and to identify new proteins that regulate the metastatic process, as such proteins may be used as targets for possible therapeutic intervention. Our previous study showed that p62/IMP2 (IGF2 mRNA binding protein 2) is overexpressed in breast cancer tissues. In our present study, some variants were generated with stable overexpression of p62/IMP2 in MDA-MB-231 cells and LM2-4 cells, and we found that overexpression of p62/IMP2 can increase breast cancer cell migration and reduce cell adhesion. We also found that the p62/IMP2 can bind to c-myc mRNA and increase the expression of c-myc in the two cell lines. To identify new p62/IMP2 targets related with cell adhesion, we performed a Human Extracelluar Matrix &amp; Adhesion Molecules PCR Array to see which gene expression changes in the p62/IMP2 overexpressed cells, compared to the control cells. Our results showed that 18 adhesion molecules are up-regulated with the overexpression of p62/IMP2 (Fold regulation&amp;gt;2, p&amp;lt;0.05) while 2 are down-regulated. We selected 7 up-regulated genes (such as CTGF, HTBS1 and COL15A1) and a down-regulated gene (ITGB4) as candidates for the further evaluation by real time PCR. All candidates genes were further verified byRNA immunoprecipitation (RIP). The data from RIP suggested that connective tissue growth factor (CTGF) may be a potential target of p62/IMP2. These results provided evidences for a better understanding of breast cancer metastasis and targets for future anti-metastatic drug design. Note: This abstract was not presented at the meeting. Citation Format: Yang Li, Bo Peng, Ningjing Lei, Wei Qian, Giulio Francia, Jianying Zhang. Identification of p62/IMP2 novel targets in breast cancer metastasis. [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 340. doi:10.1158/1538-7445.AM2015-340
Abstract 2081: The CCCTC-binding factor (CTCF) functions to downregulate the transcription of MGMT gene in human glioblastoma cells
Authors: Kalkunte S. Srivenugopal, Mohammed Ibrahim Al-Obaide
Journal: Cancer Research (2015)

Abstract The O6-methylguanine-DNA methyltransferase (MGMT) gene located at chromosome 10q26 encodes a DNA repair protein that abrogates the therapeutic effects of alkylating agents by preventing the formation of mutagenic lesions or cytotoxic DNA crosslinks. MGMT is highly expressed in human gliomas and its transcriptional regulation has emerged as a major translational focal point in neuro-oncology, because the epigenetic silencing of the MGMT gene which occurs in a subset of these malignancies confers improved treatment responses to both chemo and radiation therapies. While the promoter methylation and its contribution to glioma therapy has been much studied, the regulation of MGMT transcription per se, proteins accessory to the process and the chromatin structure thereof are not well understood. The CCCTC-binding transcription factor (CTCF) is one such multifunctional protein involved not only in DNA methylation but also with transcriptional activation/repression, and induction of short or long range chromatin looping. CTCF, an 11 zinc-finger containing protein is more frequently known for its insulating effects by binding diverse nucleotide sequences and restricting the function of transcriptional enhancers. Our bioinformatic analysis of the human MGMT gene showed an unusually high (7-10 sites) congregation of CTCF-binding sites distal to the promoter in human cancer cell lines. Given these considerations, we used CTCF siRNA to eliminate the transcription factor in two MGMT-proficient GBM cell lines (SF180 and GBM10). A specific reduction of CTCF protein by individual and pooled siRNAs was consistently accompanied by increased MGMT protein and mRNA levels. Furthermore, the DNA repair activity of MGMT was increased by 50%, which correlated with a proportional reduction of the CTCF protein in siRNA-exposed cells. Currently, we are investigating the effect of CTCF on MGMT reactivation in cells with methylation, MGMT promoter activity in CTCF silenced cells and the effect of enforced CTCF expression on MGMT transcription. Our results for the first time highlight the involvement of multivalent CTCF in MGMT expression. Since CTCF is tightly linked with DNA methylation, further studies should reveal its role in silencing of MGMT in human GBMs (supported by CPRIT RP130266 and NIH RO3CA125872 grants to KSS). Citation Format: Kalkunte S. Srivenugopal, Mohammed Ibrahim Al-Obaide. The CCCTC-binding factor (CTCF) functions to downregulate the transcription of MGMT gene in human glioblastoma 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 2081. doi:10.1158/1538-7445.AM2015-2081
Omission of Methotrexate Doses Due to Toxicity Does Not Influence the Incidence of Gvhd, Relapse, or Survival
Authors: Betty K. Hamilton, Housam Haddad, Edward A. Copelan, Lisa Rybicki, Shawnda Tench, Melissa Yurch, Brian J. Bolwell, Rabi Hanna, Ronald Sobecks, Robert M Dean, Hien K. Duong, Brian T. Hill, Matt Kalaycio
Journal: Blood (2012)
Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia (AML) with FBA/FBAA Regimen Based Reduced-Intensity Conditioning: A Multicenter Clinical Trial in China
Authors: Jianmin Wang, Weiping Zhang, Jiong Hu, Chun Wang, Xinghua Chen, Jian Hou, Yongping Song
Journal: Blood (2011)
Analysis of BRAF and KRAS mutations in colorectal cancer and rectal carcinogenesis via fluorescent allele-specific PCR.
