tbuckley/cabot-search huggingface dataset:
Abstract LB-268: Black rapsberries induced protection in pancreatic cancer mouse models
Authors: Pan Pan, Chad Skaer, Hsin Tzu Wang, Susan Tsai, Kiyoko Oshima, Yi-Wen Huang, Gary Stoner, John Lechner, Li-Shu Wang
Journal: Cancer Research (2015)

Abstract Backgrounds and objectives Pancreatic ductal adenocarcinoma (PDAC) is the 12th most common cancer worldwide with 338,000 new cases diagnosed in 2012. The estimated 5-year survival rate of diagnosed PDAC patients is less than 4%, making it the 7th leading cause of cancer death. Over-expression of epidermal growth factor (EGF) receptors and ErbB2 receptors has been associated with the development and progression of human PDAC. Diets rich in fruits and vegetables have been reported to reduce the risk of PDAC incidence and its recurrence. Our current study aimed to investigate the effects of dietary black raspberries (BRBs) on pancreatic carcinogenesis.. Methods 4-5 weeks old pancreas-specific (Pdx-1-cre) mutant mice that carry constitutively-activated oncogene K-ras (G12D) and loss-of-function tumor-suppressor gene Trp53 (R172H), hereafter refers to KPC mice, were fed with control (n = 26) or 5% BRB (n = 29) diet. In addition, orthotopic pancreatic cancer xenografts were injected with luciferase transfected human Panc-1 cells. Four weeks after Panc-1 cells were injected, these mice were given control (n = 8) or 5% BRB (n = 19) diet for 6 weeks. Results Kaplan-Meier survival analysis showed that BRBs prolonged survival of KPC mice with a medium survival of 124 days in comparison to 79 days from mice fed with control diet (p = 0.03). Molecular studies suggest that BRBs decreased the activation of EGF receptor and ErbB2 receptor signaling pathways. Further, BRBs significantly suppressed growth of Panc-1 tumors and it was associated with decreased EGF receptor activation. Conclusion These results suggest that BRBs might protect against carcinogenesis of PDAC through regulating EGF receptor and ErbB2 receptor signaling pathways. Further investigation of the downstream pathways of EGF receptor and ErbB2 receptor activation is warranted. Citation Format: Pan Pan, Chad Skaer, Hsin Tzu Wang, Susan Tsai, Kiyoko Oshima, Yi-Wen Huang, Gary Stoner, John Lechner, Li-Shu Wang. Black rapsberries induced protection in pancreatic cancer mouse models. [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-268. doi:10.1158/1538-7445.AM2015-LB-268
Abstract LB-103: Structural characterization of SPRY2-Cbl interactions
Authors: Na Zhang, Xuan Zhang, Laurie Washington, Asokan Anbanandam, Kevin Battaile, Philip Gao, Aaron Smalter Hall, Scott Lovell, Anuradha Roy, Robert Hanzlik, Raymond Perez
Journal: Cancer Research (2015)

Abstract Sprouty 2 (SPRY2) is a feedback modulator of receptor tyrosine kinase (RTK)-ERK signaling, and a potential tumor suppressor. Cbl, an E3 ubiquitin ligase and scaffold protein, binds SPRY2 with high affinity, and sequesters or targets it for degradation. Cbl also binds several growth factor receptors. Hence SPRY2, Cbl and receptors are in a dynamic equilibrium. Truncation and site-mutagenesis studies previously mapped SPRY2-Cbl interactions to two discrete domains, TKB and RING. A pY binding pocket in the TKB SH2 region is critical for binding, but the role(s) of other TKB regions and/or RING are undefined. Interactions of three Cbl recombinant proteins (P47-G351 (TKBD), and two phosphomimetic RING active-conformation constructs, P47-D435 Y371D/E) with three SPRY2 peptides (P1: Q36-N53, a putative RING binder; P2: Q36-T60 (pY55), TKB binder; and P3: 54-60(pY55), a truncated TKB binder) were characterized by computational simulation, surface plasmon resonance spectroscopy (SPR), fluorescence polarization (FP), and X-ray crystallography. In silico modeling suggested possible low-affinity binding of P1 in the groove between TKBD SH2 and 4-helix (4H) regions and near the RING, but this was not confirmed by FP, SPR, or crystallography. Apo and P2 ligand-bound structures agreed with prior published data; three previously unknown 4H interaction sites were also identified. Data on the effects of site-specific 4H mutants on P2 binding affinities are pending. Binding affinities for P2 with the TKBD, Y371E, and Y371D constructs were 160±5, 92±9, and 45±3 