tbuckley/cabot-search huggingface dataset:
Abstract PR10: CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer
Authors: Colin Steele, Saadia Karim, Josh Leach, Peter Bailey, Andrew Biankin, Rob Nibbs, Simon Barry, Owen Sansom, Jen Morton
Journal: Cancer Research (2016)

Abstract PDAC is predicted to become the second commonest cause of cancer death in the western world by 2030. Aggressive invasion and early metastases are characteristic of the disease, and even the few patients eligible for potentially curative resection inevitably develop recurrent or metastatic disease. We now show that CXCR2 signalling is upregulated in human pancreatic cancer, predominantly in neutrophils at the tumour invasive edge. In mouse models, genetic ablation or inhibition of CXCR2 abrogated metastasis while inhibition also slowed tumorigenesis, particularly when combined with chemotherapy. Depletion of neutrophils also suppressed metastasis, suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Indications from trials thus far suggest that immunotherapy will not work as a single agent strategy in pancreatic cancer patients. Importantly, we find that loss or inhibition of CXCR2 improved T-cell entry and combined inhibition of CXCR2 and PD1 in mice with established disease caused a significant extension of survival. Thus, our data highlight two novel therapeutic opportunities for PDAC: first the use of CXCR2 inhibitors in surgically-resected patients to prevent recurrence at distant sites, and second, the use of CXCR2 inhibition in combination with immunotherapy in surgically unresectable advanced disease. This abstract is also being presented as Poster B55 Citation Format: Colin Steele, Saadia Karim, Josh Leach, Peter Bailey, Andrew Biankin, Rob Nibbs, Simon Barry, Owen Sansom, Jen Morton.{Authors}. CXCR2 Inhibition Suppresses Metastasis and Improves the Response to Immunotherapy in Pancreatic Cancer. [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 PR10.
344. Targeting piggyBac Transposition Into a User-Defined Chromosomal Locus in Human Cells
Authors: Wentian Luo, Daniel L. Galvan, Dan Dorset, Shawn Levy, Matthew H. Wilson
Journal: Molecular Therapy (2015)

The piggyBac (PB) transposon system is a highly active non-viral gene delivery system capable of integrating defined DNA segments into the genomes of human cells. We have previously demonstrated biased PB integration into an artificial target site engineered into human cells (Kettlun et al., Molecular Therapy, 2011). We undertook the current investigation to see if we could engineer PB to target integration into a user-defined chromosomal locus in human cells. We chose to target the hypoxanthine phosphoribosyltransferase (HPRT) gene located on chromosome X. HPRT-deficient cells can be selected by growth in 6-thioguanine (6TG), so PB-mediated targeted knockout of HPRT can be used to isolate cells with targeted integration events. We used HT-1080 human fibrosarcoma cells which harbor one × chromosome for our studies. We engineered a series of 4 zinc finger proteins (ZFP) and 4 transcription activator-like (TAL) proteins fused to the PB transposase. The transposon used contained a splice-acceptor sequence followed by a beta-galactosidase-neomycin resistance fusion gene (b-Geo) which allowed measurement of gene transfer activity (measuring neomycin resistant colonies after transposition) as well as HPRT knockout efficiency (due to the splice-acceptor sequence). All HPRT-targeted ZFP-PB and TAL-PB proteins exhibited transposition activity. Chromatin immunoprecipitation assays revealed varied targeting-binding of the different PB chimeras to the HPRT locus. One ZFP-PB and one TAL-PB chimera demonstrated higher HPRT gene targeting via reproducible production of a higher number of 6TG resistant cells. Deep sequencing analysis revealed integration efficiency of 0.42% and 1% for the ZFP-PB and TAL-PB chimeric transposases in 6TG-resistant HT-1080 cells. Our study provides new insights into engineering PB to target locations in the human genome which will permit further refinements to improve targeting efficiency. Additionally, selection of cells with targeted integration events should allow isolation of "targeted-only" cells for consideration of therapeutic purposes.ßß
Epidemiology and clinical characterization of HCC in a tertiary center in eastern Germany.
Authors: T. Goetze, K. Schuette, J. Bornschein, M. Kipper, K. Mohnike, P. Malfertheiner
Journal: Journal of Clinical Oncology (2011)

