tbuckley/cabot-search huggingface dataset:
Abstract B41: The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival
Authors: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher
Journal: Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. PDAC is highly resistant to chemotherapy, which impels search for novel approaches for treatment. Our group has previously shown in PDAC models that the angiotensin II type 1 receptor (AT1R) blocker losartan decreases desmoplasia and solid stress, which enhances blood flow, and improves the delivery and effectiveness of cytotoxic agents (Chauhan et al, Nature Comm 2013). In contrast to losartan, which had no effects on the growth of primary PDAC, we recently found that the AT1R blocker telmisartan significantly reduces the growth of PDAC. In addition to inhibiting AT1R activity telmisartan is also a partial agonist of Peroxisome Proliferator Activated Receptor γ (PPARγ). We determined in a panel of PDAC cell lines the effects of telmisartan on cellular viability. Our findings suggest that the sensitivity to telmisartan treatment correlates with low steady-state expression of PPARγ and a mesenchymal morphology. Furthermore, telmisartan induced a transcriptional profile distinct from the response to the direct PPARγ agonist pioglitazone. In support of our correlative results, the genetic knockdown of PPARγ increased the sensitivity to telmisartan and stimulated epithelial to mesenchymal transition (e.g. decreased expression of E-cadherin, increased expression of the mesenchymal markers Snail and N-cadherin). We also tested the effects of telmisartan in orthotopically implanted and genetically engineered mouse models of PDAC. Telmisartan inhibited the growth of primary tumors, decreased the incidence of metastasis and improved mice survival. In summary, our findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice. Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher.{Authors}. The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival. [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 B41.
Gene Expression Profiling (GEP) of Purified Plasma Cells at Baseline and 48hr after-Dexamethasone (D) or Thalidomide (T) Improve Outcome Predicition of Baseline GEP Alone in Patients with Multiple Myeloma (MM) Treated with Total Therapy 2 (TT2).
Authors: Bart Burington, John Shaughnessy, Bart Barlogie, Crowley John
Journal: Blood (2005)
Three-dimensional ultrasound-based spectroscopic imaging for the detection of prostate cancer.
Authors: Hans T. Chung, Ervis Sofrani, Naum Papanicolau, Linda Sugar, Gerard Morton, Martin Yaffe, Robert Nam, Gregory J. Czarnota
Journal: Journal of Clinical Oncology (2012)

234 Background: The objective of this translational research was to investigate the use of real-time novel three-dimension, quantitative ultrasound-based spectroscopic imaging of the prostate as a means of cancer detection. Methods: Fourteen patients with T2-3 prostate cancer underwent a 6–9 MHz trans-rectal ultrasound scan of the prostate prior to radical prostatectomy. Equally spaced axial ultrasound images (0.5 cm separation) corresponding elasticity and spectroscopy data were collected in each patient. Colour-coded spectroscopic parametric maps of 0-Mhz intercept (0-Mhz), mid-band fit (MBF) and slope of line of best fit (slope) were generated indicating where the disease in the prostate gland is hypothetically located. Quantitative data (% volume of cancer over the prostate gland) were compared to whole-mount radical prostatectomy histopathology maps to determine the sensitivity and accuracy in parametrically delineating prostate cancer. Results: Representative data indicate spectral changes were associated with the presence of co-incident disease as located on correlative histopathology whole mount sections. Of the 14 patients enrolled, 7 have been analyzed and presented here. The mean % difference between 0-MHz and MBF, with H&amp;E, was 14% (SD 38%) and 21% (SD 24%), respectively. Gross areas of disease were readily visualized in ultrasound parametric maps and corresponded to a maximum 10dB decrease in 0-MHz or MBF. Parametric maps generated from the spectral slope offered no discrimination of disease. There were differences in scatterer size estimates and scatter concentration estimates between putative disease areas and the remaining tissue. Conclusions: Initial results suggest that there is good correlation between spectroscopic maps with disease on whole-mount specimens. This method may ultimately permit ultrasound-guided targeted biopsies to improve detection rates and non-invasive assessment of disease for radiotherapy planning.