nM, respectively, by SPR; FP results were similar. Direct interactions with the RING were not confirmed, but the higher P2 binding affinities observed with RING constructs suggest that this domain indirectly facilitates SPRY2 binding. Binding of P2 induced 16.9° rotation of the SH2 region and formation of new H-bonds to 4H, compressing the TKBD. Importantly, P4 induced identical conformational changes as P2, but had no direct contact with 4H. These observations are consistent with a refined model of SPRY2-Cbl interaction, where ligand docking at the pY SH2 site is sufficient to globally change TKB architecture, facilitating SPRY2 binding at previously unrecognized sites in the 4H region (Support: KU COBRE-PSF (NIH/RR017708, NIH/GM103420), KU Cancer Center, Kansas Bioscience Authority, and the George &amp; Floriene Lieberman Endowment). Citation Format: Na Zhang, Xuan Zhang, Laurie Washington, Asokan Anbanandam, Kevin Battaile, Philip Gao, Aaron Smalter Hall, Scott Lovell, Anuradha Roy, Robert Hanzlik, Raymond Perez. Structural characterization of SPRY2-Cbl interactions. [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-103. doi:10.1158/1538-7445.AM2015-LB-103
Clinical features of patients with advanced non-squamous non-small cell lung cancer treated with long-term pemetrexed
Authors: Kenichiro Hirai, Hiroshi Yokouchi, Keisuke Azuma, Hiroyuki Minemura, Satoko Sekine, Kenya Kanazawa, Yoshinori Tanino, Mitsuru Munakata
Journal: Annals of Oncology (2015)
317. HH67.2, a Promising Novel Adeno-Associated Virus (AAV) Vector, Shows Improved Muscle Specificity and Infectivity Compared To AAV9
Authors: Carrie B. Martin, Christina Mayer, Chunping Qiao, Zhenhua Yuan, Lin Yang, Jianbin Li, Juan Li, Xiao Xiao
Journal: Molecular Therapy (2015)

Currently, AAV9 serotype is considered a robust heart and muscle gene delivery vehicle widely used in preclinical studies and in a clinical trial for spinal muscle atrophy (SMA). However, the systemic delivery of AAV9 with large vector doses leads to undesirable effects such as ectopic gene expression in other tissues. These shortcomings may be overcome by using certain strategies such as the development of novel AAV vectors with muscle-specific tropism. Previously, our lab identified a novel muscle specific AAV vector, HH67, by DNA shuffling and in vivo selection. Similar to other evolved tissue-specific vectors, the HH67 vector showed reduced liver tropism, but its transduction efficiency in heart and muscle tissues was still lower than that of AAV9. We set out to introduce site-directed mutations of tyrosine (Y) to phenylalanine (F) on the surface of AAV capsids which has been shown to significantly increase gene transfer efficiency for certain AAV serotypes. In this study, we investigated whether two capsid mutations in HH67, Y445F and Y731F (named HH67.2), would enhance gene delivery to the muscle while maintaining low non-specific transgene expression. We found that the HH67.2 mutant had a significant increase in transgene delivery to the muscle compared to AAV9 after systemic delivery in C57BL/6 mice via tail-vein injection. In the muscle, expression of the LacZ reporter gene (2.5 × 10^5±65413 units/μg HH67.2 vs 7.2 × 10^4±8211 units/μg AAV9; p=0.0049) and the DNA genome copy number (4.50±2.07 VG/cell HH67.2 vs 1.15±0.197 VG/cell AAV9; p=0.0118) both increased 3.5-fold compared to AAV9. Furthermore, liver and other non-specific organs showed up to an 11-fold decrease in HH67.2 vector copy number (11.8±2.5 VG/cell HH67.2 liver vs 126.8±39.6 VG/cell AAV9 liver; p<0.0001). However, HH67.2 and AAV9 had no significant difference in gene expression in the heart. LacZ expression results were confirmed by vector genome copy number via quantitative PCR and X-Gal staining. Finally, we also introduced the same Y-F mutations in three similarly shuffled and in vivo selected AAV capsids such as M41, H43 and H48, but the mutations decreased infectivities of all these capsids. Our results suggest that HH67.2 is a novel AAV vector with enhanced muscle specificity and infectivity compared to AAV9 and could be a promising vehicle to deliver therapeutic genes to skeletal muscle or heart. **This work was part of Carrie Martin and Christina Mayer's research project for the Honors Program at the UNC Eshelman School of Pharmacy.