e12010 Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. Detailed knowledge on epidemiology of the malignancy will improve both surveillance of patients at risk to develop the disease and the therapeutic management of affected patients. Methods: With the aim to characterize the clinical presentation of patients being diagnosed with HCC and referred to a tertiary medical center in Eastern Germany we analysed clinical data of patients with the first diagnosis of HCC in between 1995 and 2010. Results: Within 15 years, 640 patients with a newly diagnosed HCC were referred to our center. 267 patients (male n = 216 (80.9%), female n = 51 (19.1%)) of these were included into the analysis. The median age at diagnosis was 66.3 years (range 17-85 years). 223 of the patients (83.5%) suffered from liver cirrhosis. Alcohol induced chronic liver disease was the main cause (49%) followed by hepatitis C infection (9%), NASH (6%), hepatitis B infection (5%), cryptogenic liver cirrhosis (5%), alcohol in combination with viral hepatitis (4%), hemochromatosis (3%) and hepatitis B and C co-infection (1%). The median body mass index (BMI) was 27.6 kg/m2 (range 18.1 – 46.3). In 46 patients BMI exceeded 30 kg/m2. 163 patients (61%) suffered from diabetes mellitus. 60.5% of patients with liver cirrhosis had no impaired liver function (CHILD A) at diagnosis of HCC, 33.6% were in stage Child B and 5.8% in Child C cirrhosis. 31.1% of patients presented with portal vein thrombosis and 64% of patients with multilocular disease. AFP was measured in 244 patients and exceeded 200 ng/dl in 101 (41.4%) of them. BCLC stage was available in 265 patients with the vast majority of patients presenting in intermediate stage of the disease (BCLC A 22.3%, BCLC B 52.8%, BCLC C 22.3%, BCLC D 2,6%). Conclusions: Among risk factors for HCC alcohol induced liver cirrhosis is the most important one in our tertiary center with great distance to other etiologies. The majority of patients still presents with intermediate or advanced stage disease at diagnosis where curative treatment is not an option any more.
Abstract 4556: Identification of novel agent for HCC treatment by GNMT-promoter orientated cell-based drug screening platform
Authors: Rajni Kant, Lucas Tung, Chung-Kuang Lu, Yi-Ming Chen, Chia-Hung Yen
Journal: Cancer Research (2015)

Abstract Glycine N-methyltransferase (GNMT) a tumor suppressor gene for hepatocellular carcinoma (HCC) plays very important role in liver detoxification and tumorigenisis. GNMT expression is highly down-regulated in HCC. Recent studies have shown that overexpression of GNMT reduce tumor growth and sensitize HuH-7 cells to rapamycin treatment in vitro and in vivo. Therefore, enhancing GNMT expression is an attractive approach for HCC therapy. In present study we developed a GNMT-promoter driven luciferase reporter assay as a drug screen platform for the identification of novel drugs for prevention and treatment of HCC. We identified crude extract 317 as highest activator of GNMT promoter activity from a Chinese medicine library containing 472 herbal extracts. Partial purified fraction “F2-6” was isolated by bioassay-guided fractionation from crude extract 317 and validated for enhancement of endogenous GNMT expression at both mRNA and protein levels. Fraction F2-6 inhibited growth of liver cancer cell lines in vitro. Moreover, orally administrated F2-6 can delay and reduce growth of HCC xenograft tumor in vivo. Next, we identified the active component in fraction F2-6 named as compound P. Furthermore, we demonstrated that combination of sorafenib with compound P led to additive toxicity on HCC cells in vitro and in vivo. The cDNA microarray and real time PCR analysis showed that compound P altered cell cycle-associated genes such as CDK6, CCND1, CDKN1C, MYC and PLK1. Finally, Compound P treatment induced apoptosis in huh7 cells were confirmed by increased sub-G1 population and caspase 3/7 activity. Collectively, our results suggest that compound P has potential to be a novel agent for prevention and treatment of HCC. Citation Format: Rajni Kant, Lucas Tung, Chung-Kuang Lu, Yi-Ming Chen, Chia-Hung Yen. Identification of novel agent for HCC treatment by GNMT-promoter orientated cell-based drug screening platform. [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 4556. doi:10.1158/1538-7445.AM2015-4556
Real-Time Imaging of Platelet-Rich Thrombi in Thick-Walled Blood Vessels Using Near-Infrared Fluorescence Light.
Authors: Gwenda J. Graham, Eiichi Tanaka, Alec M. De Grand, Rita G. Laurence, Kozo Hoshino, Roger J. Hajjar, John V. Frangioni, Robert Flaumenhaft
Journal: Blood (2006)
Gemcitabine and Platinum (GC) chemotherapy alone or with a Taxane (GC-T) as first-line therapy for urothelial cancer (UC): a meta-analysis
Authors: A. Necchi, P. Giannatempo, G. Pond, D. Raggi, N. Nicolai, R. Salvioni, G. Procopio, F. De Braud, G. Sonpavde
Journal: Annals of Oncology (2015)
692. Genome Editing for Personalized Gene Therapy of IVSI-110 Beta-Thalassemia
Authors: Petros Patsali, Claudio Mussolino, Constantinos Loucari, Coralea Stephanou, Michael Antoniou, Toni Cathomen, Carsten W. Lederer, Marina Kleanthous
Journal: Molecular Therapy (2016)