SURG-19. DAY-CASE IMAGE-GUIDED BIOPSY FOR BRAIN TUMOURS: A DECADE OF EXPERIENCE
Authors: Victoria Wykes, Simon McElligott, Jonathan Duffill, Paul Grundy
Journal: Neuro-Oncology (2016)

In the United Kingdom widespread adoption of day-case image-guided biopsy (DIB) for brain tumour has not occurred. To qualify for DIB patients are selected in the outpatient clinic and day-case is defined as arriving and being discharged from hospital on the same day. Published protocols and procedures for DIB of brain tumours were used (1). All Patients undergoing an image-guided biopsy for tumour were retrospectively identified from operative logbooks (October 2006 - March 2016 inclusive), and information recorded from online records or notes. In this 9.5 year study, 645 image-guided biopsies for tumour were performed. 355 (55%) cases were planned DIB of a supratentorial tumour. Histological diagnosis included high grade glioma (62%), low grade glioma (18%), lymphoma (8%), metastasis (5%), meningioma (1%), primitive neuroectodermal tumour (1%), other (2%) and no diagnosis (3%). 92% of DIB patients were successfully discharged at 6 hours postoperatively. 16/355 (4.5%) of DIB patients were directly admitted following identification of a postoperative haematoma > 2 cm diameter on CTH. 9/16 had no associated new deficit and were discharged the following day. 0.8% of patients required surgical evacuation of postoperative haematoma, however all made a full recovery. 0.3% DIB were complicated by infection. 0% experienced significant permanent neurological deficit that influenced further oncological treatment. 3% of cases were non-diagnostic on first biopsy. 1/355 CTH identified an asymptomatic extradural requiring evacuation that otherwise would have been discharged home at 6 hours post DIB. 0.8% of patients were readmitted within 48 hours of biopsy and none of our patients came to harm as a result of being a DIB. DIB surgery with close clinical and radiological surveillance is well-tolerated, safe and feasible. We advocate this concept is more widely adopted. REFERENCES: 1) Grundy P.L et al (2008) Br.J.Neurosurg (22) 360-367.
628. Oncogenic Ras Inhibits IRF1 To Promote Viral Oncolysis
Authors: Yumiko Komatsu, Sherri L. Christian, Nhu Ho, Theerawat Pongnopparat, Maria Licursi, Kensuke Hirasawa
Journal: Molecular Therapy (2015)

Oncolytic viruses exploit common molecular changes in cancer cells, which are not present in normal cells, to target and kill cancer cells. Ras transformation and defects in type I interferon (IFN)-mediated antiviral responses are known to be the major mechanisms underlying viral oncolysis. Previously, we demonstrated that oncogenic RAS/Mitogen-activated protein kinase kinase (Ras/MEK) activation suppresses the transcription of many IFN-inducible genes in human cancer cells, suggesting that Ras transformation underlies type I IFN defects in cancer cells. Here, we investigated how Ras/MEK downregulates IFN-induced transcription. By conducting promoter deletion analysis of IFN-inducible genes, namely guanylate-binding protein 2 and IFN gamma inducible protein 47 (Ifi47), we identified the IFN regulatory factor 1 (IRF1) binding site as the promoter region responsible for the regulation of transcription by MEK. MEK inhibition promoted transcription of the IFN-inducible genes in wild type mouse embryonic fibroblasts (MEFs), but not in IRF1-/- MEFs, showing that IRF1 is involved in MEK-mediated downregulation of IFN-inducible genes. Furthermore, IRF1 protein expression was lower in RasV12 cells compared with vector control NIH3T3 cells, but was restored to equivalent levels by inhibition of MEK. Similarly, the restoration of IRF1 expression by MEK inhibition was observed in human cancer cells. IRF1 re-expression in human cancer cells caused cells to become resistant to infection by the oncolytic vesicular stomatitis virus strain. Together, this work demonstrates that Ras/MEK activation in cancer cells downregulates transcription of IFN-inducible genes by targeting IRF1 expression, resulting in increased susceptibility to viral oncolysis.