Abstract 1073: KRAS-mediated epigenetic reprogramming upregulates RELB-dependent CXCR2 expression to promote transformation
Authors: Joel Durand, Albert Baldwin
Journal: Cancer Research (2015)

Abstract In addition to genetic aberrations, cancer cells harbor global epigenetic abnormalities. Mutant KRAS expression has been shown to induce aberrant DNA methylation and silencing of key tumor suppressors. However, nearly all attempts to directly target oncogenic KRAS have been unsuccessful, yielding an impetus for alternative strategies. Furthermore, in the majority of KRAS-driven tumors, the NF-κB pathway is constitutively active and contributes to cellular transformation. Previously, our lab has shown that knocking out the p65 subunit of NF-κB significantly reduces tumor development in a mouse model of KRAS-induced lung cancer. Here we aim to better understand KRAS-mediated epigenetic reprogramming and uncover novel effects on the NF-κB pathway. Our data suggests that KRAS-mediated epigenetic reprogramming alters the NF-κB pathway to promote transformation. Using the Infinium DNA Methylation Assay, we uncovered genome-wide changes in lung and pancreatic cells expressing KRAS(G12V) compared to wild-type cells. Expression of oncogenic KRAS was accompanied by promoter hypermethylation of tumor suppressors (e.g. FAS, BRCA1, IRAK3) and hypomethylation of oncogenes. Interestingly, we observed hypomethylation at the promoter of the RELB subunit of NF-κB in cells expressing KRAS(G12V). Hypomethylation at the RELB promoter correlated with increased expression of CXCR2, an NF-κB target gene. RNAi against RELB and CXCR2 significantly decreased colony growth in lung and pancreatic cancer cell lines expressing mutant KRAS. Together, these results support a role for KRAS in epigenetic reprogramming and suggest that RELB-dependent CXCR2 expression may be critical in KRAS-driven cancers. RELB and CXCR2 represent potential therapeutic targets that could lead to more effective treatments in the context of KRAS-driven malignancies. Citation Format: Joel Durand, Albert Baldwin. KRAS-mediated epigenetic reprogramming upregulates RELB-dependent CXCR2 expression to promote transformation. [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 1073. doi:10.1158/1538-7445.AM2015-1073
A Franco-Belgian Workshop on PNH Diagnosis by Flow Cytometry: Results of a Multicentric Evaluation of Technical Aspects and Standardized Procedures of Reference Assays on Behalf of the French Association of Cytometry (AFC)
Authors: Magali Le Garff-Tavernier, Remi Letestu, Chantal Fossat, Claire Loosen, Agathe Debliquis, Bernard Chatelain, Bernard Drenou
Journal: Blood (2011)
Second Allogeneic Stem Cell Transplantation as Treatment for Chronic Myeloid Leukemia Relapse Following a First Reduced Intensity Conditioning Allograft
Authors: Malek Benakli, Rose-Marie Hamladji, Redhouane Ahmednacer, Amina Talbi, Farih Mehdid, Rachida Belhadj, Mounira Baazizi, Nadia Rahmoune, Farida Harieche, Fatiha Zerhouni
Journal: Blood (2008)
Epidermal growth factor receptor (EGFR) mutation testing and first-line treatment with gefitinib as a strategy in the treatment of patients with advanced non-small cell lung cancer (NSCLC).
