tbuckley/cabot-search huggingface dataset:
PWE-024 Practical outcomes of thiopurine metabolite measurement in a tertiary paediatric gastroenterology and hepatology service
Authors: L P Armstrong, P McGrogan, J Bishop, P Galloway, R K Russell
Journal: Gut (2010)

<h3>Introduction</h3> Clinical response to thiopurines is dependent on the concentration of its active metabolite, 6-thioguanine nucleotide (6-TGN).<sup>1</sup> Dosing is, however, unpredictable because the concentration of 6-TGN is dependent on thiopurine methyl transferase (TPMT) activity, an enzyme with common genetic polymorphisms. Because metabolite monitoring is not commonplace in the UK, some clinicians use proxy measures to assess response to thiopurines. We aim to evaluate how measuring thioguanine metabolites measurement influences clinical practice. <h3>Methods</h3> Thiopurine metabolites were measured in children who had been on medication for 3 months or more. For each measurement, data were collected on dosage, disease severity, concomitant use of 5-ASA, haematological and biochemical indices, and changes to management. Therapeutic 6-TGN levels were defined as 235–400 pmol/8×10<sup>8</sup> RBCs. Toxicity is defined as WBC &lt;4×10 mm, neutrophils &lt;2×10 mm, and AST/ALT &gt;2× elevated. <h3>Result</h3> 64 individuals studied, median age 14 years. Underlying diagnoses were “IBD” (54/64) and “other” (10/64). 59 treated with AZA, 5 with 6-MP. 95 separate measurements were made. TPMT phenotype was measured in 51/64 patients,40/51 had “normal” phenotype, and 11/51 had heterozygous TPMT mutations. Initial 6-TGN levels were higher in heterozygotes (median levels 836 vs 328, p=0.001) at comparable doses of thiopurine (median 1.9 vs 2.2 mg/kg, p=0.11). On first measurement, only 30% patients had 6-TGN levels within therapeutic levels. 30% were subtherapeutic and 40% were supra-therapeutic. 9% had 6-TGN levels &gt;800. Toxicity occurred in 8 cases (9%). Leucopaenia (WBC&lt;4) had a sensitivity of 12.5% in predicting supra-therapeutic 6-TGN levels. Concomitant use of 5-ASA did not significantly affect 6-TGN levels at comparable doses (median (6-TGN) “5-ASA” 393 vs 451 “no 5-ASA”, p=0.26). In total, management was changed in 39 cases (41%). 6 cases of total non-compliance were exposed. 33/39 of these changes were adjudged to be exclusively or predominantly influenced by knowledge of the 6-TGN level. <h3>Conclusion</h3> Based on standard dosing regimens, clinicians can expect to achieve therapeutic levels of 6-TGN in a minority of cases. Measuring Thiopurine metabolites aids therapeutic dose alteration, detects potential toxicity, and identifies issues of non-compliance that cannot be detected on routine blood monitoring.
6. Targeted Genome Editing of Cell Lines for Improved and Scalable Production of Lentiviral Vectors for Human Gene Therapy
Authors: Alessio Cantore, Michela Milani, Johannes Lengler, Sara Bartolaccini, Tiziano Di Tomaso, Philip D. Gregory, Friedrich Scheiflinger, Angelo Lombardo, Luigi Naldini
Journal: Molecular Therapy (2015)