Authors: D. G. Stover, A. M. Cushman-Vokoun, C. L. Vnencak-Jones, J. Berlin
Journal: Journal of Clinical Oncology (2011)

436 Background: Molecular analysis has become increasingly relevant in the evaluation of colorectal carcinomas. Mutations in Ras-MAPK pathway proteins KRAS (present in 30-40% of colorectal cancer) and BRAF (10-14% of colorectal cancer) or mismatch repair (MMR) enzymes can impact response to therapy and/or can assist in defining hereditary predisposition. High frequency microsatellite instability (MSI) in colorectal cancer is associated with improved outcomes. Targeted therapies against BRAF and other components of the Ras-MAPK signaling pathway are becoming important aspects of treatment in colorectal and other cancers. Methods: A retrospective study was performed on 111 paraffin-embedded tumor specimens submitted between 1/07 and 3/09 for MSI testing based on family history and/or histologic features. DNA samples were screened for the BRAF V600E mutation and 7 KRAS mutations in codons 12 and 13 using fluorescent allele specific PCR with capillary electrophoresis. Clinical data was collected via chart review. Results: 58 males and 53 females were studied. The incidence of KRAS and BRAF mutations among the 111 samples was 49.5% and 6.3%, respectively. KRAS G12D and G12V were the most common mutations, representing 57% of total KRAS mutations. Dually positive KRAS and MSI tumors exclusively demonstrated G12D and G13D mutations. KRAS and BRAF mutations were mutually exclusive. Rectal cancers did not show evidence of BRAF V600E mutation (p=0.04). KRAS, BRAF, and MSI status did not correlate with survival, however pre-operative and post-operative carcinoembryonic antigen (CEA) levels were significantly associated with survival both in univariate and multivariate analyses. Conclusions: We demonstrate that BRAF V600E mutation is significantly associated with colon cancer and not rectal cancer, suggesting that BRAF mutations are not relevant in rectal carcinogenesis. Correlation between specific KRAS mutation and outcome may require larger populations. No significant financial relationships to disclose.
377. AAV-Mediated Transfer of FKRP Shows Therapeutic Efficacy in a Murine Model of Limb-Girdle Muscular Dystrophy Type 2i, but Requires Tight Control of Gene Expression
Authors: Evelyne Gicquel, Natacha Maizonnier, Steven J. Foltz, William Martin, Nathalie Bourg, Fedor Svinartchouk, Karine Charton, Aaron Beedle, Isabelle Richard
Journal: Molecular Therapy (2016)

Limb Girdle Muscular Dystrophies (LGMD) type 2I, a recessive autosomal muscular dystrophy, is caused by mutations in the Fukutin Related Protein (FKRP) gene. It has been proposed that FKRP, whose function remains unclear, is a participant in α-dystroglycan (αDG) glycosylation, which is important to ensure the cell/matrix anchor of muscle fibers. A knock-in mouse model of LGMD2I was generated to express the most frequent mutation (L276I) encountered in patients. The introduction of the mutation did not alter the expression of FKRP, neither at transcriptional nor at translational levels, but did alter its function since abnormal glycosylation of αDG was observed. In this model, skeletal muscles were functionally impaired from 2 months of age and a moderate dystrophic pattern was evident by histology starting from 6 months of age. Gene transfer with a rAAV2/9 vector expressing Fkrp restored the biochemical defects, corrected the histological abnormalities and improved the resistance to eccentric stress in the mouse model was obtained. However, injection of high doses of the vector induced a decrease of αDG glycosylation and laminin binding. Finally, we showed that intravenous injection of the rAAV-Fkrp vector into a dystrophic mouse model suffering of dystroglycanopathy due to skeletal muscle-specific Fukutin (Fktn) knock-out caused toxicity. The dose-dependent worsening of the dystrophic phenotype suggests requirement for a precise control of its expression.