Authors: G. Lopes, J. Segel, D. S. W. Tan, Y. Do, T. Mok, E. Finkelstein
Journal: Journal of Clinical Oncology (2011)

7598 Background: Gefitinib improves response rates, progression-free survival and quality of life (QOL) when compared to chemotherapy in patients with advanced NSCLC who have activating EGFR mutations. Yet, little is known about the cost-effectiveness (CE) of this approach Methods: A decision-analytic model was developed to determine the CE of EGFR testing and guided therapy with 1st line gefitinib for patients with activating mutations (and 1st line chemotherapy and no gefitinib for patients without) vs. standard care: first line chemotherapy and gefitinib at progression in unselected patients. Clinical data are derived from published randomized clinical trials and costs for drugs, visits, tests and treatment of adverse events from cancer centers in Singapore with a societal perspective in 2010 Singapore dollars (S$). Quality-adjusted life years (QALY) gained and incremental cost-effectiveness ratios (ICER) were calculated. Sensitivity analyses were conducted Results: EGFR testing and 1st line treatment with gefitinib is a dominant strategy (it has lower costs and greater effectiveness) compared to no testing, 1st line chemotherapy and 2nd line gefitinib in unselected patients. Because the main savings in the testing arm result from not providing gefitinib to those who do not benefit, this finding holds regardless of the prevalence of patients with activating mutations. In a secondary analysis, 1st line gefitinib was also dominant when compared to 1st line chemotherapy in patients with activating EGFR mutations, primarily due to better QOL. In a scenario in which patients did not receive second line gefitinib in the standard arm, the ICER for EGFR testing and guided treatment with gefitinib was below S$ 78,000/QALY (1.3 S$ = 1 US$) Conclusions: Based on these data, EGFR testing and first line treatment with gefitinib for patients with activating mutations should become the standard treatment in advanced NSLC. In this era of exponentially increasing costs, the use of biomarkers may improve patient selection and the CE of new therapies.
Abstract 2509: Human anti-MUC1 antibodies elicited by a prophylactic cancer vaccine for mAb and CAR-modified T cell immunotherapies
Authors: Jason J. Lohmueller, Shuji Sato, Wan Cheung Cheung, Isabel Chu, Lana Popova, Christopher A. Manning, Katherine Crosby, Christopher Grange, James D. Ham, Roberto D. Polakiewicz, Olivera J. Finn
Journal: Cancer Research (2015)

Abstract MUC1 is a tumor-associated protein that is abnormally expressed on human adenocarcinomas. In our recent clinical trial, individuals at-risk for colonic adenocarcinoma received a prophylactic MUC1 cancer vaccine. Many individuals responded to the vaccine by producing high titers of anti-MUC1 IgG antibodies (Kimura, 2013). We isolated a panel of these antibodies and are seeking to develop them as antibody and chimeric antigen receptor (CAR) T cell cancer immunotherapies. To this end we used a novel method combining proteomics and next-gen DNA sequencing to identify and recombinantly produce 12 high-affinity anti-MUC1 antibodies from the sera of vaccinated individuals. By ELISA we determined that the antibodies bind with high-affinity to diverse epitopes within the MUC1 vaccine peptide. We also found that several of the antibodies can stain MUC1+ pancreas, colon, and breast cancer cell lines, but not a cell line expressing normal MUC1. We then determined that the antibodies could stain MUC1+ human pancreas and colon tumor samples, but not normal tissues. Having established tumor-specificity we have begun assessing the antibodies in a series of functional assays. In preliminary in vitro testing we determined that several of the antibodies can be internalized by MUC1+ cells making them potential candidates for toxin delivery as antibody drug conjugates (ADCs). Additionally, we found that two of the antibodies are capable of efficiently performing complement-dependent cytotoxicity (CDC) on MUC1+ cells. Finally, we have constructed CAR lentiviral expression constructs using the variable regions of several of the antibodies as targeting domains and are testing their ability to mediate MUC1-specific T cell activation, cytokine production, and target cell lysis. As the antibodies are human-derived, indication of efficacy in pre-clinical testing has the potential to directly enable clinical trials and hopefully approval of these reagents for therapy of cancer patients. Citation Format: Jason J. Lohmueller, Shuji Sato, Wan Cheung Cheung, Isabel Chu, Lana Popova, Christopher A. Manning, Katherine Crosby, Christopher Grange, James D. Ham, Roberto D. Polakiewicz, Olivera J. Finn. Human anti-MUC1 antibodies elicited by a prophylactic cancer vaccine for mAb and CAR-modified T cell immunotherapies. [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 2509. doi:10.1158/1538-7445.AM2015-2509
51. Rapid and Long Term Protection to Pseudomonas aeruginosa Using a Platform Vaccine Concept That Mediates Both Passive and Active Immunity
Authors: Salim Bougarn, Esther Frenk, Amal Robay, Lucy Quach, Stephanie Rhee, Wenzhu Wu, Stefan Worgall, Maria J. Chiuchiolo, Ronald G. Crystal, Stephen M. Kaminsky