Lentiviral vectors (LVs) represent efficient and versatile vehicles for gene therapy. The manufacturing of clinical-grade LVs relies on transient transfection of vector components. This method is labor and cost intensive and becomes challenging when facing the need of scale-up and standardization. The development of stable LV producer cell lines will greatly facilitate overcoming these hurdles. We have generated an inducible LV packaging cell line, carrying the genes encoding for third-generation vector components stably integrated in the genome under the control of tetracycline-regulated promoters. In order to minimize the immunogenicity of LVs for in vivo administration, we set out to remove the highly polymorphic and antigenic class-I major histocompatibility complex (MHC-I) expressed on LV packaging cells and subsequently incorporated on the LV envelope. We performed genetic disruption of the β-2 microglobulin (B2M) gene, a required component for the assembly and trafficking of the MHC-I to the plasma membrane in LV producer cells, exploiting the RNA-guided Cas9 nuclease. We generated B2M-negative cells devoid of surface-exposed MHC-I, which retain the ability to produce LVs. In order to insert the LV genome of interest in the packaging cell line, we performed site-specific integration in predetermined loci of the genome of these cells, chosen for robust expression, exploiting artificial nucleases and homology-directed repair. In several independent iterations of this process, we generated producer cell lines both for LV expressing marker genes and a therapeutic gene, i.e. coagulation factor IX (FIX), the gene mutated in hemophilia B. We show that these LV producer cells are stable in culture and can produce several liters of LV-containing conditioned medium. These LVs have comparable or only slightly lower infectious titer and specific infectivity than LVs produced by state-of-the-art transient transfection process and can transduce therapeutically relevant target cells, such as hematopoietic stem/progenitor cells and T lymphocytes to high efficiency. Moreover, we intravenously administered FIX-expressing LVs produced by the cell line to hemophilia B mice and established therapeutic levels of circulating FIX. These data indicate that site-specific integration is an efficient, rapid and reproducible method to generate LV producer cells, starting from a universal stable inducible LV packaging cell line. Overall, we provide evidence that rationally designed targeted genome engineering can be used to improve the quality, safety and sustainability of LV production for clinical use.
Hepatobiliary Scintigraphy Findings Lead to the Diagnosis of Spontaneous Common Bile Duct Rupture in an Infant
Authors: Ashwani Sood, Ashwin Singh Parihar, Babu Ram Thapa, Ravi Prakash Kanojia, Bhagwant Rai Mittal, Anish Bhattacharya
Journal: Clinical Nuclear Medicine (2016)

Hepatobiliary scintigraphy is a widely used functional imaging modality for diagnosis of a variety of liver diseases, as well as for detecting biliary tract abnormalities. Neonates or infants with persistent jaundice beyond the physiological period are usually evaluated with hepatobiliary scintigraphy. The authors present a 5-month-old girl with neonatal jaundice, ascites, and umbilical and bilateral inguinal hernias in whom spontaneous rupture of the biliary duct resulted in intraperitoneal bile leak with passage of tracer into bilateral inguinal hernial sacs.
MicroRNAs as prognostic markers for survival in renal cell carcinoma conventional type T 2-4.
Authors: Z. A. Dotan, E. Fridman, Y. Spector, I. Barshack, A. Chajut, S. Rosenwald, S. Gilad, R. Catane, E. Meiri, R. Berger, R. T. Aharonov, E. Ezra, J. Ramon
Journal: Journal of Clinical Oncology (2011)

e21115 Background: Renal cell carcinoma (RCC) accounts for more than 3% of adult malignancies and causes more than 13,000 deaths per year in the US alone. Conventional type RCC (CRCC) accounts for around 90% of metastases and death due to RCC. The current prognostic factors of CRCC include stage, Fuhrman grade, performance status and other clinical predictors, which are insufficient for accurate prediction of renal cancer survival. Identification of biomarkers for survival can add prognostic information to predict cancer survival. MicroRNAs are a family of regulatory genes and a promising group of molecular biomarkers. Methods: 76 patients who were treated surgically due to CRCC T2-4 between 1992 and 2006 were identified using the Sheba's database. Patients' charts were reviewed for demographic and clinicopathological information including time to progression (TTP) and survival. High-quality totalRNA, preserving the microRNA fraction, was extracted from the resected tumors in FFPE. 50 patients were available for analysis. Expression levels of all known and Rosetta’s proprietary microRNAs were profiled using a custom array platform. Survival analysis for TTP and time to death was performed using the Kaplan Meier method, and groups were compared using the log-rank test. Multivariate Cox regression was used for building a model for predicting survival/TTP which combines microRNA expression with clinical data. Results: Of the 50 patients identified, 10 patients progressed within 2 years and additional 8 suffered progression later (at mean time 58 months), while the other 32 did not (mean follow-up 70 months). 4 microRNAs were associated with metastases or cancer death, with log-rank p<0.05, including (miR-21*, miR-29c*, mir-30a* and miR-30e). By multivariate analysis (including tumor size, tumor stage and microRNA's expression) we have demonstrated that miR-21*, miR-29c* and maximal tumor size were predictors for lack of metastases progression and cancer survival in CRCC T2-4 (p<0.05). Conclusions: Expression levels of certain microRNAs were demonstrated to be indicative of prognosis in patients with CRCC. These findings imply that microRNA expression can serve for TTP/survival prediction of these patients.
Abstract 3114: MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis
Authors: Meng-Ju Wu, Chun-Ju Chang
Journal: Cancer Research (2015)

