tbuckley/cabot-search huggingface dataset:
Evaluation of BCR-ABL/ABL Ratio Increase That Corresponds to BCR-ABL Mutation In Chronic Myeloid Leukemia Patients Treated by Imatinib.
Authors: Grigory Tsaur, Anna Ivanova, Alexander Popov, Yulia Yakovleva, Tatyana Riger, Olga Plekhanova, Yulia Ivanets, Andrey Misyurin, Marina Suchkova, Egor Shorikov, Leonid Saveliev, Larisa Fechina
Journal: Blood (2010)
Genetic polymorphisms correlate with overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with carboplatin (CBDCA) and paclitaxel (PTX)
Authors: N. Yamamoto, Y. Sato, T. Tamura, H. Kunitoh, Y. Ohe, N. Katori, J. Sawada, A. Sekine, Y. Nakamura, N. Saijo
Journal: Journal of Clinical Oncology (2008)

8034 Background: The combination of CBDCA and PTX is one of the standard chemotherapy for patients with advanced NSCLC. Several polymorphisms on the genes involved in the drug metabolism or elimination are known to be associated with pharmacokinetic (PK) or pharmacodynamic variability, but their correlations with OS have been unknown. This prospective study was investigated whether genetic polymorphisms and PK variabilities could influence OS in advanced NSCLC patients treated with CBDCA and PTX. Methods: Chemotherapy naïve stage IIIB or IV NSCLC patients, treated with CBDCA (AUC=6mg/ml/min) and PTX (200mg/m2, 3-hour), were eligible in this study. The DNA samples were extracted from peripheral blood mononuclear cells before treatment and 5,438 SNPs in 219 genes coding for a wide category of drug metabolizing enzymes or transporters were analyzed (the list available at http://gemdbj.nibio.go.jp). The full PK sampling of paclitaxel was also performed. Statistical analyses were performed by the log-rank test and Cox proportional hazards model. Results: From Jul 2002 to May 2004, 119 patients (male/female: 86/33, PS 0/1/2: 23/93/3, stage IIIB/IV: 50/69), aged 29–80 (median: 61) years, received a total of 387 cycles of treatment. The median survival time (MST) of 119 patients was 17.1 months. Of 5,438 SNPs analyzed, two SNPs were associated significantly with shortened OS: rs4149525 5’ to the SULT1E1 gene (MST for AA [n=68] + AG [n=44] and GG [n=6] were 17.6 and 4.8 months, respectively; p=3.4×10- 6, HR=8.7 (3.4–21.6) and minor allele frequency =0.26) and rs10999776 in intron 2 of the SLC29A3 gene (MST for CC [n=73] + CT [n=41] and TT [n=3] were 17.1 and 2.7 months, respectively. p=1.4×10-5, HR=16.9 (4.7–61.0) and minor allele frequency =0.22). These two SNPs were statistically significant even after multiple comparison adjustment. The paclitaxel PK parameters in the GG and TT groups were not different from those in the AA+AG and CC+CT groups, respectively. Conclusions: These two SNPs could be new biomarkers for patients with stage IIIB or IV NSCLC who receive CBDCA and PTX as the first-line chemotherapy. No significant financial relationships to disclose.
366. Hitting Two Birds with One Stone: How Efficacious Pre-Clinical Gene Therapy Cures Canavan Disease and Sheds Light onto the Pathomechanism
Authors: Dominic J. Gessler, Danning Li, Hongxia Xu, Qin Su, Reuben Matalon, Guangping Gao
Journal: Molecular Therapy (2016)