330. Genetic Modification To Achieve Targeting of Adenoviral Vectors To Malignant Cells of Lymphocyte Origin
Authors: Abdul Mohin Sajib, Payal Agarwal, Maninder Sandey, Bruce F. Smith
Journal: Molecular Therapy (2015)

Hematologic malignancies comprise tumors that affect three related cellular compartments; blood, bone marrow and lymphatics Gene therapy is an outstanding approach to treat hematological malignancies as the molecular basis of these disorders is increasingly understood. Therapeutic genes are available and alternative therapies are often lacking efficiency however, the, systemic nature of hematologic malignancies requires selective tumor targeting. Recombinant Adenoviral (Ad) vectors derived from human serotype 2 and 5, are currently, the most common vehicle for efficient in vivo transgene delivery and account for 23.8% of nearly 1700 clinical trials that were conducted by using both viral and non-viral vectors. Initial binding of virus fiber knob to the cell surface coxsackie-adenovirus receptor (CAR) followed by secondary binding with avb3/5 integrins on the cell surface are the prerequisites for successful viral internalization to the target cell. However, several studies have shown that cells of lymphocyte origin (B cell, T cell, NK cells etc.) are poorly infected by adenovirus due to the paucity of both CAR and integrins. Hence, retargeted adenovirus must be developed that will bypass both CAR and integrin requirements. Our goal is to explore mechanisms to target lymphocytes at the level of transduction (or infection). Transductional targeting provides improved gene transfer into cancerous cell and spares normal cells. This is typically accomplished through surface modification of the gene delivery vehicle to enhance specific interactions with cancer cell membrane proteins. We hypothesize that, transductional targeting of adenovirus by utilizing anti-Interleukin-2-receptor (IL-2R) antibody to target cell surface Il-2R will allow us to conduct CAR and integrin independent cell specific targeting of adenovirus to malignant lymphocytes. To accomplish this goal, the sequences of canine, human and murine IL-2 and IL-2R were compared to each other. This data shows that human and canine IL-2 and IL-2R may cross react whereas murine IL-2 has diverged significantly. Based on these results, canine IL-2 and IL-2R were cloned, followed by sub-cloning these constructs, along with the ectodomain of IL-2R (Ecto-IL-2R), into eukaryotic expression vectors. Antibody constructs will be generated by immunizing with Ecto-IL-2R. The DNA encoding these antibodies will be cloned and inserted into the adenoviral fiber gene to allow knob-scIL-2RAb fusion proteins to be produced.
Thrombotic Microangiopathy in Inverted Formin 2–Mediated Renal Disease
Authors: Rachel C. Challis, Troels Ring, Yaobo Xu, Edwin K.S. Wong, Oliver Flossmann, Ian S.D. Roberts, Saeed Ahmed, Michael Wetherall, Giedrius Salkus, Vicky Brocklebank, Julian Fester, Lisa Strain, Valerie Wilson, Katrina M. Wood, Kevin J. Marchbank, Mauro Santibanez-Koref, Timothy H.J. Goodship, David Kavanagh
Journal: Journal of the American Society of Nephrology (2016)

The demonstration of impaired C regulation in the thrombotic microangiopathy (TMA) atypical hemolytic uremic syndrome (aHUS) resulted in the successful introduction of the C inhibitor eculizumab into clinical practice. C abnormalities account for approximately 50% of aHUS cases; however, mutations in the non-C gene diacylglycerol kinase- ε have been described recently in individuals not responsive to eculizumab. We report here a family in which the proposita presented with aHUS but did not respond to eculizumab. Her mother had previously presented with a post–renal transplant TMA. Both the proposita and her mother also had Charcot–Marie–Tooth disease. Using whole-exome sequencing, we identified a mutation in the inverted formin 2 gene ( INF2 ) in the mutational hotspot for FSGS. Subsequent analysis of the Newcastle aHUS cohort identified another family with a functionally-significant mutation in INF2 . In this family, renal transplantation was associated with post-transplant TMA. All individuals with INF2 mutations presenting with a TMA also had aHUS risk haplotypes, potentially accounting for the genetic pleiotropy. Identifying individuals with TMAs who may not respond to eculizumab will avoid prolonged exposure of such individuals to the infectious complications of terminal pathway C blockade.
Mechanism of Oncogenesis by Leukemia-Associated Mutants of Shp2 (PTPN11).