Abstract Dysregulation of epigenetic controls is associated with tumorigenesis in response to microenvironmental stimuli; however, the regulatory pathways involved in epigenetic dysfunction are largely unclear. We have determined that a critical epigenetic regulator, microRNA-205 (miR-205), is repressed by the ligand jagged1, which is secreted from the tumor stroma to promote a cancer-associated stem cell phenotype. Knockdown of miR-205 in mammary epithelial cells promoted epithelial-mesenchymal transition (EMT), disrupted epithelial cell polarity, and enhanced symmetric division to expand the stem cell population. Furthermore, miR-205-deficient mice spontaneously developed mammary lesions, while activation of miR-205 markedly diminished breast cancer stemness. These data provide evidence that links tumor microenvironment and microRNA-dependent regulation to disruption of epithelial polarity and aberrant mammary stem cell division, which in turn leads to an expansion of stem cell population and tumorigenesis. This study elucidates an important role for miR-205 in the regulation of mammary stem cell fate, suggesting a potential therapeutic target for limiting breast cancer genesis. Citation Format: Meng-Ju Wu, Chun-Ju Chang. MicroRNA-205 signaling regulates mammary stem cell fate and tumorigenesis. [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 3114. doi:10.1158/1538-7445.AM2015-3114
Autologous Activated and Expanded Natural Killer Cells Kill Clonogenic Myeloma Cells: A New Therapeutic Option for Multiple Myeloma
Authors: Alejandra Leivas, Ruth M Risueño, Antonio Pérez-Martínez, María Jesús Blanchard, Dario Campana, Juan José Lahuerta, Joaquín Martínez-López
Journal: Blood (2014)
Combination therapy with gefitinib (ZD1839) and rofecoxib in platinum-pretreated relapsed non-small-cell lung cancer (NSCLC)
Authors: K. O'Byrne, L. Clarke, D. Dunlop, M. Ranson, S. Danson, N. Botwood, D. Carbone
Journal: Journal of Clinical Oncology (2004)

7101 Background: The epidermal growth factor receptor and cyclooxygenase 2 (COX2) may be targeted with inhibitors such as gefitinib (‘Iressa’, ZD1839) and rofecoxib, respectively. Methods: This Phase I/II study evaluated the safety, efficacy and pharmacokinetic interactions of gefitinib 250 mg po daily with rofecoxib in platinum-pretreated NSCLC. Rofecoxib was escalated through 3 cohorts of 6 patients from 12.5 (Level 1) to 25 (Level 2) and 50 mg po od (Level 3), the dose at which >90% of COX-2 activity is inhibited, with the final cohort expanded to 27 patients. Results: Analysis is complete on 33 recruited patients. The treatment appears generally well tolerated, the main toxicities including skin rash (grade 1/2, 44%; grade 3/4, 3%) and diarrhoea (grade 1/2, 22%). One patient at Level 1 was withdrawn due to grade 1 renal toxicity. Another had a cerebrovascular accident occurring on Day 31. Time to tumour progression was 54 days (range 46–64 days). Of 31 patients evaluable for response, 1 complete response and 2 partial responses were seen, with stable disease recorded in a further 9, giving a disease control rate of 39%. Preliminary results for a panel of potential surrogate serum/plasma markers of response indicate that IFNγ, TNFα, IL2, IL4, IL6, IL10 and big-endothelin-1 levels are similar in responders and non-responders at baseline and over time. An ongoing global serum proteomic analysis will assess if responders can be distinguished from non-responders. Study recruitment is complete and final results will be presented at the meeting. Conclusion: The combination of gefitinib with rofecoxib is generally well tolerated and may have a role to play in the management of NSCLC. 'Iressa' is a trademark of the AstraZeneca group of companies Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca Pharmaceuticals
Baseline Demographics and Disease Characteristics of Patients with Hypereosinophilic Syndrome in a Placebo-Controlled Trial Evaluating the Steroid-Sparing Effects of the Anti-IL-5 Monoclonal Antibody, Mepolizumab.
Authors: Gerald J. Gleich, Lawrence B. Schwartz, William W. Busse, Johannes Huss-Marp, Scott R. Walsh
Journal: Blood (2006)
Molecular Response, Efficacy and Safety Analysis of 168 Adult French Patients with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) From the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.
Authors: Franck Emmanuel Nicolini, Gabriel Etienne, Dominique Bordessoule, Denis Caillot, Coralie Belanger, Jean-Michel Cayuela, Aude Charbonnier, Valerie Coiteux, Agnès Guerci-Bresler, Viviane Dubruille, Thierry Lamy, Francoise Huguet, Philippe Rousselot, Michel Tulliez, Jean-Yves Cahn, Martine Gardembas-Pain, Laurence Legros, Frederic Maloisel, Delphine Rea, Hyacinthe Johnson-Ansah, Pascal Lenain, Alain Delmer, Marc Berger, Tomasz Szczudlo, Jim Wang, Mei Sheng Duh, Francois Guilhot
Journal: Blood (2009)
Abstract 1117: Who's in the driver's seat? Identifying causative variants of colorectal cancer
Authors: Nicole Coggins, Luis Carvajal-Carmona, David Segal
Journal: Cancer Research (2015)