Almost 90 years ago, Canavan Disease (CD) was described for the first time. Since then, the scientific community has unsuccessfully sought to cure this devastating leukodystrophy and understand its pathomechanism. Early hope for gene therapy was fueled with the cloning of the disease causing gene, Aspartoacylase, in 1993. Unfortunately, the only clinical trial for CD gene therapy failed to show significant clinical improvements in Canavan patients. At that time, animal models for CD were just engineered and comprehensive pre-clinical evaluation of CD gene therapy was missing. Earlier, we reported that our 1st generation IV delivered pre-clinical gene therapy was able to rescue early lethality and partially restored motor function in a mouse model of CD. Now in its 3rd generation, our gene therapy cures the disease in Canavan mice by a single intravenous injection, shown by behavioral, cognitive, and neuropathology tests. Taking advantage of this complete reversal of the disease, we used whole brain neurometabolome profiling to closely monitor the molecular efficacy and mechanism(s) in curing Canavan disease in mouse. Hierarchical cluster analysis (HCA) shows complete restoration of the disease associated metabolic derangements, including the array of detected myelin lipids. In the next step, we hypothesized that the metabolic nature of Canavan Disease mandates the origin of its pathomechanism in the metabolic regulation. We identified a specific dysregulation in the energy metabolism in vitro and in vivo that suggests the self-digestion of myelin for energetic purposes, calling current hypotheses about the Canavan disease pathomechanism into question. Currently, we are intensifying our insight into this mechanism by mircoRNAome, transcriptome analyses, a series of in vitro cell culture models, as well as supplementary and alternative strategies for the treatment of Canavan Disease. In summary, our data demonstrates strong evidence that rAAV mediated pre-clinical gene therapy not only cures the Canavan phenotype but also corrects the extensive neurometabolome, which provides meticulous evidence for gene therapy's high efficacy. Furthermore, we revealed a new pathomechanism that supports a paradigm shift in our perception of the function of ASPA and NAA in Canavan disease and their potential implications in other CNS and metabolic disorders in general.
Abstract 1275: Chemotactic factors underlying tumor infiltration by immunocompetent cells in colorectal cancer
Authors: Eleonora Cremonesi, Francesca Amicarella, Elisabetta Padovan, Manuele G. Muraro, Valentina Mele, Paul Zajac, Christian Hirt, Raoul Droeser, Daniel Oertli, Markus Zuber, Michel Adamina, Raffaele Rosso, Jesus G. Garzon, Lubor Borsig, Giulio C. Spagnoli, Giandomenica Iezzi
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is a leading cause of cancer related death. Several studies have convincingly showed that CRC infiltration by immunocompetent cells and, in particular, cytotoxic CD8+ T cells, IFN-γ-producing cells, Foxp3+ regulatory T cells and CD16+ MPO+ neutrophils, is significantly associated with prolonged patient survival. However, the factors driving these cell populations into the tumor site remain to be elucidated. We are investigating the chemokine/chemokine receptor network promoting CRC infiltration by immune cells associated to favorable prognosis. We have analysed the expression of a panel of genes encoding for 39 chemokines and for 7 markers identifying specific immune cell types in 58 freshly excised specimens of CRC and corresponding control colonic tissues. In parallel, chemokine receptor profiles on clinically relevant immunocompetent cell populations have been characterized by flow cytometry. Our results suggest that tumor infiltration by immunocompetent cells associated to favorable prognosis is linked to the expression of three main chemokine patterns: 1) CCL3, CCL5, CXCL9, and CXCL10 capable of recruiting cytotoxic CD8+ and IFN-γ producing T cells; 2) CCL22 and CXCL12 attracting Foxp3+ regulatory T cells; 3) CXCL2, CXCL5 and CXCL8 inducing migration of CD16+ MPO+ neutrophils. We have started to investigate the chemokine sources. CRC cells purified from tumor specimens were found to express chemokines potentially recruiting T and myeloid cells, including CCL3, CCL5, CXCL9, CXCL10, CXCL12, and CXCL2, CXCL5, CXCL8. The stimuli driving chemokine expression by tumor cells remain however to be clarified and are currently under investigation. Citation Format: Eleonora Cremonesi, Francesca Amicarella, Elisabetta Padovan, Manuele G. Muraro, Valentina Mele, Paul Zajac, Christian Hirt, Raoul Droeser, Daniel Oertli, Markus Zuber, Michel Adamina, Raffaele Rosso, Jesus G. Garzon, Lubor Borsig, Giulio C. Spagnoli, Giandomenica Iezzi. Chemotactic factors underlying tumor infiltration by immunocompetent cells in 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 1275. doi:10.1158/1538-7445.AM2015-1275
Abstract 4966: Identification of deubiquitinating enzyme USP19 as a regulator of EWS/FLI1 protein turnover in Ewing sarcoma
Authors: Maria E. Gierisch, Laura A. Lopez-Garcia, Franziska Pfistner, Felix K. Niggli, Beat W. Schaefer
Journal: Cancer Research (2015)