Thalassemia is amongst the commonest single-gene disorders worldwide, caused by deficient production of α- or β-globin. Of particular clinical relevance is β-thalassemia, which as a severe monogenic disease of the hematopoietic system is an ideal target for gene therapy, either by gene addition or gene correction. Problems inherent to the gene-augmentation approach for β-thalassemia, including insertional mutagenesis or low expression of the therapeutic transgene, may be avoided using targeted gene correction of mutations with site-specific designer nucleases, such as clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 or transcription activator-like effector nucleases (TALENs). Our study is focused on the development of a personalized gene-correction therapy of the common β-thalassemia mutation, HBBIVS1-110, which in most Mediterranean and many Western countries has a frequency of above 20% (with 80% on the island of Cyprus) amongst β-thalassemia carriers. HBBIVS1-110 creates an abnormal splice-acceptor site in intron I of the β-globin gene, leading to a pre-mature in-frame stop codon in the aberrantly spliced mRNA and to early transfusion dependence of homozygotes. We have developed and evaluated designer nucleases targeting the site of the HBBIVS1-110 β-thalassemia mutation, including direct comparison of targeted disruption efficiency and toxicity for CRISPR/Cas9 and TALEN tools in human embryonic kidney cells and in murine erythroleukemia (MEL) cells carrying a HBBIVS1-110mutant transgene based on the GLOBE (MA821) vector. Using the latter, we have assessed the therapeutic efficiency and cleavage properties of these designer nucleases. Analyses included immunoblots, absolute quantification of correctly and aberrantly spliced HBB mRNAs using multiplex RT-qPCR, sequencing and characterization of the resulting genome-editing events. We noted superior performance of several TALEN pairs compared to a single CRISPR/Cas9 nuclease suitable for the target site. Moreover, we demonstrate a significant increase of correct splicing and β-globin chain synthesis for genome-edited transgenic MEL MA821 HBBIVS1-110 cells. For the two most efficient TALEN pairs, β-globin protein levels in pools of edited cells reach over 20% of that detected in MEL cells harbouring a wild-type MA821 HBB control, up from 1% for the mock-treated MA821 HBBIVS1-110 control. Our findings validate our approach and indicate its suitability also for the correction of other intronic disease-causing mutations.
Abstract 3883: Clonal evolution of a lethal prostate cancer: Integrated whole genome analysis case study
Authors: Heini M.L. Kallio, Matti Annala, Kati Kivinummi, Gunilla Högnäs, Gunes Gundem, David C. Wedge, Peter Van Loo, Holger Heyn, Michael R. Emmert-Buck, William B. Isaacs, Manel Esteller, Ultan McDermott, Matti Nykter, Tapio Visakorpi, G. Steven Bova
Journal: Cancer Research (2015)