Abstract Colorectal Cancer (CRC) is one of the leading causes of mortality in the US, being the third most common cancer among both men and women. While an exact cause of CRC has not yet been elucidated, the existence of a clear heritable genetic component has been established. With the recent surge of data from Genome-Wide Association Studies, a handful of CRC-associated loci have been identified via tagSNPs. While the probability of the tagSNPs themselves being the causative variants is low, the key may lie among the number of single-base variants linked to each tagSNP. It is crucial, in order to enhance our understanding CRC tumorigenesis, to extract these functional variants from the pool of associated SNPs and validate their causative significance within the cell. This project combines bioinformatics and functional experiments to both identify and assess the role of functional variants in CRC pathogenesis. One of the major hurdles in understanding the role of CRC risk-associated SNPs is the fact that virtually all variants lie in Non-Protein Coding Region, often tens of thousands of bases away from flanking genes. By combining variant data from publically available databases, such as that of the ENCODE project, this research presents a method to prioritize all variants within a set of disease-associated loci based on potential regulatory functionality in silico. With this technique, we have identified a handful of SNPs with functional potential that may be functioning specifically in CRC initiation. In parallel, we are in the process of developing a method to effectively produce isogenic cell lines modeling the appropriate variant alleles, utilizing the CRISPR/Cas9 system to stimulate homologous recombination in the presence of a donor template. With this method, transcriptional and regulatory changes within the cell due to the single-base genomic edit can be measured in order to characterize these functional variants. Utilizing this technology, we have been able to create our first SNP model of SNP rs6983267, a known functional variant whose risk SNP promotes CRC development by means of increased binding and activation of WNT signaling pathway elements, c-Myc and β-Catenin. The ultimate goal of this project is to better understand the role of CRC risk-associated variants, the result of which could have substantial clinical relevance in the generation of new therapies and diagnostics for the treatment of CRC. Citation Format: Nicole Coggins, Luis Carvajal-Carmona, David Segal. Who's in the driver's seat? Identifying causative variants of colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1117. doi:10.1158/1538-7445.AM2015-1117
A randomized trial assessing the use of electro-acupuncture for aromatase inhibitor-induced arthralgia.
Authors: J. M. Beith, E. Segelov, K. Orme, A. McLean, B. Oh
Journal: Journal of Clinical Oncology (2011)