Abstract Ewing sarcoma belongs to the family of pediatric tumors which arise most commonly in bone. The majority of Ewing sarcoma is characterized by a balanced translocation between chromosomes 11 and 22 which encodes for the uniquely expressed fusion protein EWS/FLI1. Tumor cells are crucially dependent on expression of the fusion protein. Protein degradation is an important and highly regulated process in all cells and novel insights are beginning to be applied for cancer therapy. We aim to investigate the mechanism of turnover with the goal to diminish EWS/FLI1 protein and thereby identify novel targets for Ewing sarcoma treatment. Here, we show first that EWS/FLI1 protein stabilizes upon proteasome inhibition. Co-immunoprecipitation of EWS/FLI1 with ubiquitin shows a characteristic ubiquitination smear indicating that EWS/FLI1 is ubiquitinated and a substrate of the ubiquitin-proteasome system. We characterized the turnover itself as rather slow. Interestingly, the half-life time of the fusion protein is increased by four-fold compared to the full length protein FLI1. This increased stability possibly contributes to the oncogenic and resistant features of the fusion protein. To identify a deubiquitinating enzyme capable of regulating EWS/FLI1 turnover, we selected 20 deubiquitinating enzymes based on their expression in Ewing cell lines and tumors in-silico. Then, we established a screening approach directly measuring EWS/FLI1 protein levels as a read-out by an ELISA-like assay, allowing us to monitor the amount of 3x flag-tagged EWS/FLI1 protein. After transient knocked down of the 20 candidates, the screening revealed ubiquitin specific protease 19 (USP19) as a promising candidate. Depletion of USP19 via siRNA or shRNA was capable to diminish endogenous EWS/FLI1 protein level which led to modulation of its target gene levels. Vice versa, USP19 overexpression stabilized EWS/FLI1 protein level by twofold. Most importantly, stable knockdown of USP19 in Ewing cell lines led to a 40% reduction of cell growth and proliferation. Currently, we further characterize the influence of USP19 on EWS/FLI1 turnover and Ewing cell viability in vivo to identify novel possibilities for therapeutic interventions. Citation Format: Maria E. Gierisch, Laura A. Lopez-Garcia, Franziska Pfistner, Felix K. Niggli, Beat W. Schaefer. Identification of deubiquitinating enzyme USP19 as a regulator of EWS/FLI1 protein turnover in Ewing sarcoma. [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 4966. doi:10.1158/1538-7445.AM2015-4966
217. Combinatorial Anti-Angiogenic Gene Therapy in a Human Malignant Mesothelioma Model
Authors: Shuji Kubo, Yuki Mawatari-Furukawa, Noriyuki Kasahara
Journal: Molecular Therapy (2016)

Anti-angiogenic gene therapy represents a promising strategy for cancer; however, it has rarely been tested in malignant mesothelioma, a highly aggressive tumor associated with asbestos that has poor prognosis. In this study, we investigated whether anti-angiogenic factors such as angiostatin, endostatin, and the soluble form of vascular endothelial growth factor receptor 2 (sFlk1) were able to inhibit endothelial cell proliferation via lentivirus-mediated gene transfer into malignant mesothelioma cells in culture. We also assessed whether a dual-agent strategy had greater therapeutic benefit. Human malignant pleural mesothelioma MSTO-211H cells were transduced using lentiviral vectors that individually expressed angiostatin, endostatin, and sFlk1 and linked to enhanced green fluorescent protein (EGFP) marker gene expression via an internal ribosome entry site. The lentivirus expressing EGFP alone was used as a control. The resultant cells designated as MSTO-A, MSTO-E, MSTO-F, and MSTO-C were confirmed by Western blot and fluorescence microscopy to stably express the corresponding proteins. No differences were observed in the in vitro growth rates between any of these cells. However, coculture of MSTO-A, MSTO-E, and MSTO-F showed significant suppression of human umbilical endothelial cell growth in vitro compared with that of MSTO-C. Furthermore, a combination of any two among MSTO-A, MSTO-E, and MSTO-F significantly enhanced efficacy. These results suggest that combinational anti-angiogenic gene therapy targeting different pathways of endothelial growth factor signaling has the potential for greater therapeutic efficacy than that of a single-agent regimen.
556. Comparative In Vitro Transduction Efficiency of AAV Vector Serotypes 1-9 in Different Cellular Models
Authors: Thu T. Duong, Vidyullatha Vasireddy, Carrie E. Merkel, Jeannette L. Bennicelli, Jean Bennett
Journal: Molecular Therapy (2016)