Authors: M. Golam Mohi, Heike Keilhack, Sarah Cohen, Christina Boulton, Toshiyuki Araki, Ifor Williams, Jeffery L. Kutok, D. Gary Gilliland, Benjamin G. Neel
Journal: Blood (2004)
Abstract 5337: Anin silicoplatform for characterizing ADC bystander effects
Authors: Jackson Burton, Shu-Wen Teng, Christopher J. Zopf, Ryan Nolan, Arijit Chakravarty
Journal: Cancer Research (2015)

Abstract Introduction The “bystander effect” is the hypothesized process by which neighboring cancer cells are killed when free drug is released into the tumor environment by dying cells. The extent to which an antibody drug conjugate (ADC) elicits the bystander effect can have significant impact on the magnitude and dynamics of efficacy. Understanding the bystander effect though experimental methods (e.g. video-microscopy) are challenging; however, when supplemented with in silico modeling, mechanistic details can be elucidated. The purpose of this work is to develop a spatial-temporal in silico platform describing tumor cell progression in the presence of an ADC in order to quantify the bystander effect. Methods The model employs spatial-stochastic methods to simulate the time evolution of cell death resulting from ADCs and freely diffusing payload based on following parameters: drug to antibody ratio (DAR), linker stability, antigen concentration, ADC cell membrane permeability, ADC-antigen internalization, payload permeability, and payload potency. Specifically, a 2-D rectangular grid of tumor cells, ADCs, and payload are numerically implemented through binary pixel occupation of the grid. Governing rules are then assigned for: mobility for freely diffusing ADCs and payload, reaction rate for ADC binding to antigen-expressing cells, rate of cell death dependent on payload concentration, and internalization rate of payload into non-antigen expressing cells. The simulation is run until stopping criteria are met, e.g. all cells are killed. Baseline parameters can be optimized by fitting the model to in vitro experimental video-microscopy data. Results Experimental conditions were simulated with the model to characterize the influence of the aforementioned ADC and biological parameters on the bystander effect. Conclusions By incorporating the spatial aspect of ADC mechanics, spatially dependent metrics can be formulated to quantify the bystander effect. The model allows for wide adjustability of the ADC design parameters as well as relevant biological parameters. Thus, by understanding the relative parameter sensitivities, the model can explore design optimization of ADCs that maximize the bystander effect. Through such optimization, the magnitude and dynamics of drug exposure at the site of action can be controlled to maximize efficacy and improve the therapeutic window. Citation Format: Jackson Burton, Shu-Wen Teng, Christopher J. Zopf, Ryan Nolan, Arijit Chakravarty. An in silico platform for characterizing ADC bystander effects. [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 5337. doi:10.1158/1538-7445.AM2015-5337
“Human Development Index” Correlates with Rates and Influences Outcome of Hematopoietic Stem Cell Transplantation for Patients with Acute Leukemia.
Authors: Sebastian Giebel, Myriam Labopin, Gerhard Ehninger, Dietrich W. Beelen, Didier Blaise, Arnold Ganser, Andrea Bacigalupo, Tomasz Czerw, Jerzy Holowiecki, Francesco Frassoni, Evandro M. Fagundes, Elzbieta Nowara, Vanderson Rocha
Journal: Blood (2009)
Development of an online platform for registration and outcome measurement of urogynecological implants according to IDEAL-system
Authors: D. Barski, H. Gerullis, T. Ecke, R. Joukhadar, J. Kranz, R. Tahbaz, F. Queissert, L. Schneidewind, S. Mühlstädt, M. Grabbert, N. Huppertz, A.E. Pelzer, U. Klinge, M. Boros, W. Bader, F. Puppe, T. Otto
Journal: International Journal of Surgery (2016)
Phase 1 AML Study of AC220, a Potent and Selective Second Generation FLT3 Receptor Tyrosine Kinase Inhibitor
Authors: Jorge E. Cortes, Darejan Ghirdaladze, James M. Foran, Marcel P. DeVetten, Mamia Zodelava, Mark J. Levis, Norman M. Padre, James Joyce, Patrick P. Zarrinkar, Robert Corringham
Journal: Blood (2008)
Smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable intracellular prodrug release, photodynamic treatment and aggregation induced photothermal therapy of hepatocellular carcinoma
Authors: Da Zhang, Aixian Zheng, Juan Li, Ming Wu, Lingjie Wu, Zuwu Wei, Naishun Liao, Xiaolong Zhang, Zhixiong Cai, Huanghao Yang, Gang Liu, Xiaolong Liu, Jingfeng Liu
Journal: Theranostics (2016)

This study describes smart Cu(II)-aptamer complexes based gold nanoplatform for tumor micro-environment triggered programmable prodrug release, in demand photodynamic therapy and aggregation induced photothermal ablation of hepatocellular carcinoma. The nanoplatform is consist of monodispersed gold nanoparticle (GNP) that is binding to HCC cell specific targeting aptamers (TLS11a) through Au-S bond; the aptamer is labeled with Ce6 at the 5'end and coordinated with Cu(II) through (GA)10 repeating bases to load AQ4N at the 3' end. In normal physiological conditions, the fluorescence and ROS generation ability of Ce6 are quenched by GNPs via RET; but in cancerous cells, the fluorescence and the ROS generation of Ce6 could be recovered by cleavage of Au-S bond through high level of intracellular GSH for real-time imaging and in demand PDT. Meanwhile, the prodrug AQ4N release could be triggered by acid-cleavage of coordination bonds, then accompanied by a release of Cu(II) that would induce the electrostatic aggregation of GNPs for photo-thermal ablation; furthermore, the significantly enhanced chemotherapy efficiency could be achieved by PDT produced hypoxia to convert AQ4N into AQ4. In summary, here described nanoplatform with tumor cell specific responsive properties and programmable PDT/PTT/chemotherapy functions, might be an interesting synergistic strategy for HCC treatment.
