tbuckley/cabot-search huggingface dataset:
9. AAV-Mediated Gene Transfer as a Therapeutic Approach for Familial LCAT Deficiency
Authors: Devin M. Christopher, Jeff Billheimer, Dawn Marchadier, Katalin Susztak, Alan Remaley, James Wilson, Daniel J. Rader
Journal: Molecular Therapy (2015)

Lecithin Cholesterol Acyltransferase (LCAT) is a plasma enzyme secreted by the liver and responsible for esterification of free cholesterol to cholesteryl ester in the blood compartment. Familial LCAT deficiency (FLD) is an autosomal recessive disorder caused by loss-of-function mutations of the LCAT gene and is characterized by extremely low levels of high density lipoprotein cholesterol (HDL-C), anemia, corneal opacities, and chronic progressive renal disease leading to end-stage kidney disease as early as the third decade of life. Currently, there is no specific treatment for FLD. The fact that patients with even very low levels of plasma LCAT activity do not develop kidney disease make FLD an attractive candidate for liver-directed gene therapy with adeno-associated viral (AAV) vectors. LCAT is activated by apolipoprotein A-I (apoA-I) and this interaction is highly species specific. Therefore, LCAT KO mice were crossed with human apoA-I transgenic (hApoAITg) mice in order to facilitate experiments involving expression of human LCAT. LCAT KO/hApoAI transgenic mice received a single IP injection of AAV8 encoding human LCAT in a dose range of 5e10 GC/kg to 5e11 GC/kg. HDL-C increased in a dose-dependent fashion, from 32 mg/dL in the control group to 103 mg/dL at the dose of 1.5e11 GC/kg and 473 mg/dL at the dose of 5e11 GC/kg. Plasma% cholesterol ester, a sensitive indicator of LCAT activity, was normalized at the low dose of 1.5e11 GC/kg. Thus, we demonstrate that low doses of AAV8-hLCAT provide stable expression of the LCAT enzyme and correct dyslipidemia in a 'humanized' mouse model of LCAT deficiency. Studies designed to demonstrate prevention of kidney disease in this mouse model are ongoing. These proof-of-concept studies provide a foundation for further development of AAV-based gene therapy for familial LCAT deficiency.
Blood Transfusion and Erythropoiesis Stimulating Agents (ESAs) Use In Patients with Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Nicolas Batty, Elham Ghonimi, Lei Feng, Anas Younes, Rodriguez Alma, Elizabeth Wager, Fernando Martinez, Michael Wang, Peter McLaughlin, Nathan Fowler, Fredrick Hagemeister
Journal: Blood (2010)
Active treatment near the end-of-life in metastatic cancer patients
Authors: S. Bolzonello, E. Poletto, L. Gerratana, M. Bonotto, M. Cinausero, V. Fanotto, B. Alessandra, E. De Carlo, P. Ermacora, F.E. Pisa, F. Puglisi, G. Fasola
Journal: Annals of Oncology (2015)
Bone Marrow Iron Concentration as a Marker of Iron Accumulation and Marrow Expansion in Patients with Beta Thalassemia Major.
Authors: Paola Polchi, Rossella Palmieri, Marco Andreani, Javid Gaziev, Cecilia Alfieri, Gioia De Angelis, Cristiano Gallucci, Antonella Isgro, Marco Marziali, Katia Paciaroni, Andrea Roveda, Pietro Sodani, Guido Lucarelli
Journal: Blood (2008)
Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22
Authors: F Arruga, B Gizdic, C Bologna, S Cignetto, R Buonincontri, S Serra, T Vaisitti, K Gizzi, N Vitale, G Garaffo, E Mereu, F Diop, F Neri, D Incarnato, M Coscia, J Allan, R Piva, S Oliviero, R R Furman, D Rossi, G Gaidano, S Deaglio
Journal: Leukemia (2016)
Abstract 4871: A new multiple feature approach for rapid and highly accurate somatic structural variation discovery from whole cancer genome sequencing
Authors: Li C. Xia, John Bell, Jiamin Chen, Nancy R. Zhang, Hanlee P. Ji
Journal: Cancer Research (2015)