TPS120 Background: Arthralgia is one of the main side effects of aromatase inhibitor (AI) therapy and does not respond to conventional pain medication. It may occur in up to 50% of women and lead to cessation of therapy and jeopardize their chance of cure. Acupuncture is currently used to treat a variety of conditions, including musculoskeletal pain. Crew et al published a trial which showed a benefit of acupuncture to treat AI induced joint symptoms. We commenced a feasibility study in 2009 to assess the use of acupuncture for AI induced arthralgia. We recruited 30 women and now have expanded this trial to assess efficacy. Methods: This prospective controlled, double blinded randomized study is recruiting women who are have early breast cancer and who have been taking a third generation AI for at least 6 months and are experiencing Brief Pain Inventory-Short Form (BPI-SF) score of ≥3. They are randomized to receive either real electro-acupuncture (REA) or sham electro-acupuncture (SEA). The sham group receives sham acupuncture via specially designed non-skin penetrating needles placed at points close to the real acupoints in the study. The acupuncture is administered twice weekly for 6 weeks. Surveys to assess pain, stiffness and physical function, inflammatory cytokines and clinical examination and grip strength are performed before, after completing 6 weeks of therapy and 6 weeks later. The primary objective is to compare the mean BPI-SF worst pain score at 6 weeks between the real and sham electro-acupuncture. 44 women are required to yield 80% power to detect a reduction of ≥ 2 points on the BPI-SF worst pain item at a 5% significance level, assuming a standard deviation of difference in score between treatment groups of 2.3 points. Paired t-tests will be used to compare pre and post values for each of the outcome measurements. In addition, two-sample t-tests will be used to compare the average change in score for the group randomly assigned to receive electro-acupuncture with that for the group assigned to receive sham electro-acupuncture. 34 of a planned 50 participants have been recruited. Reference: Crew et al. J Clin Oncol 28: 1154-1160, 2010. Funded by Cancer Institute NSW Research Innovation Grant.
Abstract 3551: A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma
Authors: Fengfei Wang, Marc Remke, Kruttika Bhat, Eric Wong, Shuang Zhou, Vijay Ramaswamy, Adrian Dubuc, Ekokobe Fonkem, Saeed Salem, Hongbing Zhang, Tze-chen Hsieh, Stephen O'Rourke, Lizi Wu, David Li, Cynthia Hawkins, Isaac Kohane, Joseph Wu, Min Wu, Michael Taylor, Erxi Wu
Journal: Cancer Research (2015)

Abstract Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in MB patients. Our study may resolve the controversy on the role of PDGFRs in MB and unveils JAG2 as a key downstream effector of a PDGFRβ-driven signaling cascade and a potential therapeutic target. Citation Format: Fengfei Wang, Marc Remke, Kruttika Bhat, Eric Wong, Shuang Zhou, Vijay Ramaswamy, Adrian Dubuc, Ekokobe Fonkem, Saeed Salem, Hongbing Zhang, Tze-chen Hsieh, Stephen O'Rourke, Lizi Wu, David Li, Cynthia Hawkins, Isaac Kohane, Joseph Wu, Min Wu, Michael Taylor, Erxi Wu. A microRNA-1280/JAG2 network comprises a novel biological target in high-risk medulloblastoma. [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 3551. doi:10.1158/1538-7445.AM2015-3551
Abstract SY23-03: Intratumoural heterogeneity in human serous ovarian carcinoma
Authors: John P. Stingl
Journal: Cancer Research (2015)

Abstract To investigate the hierarchical organization of cells within human high grade serous ovarian carcinomas (HGSOC), we used a combination of multi-parameter flow cytometry and in vitro and in vivo functional assays to interrogate the growth and differentiation properties of phenotypically distinct cell populations present within 86 freshly isolated, non-cultured HGSOC tissues. Our results indicate that 3 functionally distinct subpopulations of epithelial cells can be identified. One population expresses high levels of the epithelial cell protein EpCAM, whereas the other two populations are EpCAM-, but express podoplanin (PDPN) and variable levels of CD34. All detectable growth in vitro colony-forming cell and sphere-forming assays is restricted to the two EpCAM- cell populations, although the types of progeny the two EpCAM- subpopulations differ from one another. Xenotransplantation of lentivirally marked HGSOC cell subpopulations into immune-deficient mice reveals that in vivo engrafting ability is restricted to only EpCAM-PDPN+CD34- cells. Treatment of mice harbouring HGSOC xenografts with cisplatin reveals that non-cycling EpCAM- cells appear to have a selective survival advantage during the course of chemotherapy. Citation Format: John P. Stingl. Intratumoural heterogeneity in human serous ovarian carcinoma. [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 SY23-03. doi:10.1158/1538-7445.AM2015-SY23-03