Abstract 1782: Post-translational regulation of cyclins by Aspirin through 26S proteasome: Implications in chemoprevention
Authors: Rakesh Dachineni, Guoqiang Ai, Hemachand Tummala, Jayarama B. Gunaje
Journal: Cancer Research (2015)

Abstract Recent studies have shown that, regular use aspirin for 5 years or more, decreases the occurrence of cancer of the colon, skin, breast, prostate and lung tissues. However, the mechanism of its anti-cancer effects are not completely understood. We hypothesized that Aspirin's chemo preventive action may involve proteins important in the regulation of cell cycle. Using multiple colon and skin cancer cells, we studied whether aspirin modulates the expression of cyclin B1. Cyclin B1 is a regulatory protein involved in mitosis and promotes the passage of cell cycle from G2 to M phase. Cyclin B1 along with Cyclin dependent Kinase 1(CDK1) regulates chromosomal condensation, nuclear envelope break down and spindle pole assembly in early mitosis. We demonstrate that, in HT-29 human colon and Sk-Mel 28 skin cancer cells, aspirin dose dependently decreased the levels of cyclin B1. This was further confirmed using immunofluorescence studies. To determine the involvement of proteases, we determined whether the lactacystin, a 26S proteasomal inhibitor, would reverse the inhibitory effect of aspirin on cyclin B1. We observed that pretreatment of cells with lactacystin completely reversed the decrease in levels of cyclin B1 in aspirin treated cells. Transfection of the DDK tagged cyclin B1 into HT-29 cells were carried out to establish whether the decrease observed occurs through a nuclear independent and post-translational mechanism. We observed that, aspirin significantly decreased the exogenously transfected DDK tagged cyclin B1 protein. Our results, for the first time show that anticancer effects of aspirin may occur through cyclin B1 degradation mediated by 26S proteasomes. Citation Format: Rakesh Dachineni, Guoqiang Ai, Hemachand Tummala, Jayarama B. Gunaje. Post-translational regulation of cyclins by Aspirin through 26S proteasome: Implications in chemoprevention. [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 1782. doi:10.1158/1538-7445.AM2015-1782
Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with a Related Donor in Chronic Myeloid Leukemia (CML): An Explanation for Fast Improvement of Survival in Two Consecutive German CML Studies.
Authors: Markus Pfirrmann, Susanne Saussele, Armin Leitner, Nadine Pletsch, Michael Lauseker, Martin C Mueller, Claudia Haferlach, Brigitte Schlegelberger, Susanne Schnittger, Gerhard Ehninger, Thomas Fischer, Dieter K Hossfeld, Hans-Jochem Kolb, Stefan W Krause, Christoph Nerl, Hans Pralle, Andreas Tobler, Hermann Heimpel, Dietrich W Beelen, Axel R Zander, Donald Bunjes, Hubert Schrezenmeier, Ulrike Feldmann, Carlheinz Mueller, Helen Baldomero, Urs Schanz, Andreas Hochhaus, Joerg Hasford, Alois Gratwohl, Ruediger Hehlmann
Journal: Blood (2009)