Amplified canonical transforming growth factor-β signalling <i>via</i> heat shock protein 90 in pulmonary fibrosis
Authors: Zaneta Sibinska, Xia Tian, Martina Korfei, Baktybek Kojonazarov, Janina Susanne Kolb, Walter Klepetko, Djuro Kosanovic, Malgorzata Wygrecka, Hossein Ardeschir Ghofrani, Norbert Weissmann, Friedrich Grimminger, Werner Seeger, Andreas Guenther, Ralph T. Schermuly
Journal: European Respiratory Journal (2016)

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of idiopathic pulmonary fibrosis (IPF), and is governed by transforming growth factor (TGF)-β/Smad signalling. We sought to define the role of heat shock protein (HSP)90 in profibrotic responses in IPF and to determine the therapeutic effects of HSP90 inhibition in a murine model of pulmonary fibrosis.We investigated the effects of HSP90 inhibition in vitro by applying 17-AAG (17-allylamino-17-demethoxygeldanamycin) to lung fibroblasts and A549 cells and in vivo by administering 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin) to mice with bleomycin-induced pulmonary fibrosis.HSP90 expression was increased in (myo)fibroblasts from fibrotic human and mouse lungs compared with controls. 17-AAG inhibited TGF-β1-induced extracellular matrix production and transdifferentiation of lung fibroblasts and epithelial-mesenchymal transition of A549 cells. The antifibrotic effects were associated with TGF-β receptor disruption and inhibition of Smad2/3 activation. Co-immunoprecipitation revealed that HSP90β interacted with TGF-β receptor II and stabilised TGF-β receptors. Furthermore, 17-DMAG improved lung function and decreased fibrosis and matrix metalloproteinase activity in the lungs of bleomycin-challenged mice.In conclusion, this is the first study to demonstrate that HSP90 inhibition blocks pulmonary fibroblast activation and ameliorates bleomycin-induced pulmonary fibrosis in mice.
Prior Therapy with Rituximab (R) in Patients with Follicular Lymphoma (FL) Does Not Affect Relapse-Free (RFS) or Overall Survival (OS) after High Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT).
Authors: Tyler Y. Kang, John William Sweetenham, Snehal G. Thakkar, Lisa A. Rybicki, Stacey Brown, Robert Dean, Mikkael A. Sekeres, Anjali Advani, Ronald Sobecks, Matt Kalaycio, Brad Pohlman, Brian J. Bolwell
Journal: Blood (2006)
Acquired Resistance to Bortezomib in Human RPMI-8226 Multiple Myeloma Cells: Molecular Characterization, Cross-Resistance with Other Proteasome Inhibitors but Marked Sensitization to Glucocorticoids
Authors: Niels E Franke, Gertjan L Kaspers, Nynke van den Berg, Ina van Zantwijk, Katarina Vojtekova, Uzma Yaqub, Serge Smeets, Bauke Ylstra, Sonja Zweegman, Gerrit Jansen, Jacqueline Cloos
Journal: Blood (2008)
Activity of VT-464, a selective CYP17 lyase inhibitor, in the LNCaP prostate cancer xenograft model.
Authors: Stephen Todd Pisle, Heather M Pressler, Sarah M Troutman, Joel Robert Eisner, Stephen W Rafferty, Robert J Schotzinger, William R Moore, William Douglas Figg
Journal: Journal of Clinical Oncology (2012)

64 Background: With the recent FDA approval of abiraterone acetate, CYP17 (17α hydroxylase/C17, 20-lyase) has become a proven target for the treatment of castration- resistant prostate cancer. Inhibition of CYP17-lyase causes a decrease in circulating androgens, severely hampering activation of the androgen receptor signaling pathway that prostate cancer relies on for proliferation. However, inhibition of CYP17-hydroxylase, a second enzymatic activity of CYP17, leads to an increase in upstream steroids that can cause mineralocorticoid excess syndrome as well as a decrease in cortisol production. VT-464 is a novel, selective CYP17 lyase inhibitor with decreased activity against CYP17 hydroxylase. The study objectives were to observe the effects of VT-464 in a prostate cancer xenograft model and to compare its activity to abiraterone acetate and surgical castration. Methods: SCID mice were implanted subcutaneously with LNCaP cells. When tumors reached 100mm 3 , mice were randomized to receive vehicle (0.5% CMC in saline, 5ml/kg), or VT-464 at 15, 50, or 100mg/kg p.o. bid. A second cohort of LNCaP tumor-bearing mice received vehicle, surgical castration, or VT-464 or abiraterone acetate at 100mg/kg p.o. bid for 28 days. Results: In the LNCaP xenograft model, percent growth inhibition (± S.E.) of 9.6 (±15.6), 38.5(±12.4), and 73.9 (±13.2) was observed on day 21 of treatment for the VT-464 doses of 15, 50, and 100 mg/kg, respectively. VT-464 -treated (100mg/kg) mice had a signiﬁcantly reduced tumor volume ratio (V/V 0 ) on day 28 compared to control and abiraterone acetate (p&lt;0.05, p&lt;0.01, respectively). Reduction in tumor volume ratios were similar between VT-464-treated (100 mg/kg) and castrate animals. Conclusions: VT-464 exhibited dose-dependent growth inhibition with significantly reduced tumor growth at the highest dose compared to abiraterone acetate. The reduction in tumor growth in VT-464-treated animals was similar to that of castrate animals. These preclinical results show promising activity of VT-464 in the treatment of prostate cancer.