Recombinant viral vectors can be useful tools for expressing transgenes in neuronal cells to study disease mechanisms and to test for therapeutic effect. Recombinant adeno-associated virus (AAV), generated from a nonpathogenic parvovirus, has become the most widely used vector in gene therapy applications in human. However, lack of suitable animal models that accurately reflect the human disease phenotype often stalls the development of treatment strategies. To overcome this problem, research is focused on generating induced pluripotent stem cells (iPSCs) from affected human subjects as in vitro models to explore the potential of gene augmentation therapy. An advantage of iPSCs is that these cells can be differentiated along a retinal cell lineage. In this study, we differentiated iPSCs into Neural Progenitor Cells (NPC) and compared the in vitro transduction efficiency of AAV serotypes 1-9. Differentiated NPCs were characterized by immunocytochemistry with the expression of NPCs specific markers (Sox2, Nestin, Pax6). Experiments were carried out using different AAVs serotypes containing the same transgene cassette: an enhanced green-fluorescent protein (eGFP) reporter gene driven by the cytomegalovirus immediate-early (CMV) promoter. At 24 to 48 hours post transduction, positive GFP expressing cells are examined by laser scanning in Typhoon. Relative GFP expression was evaluated by using the software ImageJ. In addition to the laser scanning method, flow cytometry was used to evaluate GFP expression in the cell population. Live cell imaging and flow cytometry evaluation revealed that AAV2 is the most efficient vector for in vitro transduction in NPC followed by AAV1, AAV3 and AAV6 while AAV4, AAV5, AAV7, AAV8 and AAV9 showed no transduction or extremely low transduction efficiency.
Changes in cancer survival by ethnicity between 1992-96 and 2002-06: Are survival disparities increasing or decreasing?
Authors: D. Pulte, T. Redaniel, H. Brenner, M. Jeffreys
Journal: Journal of Clinical Oncology (2011)

6013 Background: Survival is lower in patients of minority race/ethnicity for most cancer sites. Little data is available on whether the survival disparities are decreasing or increasing over time. We examine changes in survival by race/ethnicity of patients with common cancers over a 10-year time period. Methods: We used model-based period analysis to determine 5-year relative survival rates (RSR) for non-Hispanic white (nHw), African-American (AA), and Hispanic (H) patients in 1992-96 and 2002-06 using data from the Surveillance, Epidemiology, and End Results database. Population mortality rates were calculated from race-specific tables. Results: RSR were greater for nHw than for AA/H in all cancer types except for myeloma and pancreatic cancer in both time periods (see table). Greater improvement was seen for AA and H than nHw in prostate and breast cancer and non-Hodgkin lymphoma (NHL). Less improvement was seen for AA/H patients than for nHw for lung cancer, pancreatic cancer, and multiple myeloma and for AA with acute leukemia. Conclusions: Progress has been made in decreasing inequalities in survival between nHw and minorities in prostate cancer, breast cancer, and NHL, although disparities are still observed. Survival disparities worsened for other studied cancer types. Further examination of differences in screening and treatment of cancer in minority populations may reveal the reasons for these findings. 5-year RSR (standard error) for patients diagnosed with selected cancers in 1992-96 and 2002-06. Cancer Ethnic group 1992-96 2002-06 Breast nHw 87.4 (0.2) 92.2 (0.2)* AA 72.1 (0.5) 79.1 (0.7)* H 82.7 (0.6) 88.6 (0.9)* Prostate nHw 94.9 (0.1) 99.7 (0.2)* AA 86.3 (0.3) 98.3 (0.7)* H 92.6 (0.5) 98.7 (1.2)* Pancreatic nHw 5.4 (0.3) 7.5 (0.2)* AA 5.4 (0.6) 6.9 (0.6)** H 7 (1.1) 8.7 (1.1) NHL nHw 52.9 (0.4) 69.3 (0.4)* AA 41.7 (1.2) 61.2 (1.3)* H 45.1 (1.5) 65.1 (1.7)* Lung nHw 15.6 (0.2) 17.7 (0.1)* AA 12.9 (0.4) 14.1 (0.4)** H 15.6 (0.7) 14.9 (0.8) Myeloma nHw 29.1 (0.7) 36.3 (0.7)* AA 33 (1.5) 35.8 (1.6) H 36.7 (2.7) 39.8 (3.3) Leukemia nHw 15.9 (0.6) 22 (0.5)* AA 17.2 (1.9) 20.2 (1.9) H 23.3 (2.3) 31.2 (2.4) *p value <0.001. **p=0.03 for difference in RSR between 1992-96 and 2002-06.
Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay
Authors: Li Zhang, Zhihong Yang, Jocelyn Trottier, Olivier Barbier, Li Wang
Journal: Hepatology (2016)