Journal: Molecular Therapy (2015)

We have developed a platform technology against infectious agents that mediates both passive and active immunity, with rapid, passive protection through the genetic delivery of an anti-pathogen monoclonal antibody together with long term protective active immunity evoked through the presentation of a defined pathogen neutralizing epitope. Both strategies are incorporated into an E1 E3 adenovirus (Ad) vector through the coding of an antibody in the transgene and incorporation of a pathogen antigenic sequence into the hexon capsid protein, respectively. As a model to evaluate the vaccine, we have applied this to a public health-important infectious agent, Pseudomonas aeruginosa, a gram-negative ubiquitous pathogen associated with persistent pulmonary infection in hosts with bronchiectasis, such as cystic fibrosis, compromised immune function or who have pulmonary clearance mechanisms disrupted by endotracheal tubes. Although P. aeruginosa is susceptible to antibiotic therapy, chronic colonization of the respiratory tract with frequent exacerbations is typical of high risk populations. Pathogenicity linked to P. aeruginosa infection results from the release of numerous virulence factors that can degrade tissues such as proteases and phospholipase and others that diminish cellular functions via exotoxins. The passive vaccine mediates expression of an antibody to an exotoxin secreting protein, PcrV, a known P. aeruginosa a neutralizing target. Antibody expression is mediated by the nonhuman C7 serotype Ad to avoid the highly prevalent preexisting immunity to serotype 5 Ad. In parallel, the Ad capsid hexon protein has a short epitope, Epi8, derived from the outer membrane protein F of P. aeruginosa, an established neutralizing epitope for long term active immune protection to P. aeruginosa. Western analysis confirmed the expression of the anti-PcrV antibody and ELISA assays of anti-Epi8 antibodies evoked from the hexon modified Ad confirmed the active response. In vivo challenge assays in mice used agar-encapsulated P103 strain of P. aeruginosa titered for lethality. The passive vaccine significantly reduced colonization of the lung of mice intranasally challenged with a lethal dose of P. aeruginosa at 3, 5 and 10 days after vaccination in comparison to mice vaccinated with a control Ad vector, whereas the active vaccine significantly reduced colonization at 5 wk post-vaccination. The combination of the active and passive vaccines therefore provides immediate and long term protection to exposure of P. aeruginosa. The concept of a combined passive and active vaccine to provide immediate protection with long-term immunity could be an important tool for public health, particularly for bioterror-related infectious agents.
Efficacy of Staged Excision With Permanent Section Margin Control for Cutaneous Head and Neck Melanoma
Authors: Jeffrey S. Moyer, Shannon Rudy, Philip S. Boonstra, Casey Kraft, Steven B. Chinn, Shan R. Baker, Jennifer L. Schwartz, Christopher K. Bichakjian, Douglas Fullen, Alison B. Durham, Lori Lowe, Timothy M. Johnson
Journal: JAMA Dermatology (2016)

Melanoma arising in chronically photodamaged skin, especially on the head and neck, is often characterized by poorly defined clinical margins and unpredictable occult extension. Staged excision techniques have been described to treat these challenging melanomas.To investigate the local recurrence rates and margin to clearance end points using staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control.In this observational cohort study performed from October 8, 1997, to December 31, 2006, with a median follow-up of 9.3 years, 806 patients with melanoma on the head and neck, where clinical occult extension is common, were studied at an academic medical center.Staged excision with comprehensive hematoxylin-eosin-stained permanent section margin control commonly known as the square technique.Local recurrence rates and margin to clearance end points.A total of 806 patients (276 women [34.2%]; 805 white [99.9%]) with a median age at the time of first staged excision procedure of 65 years (range, 20-94 years) participated in the study. The estimated local recurrence rates were 1.4% at 5 years, 1.8% at 7.5 years, and 2.2% at 10 years. For each 50-mm2 increase in the size of the clinical lesion, there was a 9% increase in the rate of local recurrence (hazard ratio, 1.09; 95% CI, 1.02-1.15; P = .02). The mean (SD) margin from lesion to clearance for melanoma in situ was 9.3 (5.1) mm compared with 13.7 (5.9) mm for invasive melanoma. For melanoma in situ, margins were clear after 5 mm or less in 232 excisions (41.1%) and after 10 mm or less in 420 excisions (74.5%). For invasive melanoma, margins were clear after 5 mm or less in 8 excisions (3.0%) and after 10 mm or less in 141 excisions (52.2%).Staged excision with comprehensive permanent section margin control of melanomas arising in chronically sun-damaged skin on the head and neck has favorable recurrence rates when melanoma margins are difficult to assess, and recurrence rates are high with traditional techniques.