Abstract Prostate cancer (PC) is prevalent in both indolent and lethal forms. Although many PC patients diagnosed today have organ-confined disease curable by prostatectomy or radiation therapy, 20-30% of PCs will relapse to lethal disease within 5-years of treatment. Relatively little attention has been paid to distinguishing the molecular characteristics of proven lethal metastatic PC from non-lethal cancers. A better understanding of the origins and evolution of lethal cancers should allow screening and treatment to be better tailored to the needs of each patient. To this end, we performed an integrative molecular profiling of a lethal PC from one patient (A21). High-coverage whole genome sequence, transcriptome sequence, and methylation analysis was performed on 9 anatomically separate metastases obtained by autopsy, and targeted sequencing was performed in multiple cancerous and noncancerous foci within the radical prostatectomy specimen removed 5 years prior to death. Molecular results were analyzed in relation to detailed clinical data. Integrated whole genome sequence analysis revealed convergent evolution of AR gene amplification events, and inception of p.L702H mutation in the AR present only in liver metastases. In addition, the analysis showed parallel increases in AR regulated transcripts in the liver metastases, suggesting a dominant effect by the mutation. Mutation of PI3/PI4 kinase member PIK3CG was found in all metastases but in no primary tumor foci studied. The study demonstrated the power of an integrated approach to interrogate clonal evolution of cancer suggesting that such studies are valuable on the individual level and could lead the way towards personalized treatment. In the individual studied, cessation of corticosteroid treatment and/or therapeutic manipulation of PI3K/AKT/mTOR activity theoretically could have provided a personalized benefit. These findings suggest that similar integrated analysis in large cohorts of patients with metastatic cancer could accelerate progress in establishing effective personalized cancer medicine. Citation Format: Heini M.L. Kallio, Matti Annala, Kati Kivinummi, Gunilla Högnäs, Gunes Gundem, David C. Wedge, Peter Van Loo, Holger Heyn, Michael R. Emmert-Buck, William B. Isaacs, Manel Esteller, Ultan McDermott, Matti Nykter, Tapio Visakorpi, G. Steven Bova. Clonal evolution of a lethal prostate cancer: Integrated whole genome analysis case study. [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 3883. doi:10.1158/1538-7445.AM2015-3883
Train all maternity staff to treat postpartum haemorrhage, say guidelines
Authors: Jacqui Wise
Journal: BMJ (2016)

All staff involved in maternity care should have appropriate training in preventing and treating excessive bleeding after childbirth, including team rehearsals, say new guidelines from the Royal College of Obstetricians and Gynaecologists (RCOG).1

The guideline follows the 2012-14 Confidential Enquiries into Maternal Deaths and Morbidity report published last week, which identified 13 deaths from haemorrhage.2 3 This makes postpartum haemorrhage the third leading cause of direct maternal death in the United Kingdom.

New research published in the British Journal of Obstetrics and Gynaecology shows that assisted reproductive technology, particularly when it results in multiple pregnancies, is associated with an increased risk of severe postpartum haemorrhage.4 …
Abstract 4759: Whole genome sequencing of sequentially acquired lung and lymph node metastatic sites from a never smoker lung adenocarcinoma patient revealed extensive genomic heterogeneity
Authors: Shaojian Gao, Constance Cultraro, Romi BIswas, Corey A. Carter, Tapan K. Maity, Anish Thomas, Arun Rajan, Paul Meltzer, David Schrump, Giuseppe Giaccone, Javed Khan, Udayan Guha
Journal: Cancer Research (2015)

Abstract Recent large-scale cancer genome sequencing studies have uncovered extensive diverse mutational landscapes in lung cancer patients. Furthermore, tumor heterogeneity has been widely recognized and it has significant clinical implications in selection of targeted treatment strategies as well as treatment response. Using whole genome sequencing, we demonstrate an unprecedented genomic heterogeneity between sequentially acquired lung and lymph node metastatic sites from an African American never-smoker lung adenocarcinoma patient who has survived with metastatic disease for over seven years while being treated with single or combination HER2-directed therapies. We determined that less than 1% of somatic variants were common between the two tumor sites. Copy number variations were more intense in the lung tumor than in the metastatic lymph node. We identified several novel somatic mutations in key cancer genes in both sites. Interestingly, one novel translocation, PLAG1-ACTA2 was highly expressed in both the lung and lymph node metastases resulting in overexpression of ACTA2, which has been suggested to increase the metastatic potential in lung adenocarcinoma. Using ultra deep targeted re-sequencing, we validated all non-synonymous variants, and approximately 80% of those identified in the metastatic lymph node were also present in a second lymph node biopsied two years after the first one. Although this degree of tumor heterogeneity was surprising, somatic variants affected key hallmarks of tumorigenesis in both sites. These findings suggest a model of early metastatic spread and parallel clonal evolution in disparate metastatic sites. Citation Format: Shaojian Gao, Constance Cultraro, Romi BIswas, Corey A. Carter, Tapan K. Maity, Anish Thomas, Arun Rajan, Paul Meltzer, David Schrump, Giuseppe Giaccone, Javed Khan, Udayan Guha. Whole genome sequencing of sequentially acquired lung and lymph node metastatic sites from a never smoker lung adenocarcinoma patient revealed extensive genomic heterogeneity. [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 4759. doi:10.1158/1538-7445.AM2015-4759
ATG Use Is Associated with Frequent Occurrence of Positive Blood Cultures in Patients in the Early Phase After Hematopoietic Stem Cell Transplantation
Authors: Marek Seweryn, Urszula Jarosz, Malgorzata Krawczyk-Kulis, Miroslaw Markiewicz, Grzegorz Helbig, Grazyna Bober, Slawomira Kyrcz-Krzemien
Journal: Blood (2011)
Combined 18F-FDG PET/CT and 68Ga DOTATATE PET/CT “Superscan” in Metastatic Pancreatic Neuroendocrine Tumor
Authors: Mico Chan, Geoffrey Paul Schembri
Journal: Clinical Nuclear Medicine (2016)