Bile acids (BAs) play critical physiological functions in cholesterol homeostasis, and deregulation of BA metabolism causes cholestatic liver injury. The long noncoding RNA maternally expressed gene 3 (MEG3) was recently shown as a potential tumor suppressor; however, its basic hepatic function remains elusive. Using RNA pull-down with biotin-labeled sense or anti-sense MEG 3RNA followed by mass spectrometry, we identified RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) as a MEG3 interacting protein and validated their interaction by RNA immunoprecipitation (RIP). Bioinformatics analysis revealed putative binding sites for PTBP1 within the coding region (CDS) of small heterodimer partner (SHP), a key repressor of BA biosynthesis. Forced expression of MEG3 in hepatocellular carcinoma cells guided and facilitated PTBP1 binding to the Shp CDS, resulting in Shp mRNA decay. Transient overexpression of MEG3 RNA in vivo in mouse liver caused rapid Shp mRNA degradation and cholestatic liver injury, which was accompanied by the disruption of BA homeostasis, elevation of liver enzymes, as well as dysregulation of BA synthetic enzymes and metabolic genes. Interestingly, RNA sequencing coupled with quantitative PCR (qPCR) revealed a drastic induction of MEG3 RNA in Shp-/- liver. SHP inhibited MEG3 gene transcription by repressing cAMP response element-binding protein (CREB) transactivation of the MEG3 promoter. In addition, the expression of MEG3 and PTBP1 was activated in human fibrotic and cirrhotic livers.MEG3 causes cholestasis by serving as a guide RNA scaffold to recruit PTBP1 to destabilize Shp mRNA. SHP in turn represses CREB-mediated activation of MEG3 expression in a feedback-regulatory fashion. (Hepatology 2017;65:604-615).
Donor KIR Genotype Does Not Affect VZV Reactivation after Allogeneic Haematopoietic Stem Cell Transplantation.
Authors: Sujaatha Narayanan, Sandeep Nagra, Premini Mahendra, Fiona J. Clark, Charles F. Craddock, Husam Osman, David C. Briggs, Paul A. Moss, Mark A. Cook
Journal: Blood (2005)
The usefulness of Holter monitoring in the evaluation of antiarrhythmic drug efficacy for tachycardia.
Authors: Takashi Yanaga, Yuhei Ichimaru, Terunori Ueno, Yoichi Hata, Kenji Okamoto, Yasuyuki Kodama, Kuniaki Otsuka
Journal: Circulation (1983)

Using Holter monitoring tachycardia was found in 145 out of 2058 patients suffering from various underlying diseases. Three thousand seven hundred and forty monitorings were performed. The mean age of patients was 54.5 years with a range of 19 to 83 years. The observed tachycardia was classified into three types: tachycardia with short duration, tachycardia with long duration and tachycardia with complex form. The attacks of tachycardia were more frequently observed during periods of physical activity than during sleeping periods. The relationship of the number of tachycardia with short duration between 24-hour Holter monitorings was examined in order to establish day to day variability of the attacks. The 95% confidence interval about the resultant regression line was calculated and the percent reduction required for the evaluation of drug efficacy to avoid the chances of interference of spontaneous variation was found to be about 44.0, 55.0 and 82% when the total number of attacks during a 24-hour period were 50, 100 and 1,000, respectively. Holter monitoring showed higher positive results as compared to exercise testing for detection of tachycardia. Higher correlation coefficients between numbers of premature ventricular contractions (PVCs) and the plasma concentrations of procainamide or N-acetylprocainamide were observed in 3 or more successive PVCs than in individually occurring PVCs. Using repeated 24-hour Holter monitorings a significant reduction in the number of tachycardia was observed when the therapeutic concentration was reached after the combined or single administration of the drug. These results suggest that repeated Holter monitorings, exercise testing and determination of plasma level of the drug may be useful for the evaluation of antiarrhythmic drug efficacy for tachycardia.
ABCG2/BCRP: Specific and Nonspecific Modulators
Authors: Diana Peña‐Solórzano, Simone Alexandra Stark, Burkhard König, Cesar Augusto Sierra, Cristian Ochoa‐Puentes
Journal: Medicinal Research Reviews (2016)

Abstract Multidrug resistance (MDR) in cancer cells is the development of resistance to a variety of structurally and functionally nonrelated anticancer drugs. This phenomenon has become a major obstacle to cancer chemotherapy seriously affecting the clinical outcome. MDR is associated with increased drug efflux from cells mediated by an energy‐dependent mechanism involving the ATP‐binding cassette (ABC) transporters, mainly P‐glycoprotein (ABCB1), the MDR‐associated protein‐1 (ABCC1), and the breast cancer resistance protein (ABCG2). The first two transporters have been widely studied already and reviews summarized the results. The ABCG2 protein has been a subject of intense study since its discovery as its overexpression has been detected in resistant cell lines in numerous types of human cancers. To date, a long list of modulators of ABCG2 exists and continues to increase. However, little is known about the clinical consequences of ABCG2 modulation. This makes the design of novel, potent, and nontoxic inhibitors of this efflux protein a major challenge to reverse MDR and thereby increase the success of chemotherapy. The aim of the present review is to describe and highlight specific and nonspecific modulators of ABCG2 reported to date based on the selectivity of the compounds, as many of them are effective against one or more ABC transport proteins.