Abstract We present SWAN, a statistical framework with implemented software package for accurate detection of genomic structural variants in next-generation sequencing (NGS) data from cancer. SWAN is designed to sensitively detect submicroscopic and lesser size genome structural variants that could possibly present at low allele frequency in the sample as may be the case in clonal subpopulations of a primary tumor. The likelihood ratio scan statistics module of SWAN collectively quantifies evidence from read-pair, hang-reads based on Marked Poisson Process models while the softclipping module additionally integrates the evidence from remapped soft-clipped reads. Using a spike-in dataset, we compared SWAN against established structural variant callers in recovering simulated homozygous and heterogeneous variants of various sizes and types. SWAN maintained high accuracy, high precision and low false positives across this broad spectrum and outperformed all the other callers. In additional benchmark with golden standard real data from sample NA12878, SWAN again showed the best-balanced accuracy among all callers and was 30% more sensitivity in detecting validated deletions than the next runner-up caller LUMPY in 50x coverage. Even at 5x coverage, SWAN was able to find 40% of the validated deletions while LUMPY did less than 20%. As an application to whole cancer genome sequencing, we analyzed a matched sequenced colorectal adenocarcinoma sample and found 39 somatic deletions, insertions and duplications, some of which could potentially drive the cancer progression. SWAN is quite efficient in memory utilization and speed, and can be used for large-scale genome-wide structural variant genotyping and discovery based on NGS data. Citation Format: Li C. Xia, John Bell, Jiamin Chen, Nancy R. Zhang, Hanlee P. Ji. A new multiple feature approach for rapid and highly accurate somatic structural variation discovery from whole cancer genome sequencing. [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 4871. doi:10.1158/1538-7445.AM2015-4871
Abstract LB-145: Pten deletion in SOX9+ cells synergizes with hepatic injury to drive tumor development in mouse liver
Authors: Ni Zeng, Anketse Kassa, Janel Kopp, Lina He, Maike Sander, Bangyan Stiles
Journal: Cancer Research (2015)

Abstract Liver cancer is an extremely deadly disease ranked as the third most common cancer and the second leading cause of male cancer-related death worldwide. Among primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the two most frequent subtypes, accounting for 85-95% of the total liver cancer cases, and both types of liver cancer have been found to originate from the expansion and differentiation of tumor initiating cells (TICs). Thus, it is critically important to understand mechanisms that regulate liver TICs activation. By utilizing a Pten(loxp/loxp); Albumin-Cre+ mouse liver cancer model (L-PKO), our previous studies have confirmed the activation of TICs during liver tumorigenesis. We also found that SOX9 was expressed in both HCC and CC, suggesting that SOX9 might serve as a liver TICs marker. We thus used the Pten(loxp/loxp); SOX9-CreER+ mouse model (TIC-PKO) to study the role of PTEN in TICs during liver tumorigenesis. Liver tumor development was observed in TIC-PKO mice at the age of 12 months old, and immunohistochemical analysis revealed that the tumors were heterogeneous, indicating TICs were involved in the tumorigenesis process. In addition, treatment of DDC, which is a liver toxin and thus causes hepatocyte death, dramatically increased the incidence and led to the early onset of liver tumorigenesis in the mutant but not the control mice, suggesting that liver injury served as an essential microenvironmental niche in promoting liver tumor development. Together, our observations suggested that the PTEN signaling is critical for TICs regulation and Pten deletion synergizes with liver injury to drive both TICs activation and liver tumorigenesis. Citation Format: Ni Zeng, Anketse Kassa, Janel Kopp, Lina He, Maike Sander, Bangyan Stiles. Pten deletion in SOX9+ cells synergizes with hepatic injury to drive tumor development in mouse liver. [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 LB-145. doi:10.1158/1538-7445.AM2015-LB-145
608. Evaluation of Pre-Existing Neutralizing Antibodies Against Tyrosine-Mutant AAV2 in Leber Hereditary Optic Neuropathy (LHON) Patients
Authors: Rajeshwari D. Koilkonda, William W. Hauswirth, Vince Chiodo, Sanford L. Boye, Phillip Gonzalez, John Guy
Journal: Molecular Therapy (2015)