Metastatic neureoendocrine tumor to bone is well recognized. Typically, this has an appearance of multiple focal lesions. We present an example of diffuse skeletal involvement on both F-FDG PET/CT and Ga DOTATATE PET/CT with a pattern similar to the superscan appearance described on skeletal scintigraphy.
672. iCELLisTM Fixed-Bed Technology for Adherent Cells Is an Efficient Scalable System for Viral Vector Production Applications
Authors: Hanna P. Lesch, Piia Valonen, Kati Heikkilä, Eevi Lipponen, Achim Müller, Eva Räsänen, Tarja Tuunanen, Joonas Malinen, Anne Martikainen, Tuula Salonen, Elisa M. Nurminen, Minna Hassinen, Minna Karhinen, Nigel Parker, Robert Shaw, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2015)

To date many early phase gene therapy trials have been successful. However, phase III and commercial phase have brought further challenges in producing viral vectors in sufficient large quantities. Upscaling the process on suspension cells is feasible, but many viral production applications are still applicable only in adherent settings. Scaling up the adherent system has proven to be troublesome and costly. The PALL iCELLisTM disposable fixed-bed bioreactors offer an efficient option for viral vector manufacturing in large quantities in an adherent environment. In iCELLisTM Nano, the cultivation area 0.53-4 m2 for smaller batches, is ideal for process development purposes. In iCELLIs500 the cultivation area varies between 66 and 500 m2 and is ideal to satisfy demand for phase3/commercial requirements. We have optimized adenovirus type 5 manufacturing using iCELLisTM Nano. HEK293 cell cultivation, infection and harvest of the virus by lysing the cells inside the bioreactor were efficient, reaching total yield of 3.4 × 10^14 vp/batch. When upscaling the process into 100 m2 cultivation area with iCELLis500, 1.2 × 10^16 vp/batch were produced. iCELLisTM technology is applicable also to other vector types which require for example plasmid transfection. Virus can also be harvested by perfusion from the medium. Lentiviral vector production in 293T cells was tested in iCELLisTM Nano and we achieved high plasmid transfection efficiency, leading to the comparable titers and productivity as in flasks. To conclude, iCELLisTM equipment has provided us an efficient way to manufacture large batches of different kinds of gene therapy products suitable for large preclinical animal models and up to phase III trial and beyond.
Serum Levels of B-Cell Maturation Antigen Are Elevated in Waldenström's Macroglobulinemia Patients and Correlate with Disease Status and Conventional M-Protein and IgM Levels
Authors: Suzie Vardanyan, Kirsten Meid, Kyle A Udd, James Wang, Mingjie Li, Eric Sanchez, Cathy Wang, Abigail Gillespie, Maya Spitzer, Tanya M. Spektor, Anna Shvartsur, Nika Manik Harutyunyan, Gigi Garzio, George Tang, Haiming Chen, Steven P Treon, James Berenson
Journal: Blood (2015)
Inhibition of BET Recruitment to Chromatin As An Effective Treatment for MLL-Fusion Leukaemia
Authors: Mark A Dawson, Rab Prinjha, Antje Dittman, George Giotopoulos, Marcus Bantscheff, Wai-In Chan, Samuel Robson, Chun-wa Chung, Carsten Hopf, Mikhail Savitski, Konstanze Döhner, Alan K Burnett, Ruud Delwel, Huthmacher Carola, Emma Gudgin, Dave Lugo, Soren Beinke, Peter Soden, Kurt R. Auger, Olivier Mirguet, Phillip Jeffrey, Gerard Drewes, Kevin Lee, Tony Kouzarides, Brian J.P. Huntly
Journal: Blood (2011)