Idarucizumab Fully Restores Dabigatran-Induced Alterations on Platelet and Fibrin Deposition on Damaged Vessels: Studies in Vitro with Circulating Human Blood
Authors: Eduardo Arellano-Rodrigo, Irene Lopez-Vilchez, Patricia Molina, Marcos Pino, Maribel Diaz-Ricart, Joanne van Ryn, Gines Escolar
Journal: Blood (2014)
PTH-053 Vitamin D and other micronutrient status in patients with ald and other liver diseases
Authors: C Raychaudhuri, A Al-Joudeh, M Srinivas, B Ellis, K D Bardhan, P J Willemse, P Basumani, B Höroldt
Journal: Gut (2010)

<h3>Introduction</h3> Vitamin D deficiency is associated with non-specific symptoms, carries long-term risk to bone health, and certain groups are at higher risk (alcohol excess, old age, Asians). The prevalence among patients attending hepatology clinics is unclear; this prompted our pilot study. <h3>Methods</h3> Measurements: vitamin D, calcium profile, LFT, FBC available for all; vitamin B12, folate, ferritin/iron studies available for 256 patients. Use of OTC supplements was checked and those on vitamin (other than oral thiamine or Vitamin B complex) preparations were excluded. Frequencies were compared by Fisher exact test. <h3>Results</h3> 288 patients were included (170 male, median (range) age: 54.81 (17–92), 155 Caucasian). 113 had alcoholic liver disease (112 Caucasians), 175 other liver diseases (non-ALD: 29 autoimmune liver disease, 52 fatty liver, 65 viral liver hepatitis, 29 other). 37 patients had liver cirrhosis (29 ALD, 8 non-ALD). (a) Overall median vitamin D level was 37 nmol/l and was lower in ALD vs non-ALD patients: 30 vs 47 nmol/l. (b) Median vitamin D level in south-east Asian was 23 nmol/l, deficiency was significantly more common (50 vs 30%, p=0.02); these patients were excluded from subsequent analysis. (c) Vitamin D deficiency was significantly more common in ALD patients (33 vs 13%, p=0.001). (d) In ALD cirrhosis was not significantly associated with vitamin D deficiency (p=0.08). (e) In ALD, there was trend towards increased vitamin D deficiency in females (p=0.06), in patients over 60 years (p=0.053) and towards worsening vitamin D deficiency in spring compared to autumn (p=0.07). (f) In non-ALD, vitamin D deficiency was significantly more common in patients &gt;60 years (p=0.02); but not in women (p=1.0). Seasonal variation was not significant for deficiency (p=0.07), but for combined deficiency/insufficiency (p=0.004). (g) In non-ALD cirrhosis, vitamin D deficiency was more common but this did not reach statistically significance (33 vs 12%, p=0.09). (h) Folate (10%) and iron deficiency (14%) were more common in ALD (non-ALD both 4%) but vitamin B12 deficiency was not (8.8 vs 8.2%). <h3>Conclusion</h3> Vitamin D is common in ALD, it9s prevalence in other liver diseases is around 12%, higher than other micronutrient deficiencies. It is increased in older subjects and South-East Asians and seasonal variation is less then expected. It should be screened for in all ALD patients and in non-ALD in those at increased risk (older age, South-East Asian and cirrhosis).