PURPOSE: Pre-existing neutralizing antibodies against adeno-associated virus (AAV), due to natural AAV infections could interfere with the recombinant AAV vector-mediated gene transfer, thus decreasing the efficiency and preventing effective vector readministration. Here, we measured neutralizing antibody (NAb) titers against tyrosine-mutant AAV serotype 2 in Leber Hereditary Optic Neuropathy (LHON) patients. METHODS: Serum samples from LHON patients (n=53, age =33 + 1.9 yrs, average + se) were screened for the existence of NAbs to AAV2 using an invitro assay. For this, a self-complimentary AAV2(Y444,500,703F)-smCBA-mCherry vector was pre-incubated with heat inactivated LHON patient serum samples at various dilutions, beginning with a 1:5 dilution and ending at 1:20,480. The serum-vector mixtures were used to infect RGC5 cells at multiplicity of infection of 5000 vector genomes/per cell. Two days post-infection, cell viability was confirmed by microscopy and transduction scored by flow cytometry. Expression of mCherry was quantified by multiplying the percentage of cells positive for mCherry by the mean fluorescence intensity. The neutralizing antibody (NAb) titer was reported as the highest serum dilution that inhibited self-complementary AAV2 (Y444,500,703F)-smCBA-mCherry transduction >50% compared to no serum control. RESULTS: We found that the prevalence of NAbs to AAV2 (Y444,500,703F) among the LHON subjects was variable with majority, 49% (26/53) showing low NAb titers (<1:80), 19% (10/53) showed moderate NAb titers (< 1:5120). However, 32% (17/53) showed a higher NAb titer <1:20,480. Prevalence of NAb's was not associated to any specific age group (p>0.05). CONCLUSIONS: Previous AAV2 exposure among LHON patients is low to high and these findings as they relate to the ongoing clinical human gene therapy trial (NCT02161380) will be discussed.
Human Immunodeficiency Virus (HIV)-Associated Acute Myeloid Leukemia (AML) in the Era of Highly Active Antiretroviral Therapy (HAART): High Complete Remission Rate, but Poor Tolerance of Consolidation Therapy and Short Disease-Free Survival.
Authors: Michael W Evans, Anthony Sung, Ivana Gojo, Michael L Tidwell, Jacqueline Greer, Mark Levis, Judith Karp, Maria R Baer
Journal: Blood (2009)
Abstract 4276: Engineering a trivalent lupus anti-DNA autoantibody fragment for cancer therapy
Authors: Jaymin M. Patel, Phil W. Noble, Grace Chan, Richard H. Weisbart, James E. Hansen
Journal: Cancer Research (2015)

Abstract Discovery and design of agents that selectively kill malignant cells but spare normal tissue is critical to the development of effective cancer therapies. 3E10 is a lupus anti-DNA autoantibody that penetrates cell nuclei, binds DNA and inhibits DNA repair in a manner that does not kill normal cells but is synthetically lethal to cancer cells with defective homology-directed repair of DNA double-strand breaks due to BRCA2-deficiency. To develop a more potent version of 3E10 for further testing in cancer therapy, we have engineered a trivalent fragment of 3E10 with mutations that enhance nuclear penetration and DNA binding. cDNA encoding a tandem trivalent single chain variable fragment of 3E10 (3E10 tri-scFv) with the D31N enhancing mutation in CDR1 of the heavy chain variable regions was designed and cloned into the pPICZαA yeast expression vector. 3E10 tri-scFv was expressed in and purified from Pichia pastoris. Biochemical characterization of 3E10 tri-scFv by SDS-PAGE and Western blotting confirmed purification of the expected protein product, and cell-penetration assays demonstrated increased efficacy of nuclear uptake by 3E10 tri-scFv. Clonogenic survival assays with BRCA2-deficient cancer cells similarly indicated enhanced synthetic lethality mediated by 3E10 tri-scFv. These findings indicate 3E10 tri-scFv is a promising candidate for further development as a targeted therapy for DNA repair-deficient malignancies and demonstrate the potential utility in engineering multivalent derivatives of other promising lupus autoantibodies intended for development as targeted cancer therapies. Citation Format: Jaymin M. Patel, Phil W. Noble, Grace Chan, Richard H. Weisbart, James E. Hansen. Engineering a trivalent lupus anti-DNA autoantibody fragment for cancer therapy. [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 4276. doi:10.1158/1538-7445.AM2015-4276
Abstract 2606: Antitumor activity of the selective RAF inhibitor HM95573 in melanoma
Authors: InHwan Bae, YoungGil Ahn, Namgoong GwangMo, SuHyeon Kim, JiYeon Song, TaeHun Song, JaeHo Lee, KyuHang Lee, Young-Mi Lee, YoungHoon Kim, KweeHyun Suh
Journal: Cancer Research (2015)

Abstract The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of tumor cells. Activation of the MAPK pathway due to mutations in BRAF and NRAS is considered one of the causes of melanoma. HM95573 is a novel, highly potent RAF kinase inhibitor. Biochemically assayed for over 120 kinases, HM95573 showed the high selectivity toward BRAF mutant and CRAF kinases. The half maximal inhibition concentrations (IC50) of HM95573 against BRAFWT, BRAFV600E and CRAF kinases were 41nM, 7nM and 2nM, respectively. The strongly inhibited kinases subsequent to RAF kinases appeared to be CSF1R (44nM), DDR1 (77nM) and DDR2 (182 nM). HM95573 potently inhibited the growth of mutant BRAF melanoma cell lines such asA375 (IC50: 57nM) and SK-MEL-28 (69nM) and of mutant NRAS melanoma cell lines such asSK-MEL-2 (53nM) and SK-MEL-30 (24nM). In addition, the phosphorylations of MEK and ERK downstream kinases associated with cell proliferation were effectively inhibited with treatment of HM95573in mutant BRAF and mutant NRAS melanoma cells.HM95573inhibited the downstream signaling in melanoma cells even in the presence of HGF which is known to mediate innate resistance to RAF inhibitors. HM95573 showed the excellent antitumor activity in mouse models xenografted with both of BRAF mutation cell lines (e.g. A375 and SK-MEL-28) and NRAS mutation cell lines (such as SK-MEL-2 and SK-MEL-30) compared to two RAF inhibitors approved in melanoma which were effective to only BRAF mutation cell lines under conditions tested. Furthermore, HM95573 did not show a potential to paradoxical activation inducing tumor growth in mouse xenograft study using A431 cuSCC (cutaneous squamous cell carcinoma)cancer cell. Now, HM95573 is currently in phase I development in patients with advanced solid tumors including melanoma in Korea. Citation Format: InHwan Bae, YoungGil Ahn, Namgoong GwangMo, SuHyeon Kim, JiYeon Song, TaeHun Song, JaeHo Lee, KyuHang Lee, Young-Mi Lee, YoungHoon Kim, KweeHyun Suh. Antitumor activity of the selective RAF inhibitor HM95573 in melanoma. [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 2606. doi:10.1158/1538-7445.AM2015-2606
Therapeutic approaches targeting inflammation for diabetes and associated cardiovascular risk
Authors: Allison B. Goldfine, Steven E. Shoelson
Journal: Journal of Clinical Investigation (2017)

Obesity-related sub-acute chronic inflammation has been associated with incident type 2 diabetes and atherosclerotic cardiovascular disease. Inflammation is increasingly considered to be a pathologic mediator of these commonly co-occurring diseases. A growing number of preclinical and clinical studies support the inflammatory hypothesis, but clinical trials to confirm the therapeutic potential to target inflammation to treat or prevent cardiometabolic conditions are still ongoing. There are multiple inflammatory signaling pathways. Regulation is complex, with substantial crosstalk across these multiple pathways. The activity of select pathways may be differentially regulated in different tissues. Pharmacologic approaches to diabetes management may have direct or indirect antiinflammatory effects, the latter potentially attributable to an improved metabolic state. Conversely, some antiinflammatory approaches may affect glucose metabolism and cardiovascular health. To date, clinical trials suggest that targeting one portion of the inflammatory cascade may differentially affect dysglycemia and atherothrombosis. Understanding the underlying biological processes may contribute to the development of safe and effective therapies, although a single approach may not be sufficient for optimal management of both metabolic and athrothrombotic disease states.
The role of minimal residual disease (MRD) by flow cytometry (FC) in predicting outcome in similarly treated acute lymphoblastic leukemia (ALL) patients.
Authors: H. J. Lee, K. M. Wright, E. Kandeel, W. Tan, G. E. Wilding, L. A. Ford, S. N. Sait, A. M. W. Block, M. P. Barcos, P. L. McCarthy, C. E. Vigil, E. A. Griffiths, J. E. Thompson, E. S. Wang, P. K. Wallace, M. Wetzler
Journal: Journal of Clinical Oncology (2011)