Health-Related Quality of Life in Children with Sickle Cell Disease: Impact of Blood Transfusion Therapy
Authors: Lauren M Beverung, John J. Strouse, Monica L. Hulbert, Kathleen A Neville, Robert I. Liem, Baba PD Inusa, Beng Fuh, Allison King, Emily R. Meier, James F. Casella, Michael R. DeBaun, Julie A. Panepinto
Journal: Blood (2014)
Abstract 2832: Targeting and depletion of circulating cancer cells by lipophilic antibody-modified erythrocytes
Authors: Dmitri Simberg
Journal: Cancer Research (2015)

Abstract There is a great interest in targeting and selective ablation of populations of circulating cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers (natural life is 120 days) that are amenable to chemical modifications, drug loading and reinjection. Here we demonstrate that using our previously described lipophilic ligand painting strategy, red blood cells (RBCs) could be in one step converted into targeted entities that selectively seek and bind various cells in vitro and in vivo. In vitro, RBCs modified with lipophilic anti-EpCAM or anti-CD45 antibodies efficiently bound to cancer cells and leukocytes, forming characteristic rosettes. In vivo, intravenously injected RBCs painted with anti-CD45 antibody immediately associated with CD45 positive cells in blood, forming RBC-leukocyte rosettes. Moreover, anti-CD45-modified RBCs, but not the same amount of anti-CD45 antibody or anti-CD45-lipid conjugate (1-2 microgram per mouse), depleted over 50% of CD45+ leukocytes from circulation, with main clearance organs of leukocytes being liver and spleen with no visible deposition in kidneys and lungs. Anti-CD20 (rituximab)-painted RBCs efficiently (over 90%) depleted CD19+/CD20+/CD45+ human lymphoma cells in mantle cell lymphoma (MCL) JeKo-1 model, while the same amount of rituximab-lipid (2 microgram per mouse) was much less efficient in lymphoma cell depletion. Treatment of MCL mice with rituximab-modified RBCs carrying only 2 μg of the antibody resulted in a significant prolongation of survival as compared to the same amount of antibody control. Lipophilic ligand-painted RBCs is a novel tool that can be utilized for targeting blood borne cells for experimental immunology and cancer therapy applications. Citation Format: Dmitri Simberg. Targeting and depletion of circulating cancer cells by lipophilic antibody-modified erythrocytes. [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 2832. doi:10.1158/1538-7445.AM2015-2832
Abstract 3492: Metformin inhibits salivary gland tumor growth through cell cycle arrest and apoptosis
Authors: Yuqi Guo
Journal: Cancer Research (2015)

Abstract Human salivary gland cancer (SGC) is one of the common malignancies found in the head and neck area. The limitation of the treatment and poor prognosis are calling for more investigations into novel intervention to improve the treatment modality in SGCs. Metformin as a widely used anti-type-2 diabetes medicine had demonstrated its anti-tumor potential in many different types of cancers. Our previous work demonstrated that metformin effectively targeted c-Myc oncogene to prevent the initiation and progression of prostate cancer. Interestingly, the overexpression of c-Myc has also been shown in some SGCs, such as salivary gland adenoid cystic carcinoma. Therefore, it is intriguing to explore metformin's anti-neoplastic efficacy of metformin in SGC. In this study, we used a human salivary adenocarcinoma cell line, HSY cell line as a model for salivary gland tumor. Our in vitro results show metformin prominently suppresses the growth of HSY cell through stimulation of cell cycle arrest and apoptosis. Meanwhile, metformin significantly down-regulates cMyc expression and rescues p53 tumor suppressor gene expression. Considering that mTOR inhibitors resistance could occur when tumors over-express cMYC. PP242, a novel and potent mTOR inhibitor was used in combination with metformin to inhibit HSY cell growth. As expected, metformin enhanced the inhibitory effects of PP242 associated with reduced c-MYC levels in vitro. Further in HSY xenograft tumors, massive necrotic areas were observed inside the tumors from metformin treated mice while only limited necrotic area in the core of tumors from PBS treated mice. Staining of proliferation marker Ki-67 confirmed lower proliferation rate in tumors from metformin treated group compare to that from the PBS group. In conclusion, our novel finding of metformin efficacy in SGC not only proves metformin plays a pivotal role in suppressing SGCs through cell cycle arrest and apoptosis, but also suggest that a combination treatment using metformin and mTOR inhibitors together may yield better inhibitory efficacy. Citation Format: Yuqi Guo. Metformin inhibits salivary gland tumor growth through cell cycle arrest and apoptosis. [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 3492. doi:10.1158/1538-7445.AM2015-3492