6592 Background: MRD measured by FC and polymerase chain reaction are independent prognostic indicators for pediatric and adult ALL with significant cost benefit for the former. Methods: We queried our ALL database between 1995 to 2009 for newly diagnosed untreated patients (pts) age ≥17 years, karyotype and FC at diagnosis, week (wk) 8 (range 7-9) and wk 16 (range 15-17) post diagnosis. Pts were treated on or per Cancer and Leukemia Group B protocols. The gating strategy used a series of Boolean regions that best defined the diagnostic abnormal population based on its expression patterns; for B-ALL CD 5, CD 10, CD 19 and kappa before 2003 and CD10, CD19, CD34, and CD38 after 2003, and for T-ALL CD 5, CD 10, CD 19 and CD 34 throughout. The same regions were applied to the post induction samples, and the number of residual events was determined. MRD positivity (+) was defined as >0.01% of the gated population. Results: 79 ALL pts with a median age of 52 years (range, 19-80), including 44 males:35 females were analyzed. All pts achieved complete remission; median follow-up was 20 months (mos) (range: 4.9 to 148.7), and 42 (52%) pts relapsed. 64 (81%) pts had B lineage, 6 (8%) had bi-phenotypic and 9 (11%) had T cell phenotype. Karyotype: 2 had favorable, 35 intermediate and 40 adverse karyotype; 2 were not available. The median white blood cell count was 8.97 x 109/L (range 0.6-493.98); 32 (40.5%) pts underwent transplantation (SCT) in first remission. In multivariate analysis MRD+ at 8 wks was associated with inferior progression-free survival (PFS) [40.2 vs. 2.3 mos; 95% confidence interval (CI) 4.6 to not reached (NR) vs. 0.92 to 40.016] (P=0.0080) but not overall survival (OS). MRD+ at 16 wks was associated with both inferior PFS [22.1 vs. 5 mos; 95% CI 12.7 to NR vs. 2.9 to 8.7 (P=0.0001)] and OS (46.2 vs. 14.3 mos; 95% CI 19.7 to NR vs. 10.41 to 26.283) (P=0.0029)]. In pair-wise comparison those who were MRD negative at wk 16 did not benefit from SCT compared to the non SCT group. Conclusions: MRD+ by FC at wk 16 following induction was predictive of inferior survival and identified a subgroup of pts who benefitted from SCT. Pts with MRD negativity by FC at wk 16 did not benefit from SCT.
Analysis of the ETS Family Member Genes ERG, ETS2, ETS1 and FLI1 in Acute Myeloid Leukemia (AML) Patients with Normal Cytogenetics: Expression Levels and Impact On Clinical Outcome. A Study of the AMLSG.
Authors: Verena I. Gaidzik, Cailian Wang, Richard F. Schlenk, Lars Bullinger, Peter Paschka, Frank G. Rücker, Andrea Corbacioglu, Karina Eiwen, Jürgen Krauter, Brigitte Schlegelberger, Arnold Ganser, Manuela Zucknick, Axel Benner, Hartmut Döhner, Konstanze Döhner
Journal: Blood (2009)
Abstract 4991: RET and integrins cooperate in cell-microenvironment response
Authors: Eric Lian, Mathieu J.F. Crupi, Jessica G. Cockburn, Simona M. Wagner, Anirudh Goel, Lois M. Mulligan
Journal: Cancer Research (2015)

Abstract The RET receptor tyrosine kinase is expressed in neural crest-derived cell types, where it is activated by soluble ligands of the Glial Cell-derived Neurotrophic Factor (GDNF) family and signals through multiple downstream pathways, contributing to cell growth, survival, and migration during embryonic development. In addition to its normal developmental roles, oncogenic mutations or aberrant expression of RET are also linked to tumour spread and metastasis in multiple human tumour types. Thus, a consistent feature of RET involvement in these disease processes is its contribution to directional cell motility. We have previously shown that RET-mediated cell-adhesion and migration requires multiple members of the integrin family of cell adhesion molecules, including integrin β1 (ITGB1) and β3 (ITGB3) subunits, however the regulation of cell migration and invasion by RET and integrins has not been explored. In this study, we showed that GDNF-mediated RET activation induced rapid ITGB1 and ITGB3 activation with transiently increased cell adhesion, followed by enhanced cell protrusion formation and reduced adhesion typical of more migratory cells. In addition, we showed that directional cell migration in response to GDNF requires the presence of both extracellular matrix and a GDNF concentration gradient. Our data also suggest that ITGB1 and ITGB3 play complementary but non-compensatory roles in the initiation of RET-mediated cell migration and invasion, and that the inhibition of either ITGB1 or ITGB3 resulted in impaired migration and invasion in both 2D and 3D culture conditions. We have also shown that multiple signaling pathways downstream of RET are involved in these processes and that these pathways contribute differently to migration in 2D vs 3D microenvironments. These data highlight the ability of tumour cells to leverage different signaling pathways to mediate cell migration and invasion downstream of RET, and reveal ways in which cooperation between RET and integrins might affect aspects of tumour progression. Our data, together with other studies which have shown combination therapy targeting integrins and RTKs to be more effective than monotherapy, suggest that adjuvant treatment with agents targeting integrin function may further enhance therapeutic options for tumours where RET is expressed. Citation Format: Eric Lian, Mathieu J.F. Crupi, Jessica G. Cockburn, Simona M. Wagner, Anirudh Goel, Lois M. Mulligan. RET and integrins cooperate in cell-microenvironment response. [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 4991. doi:10.1158/1538-7445.AM2015-4991
Mutational Analysis of BCR-Abl From Subjects with Relapsed Ph+ALL Treated On the COG Protocol AALL0031: a Report From the Children's Oncology Group.
Authors: Bill H Chang, Stephanie G Willis, Linda C. Stork, Stephen P Hunger, William L. Carroll, Bruce Camitta, Naomi J. Winick, Brian J. Druker, Kirk R. Schultz
Journal: Blood (2009)