tbuckley/cabot-search huggingface dataset:
36. Translation of an Adenovirus-Based Cocaine Vaccine dAd5GNE to a Clinical Trial
Authors: David F. Havlicek, Bishnu De, Jonathan Rosenberg, Odelya Pagovich, Dolan Sondhi, Stephen Kaminsky, Ronald Crystal
Journal: Molecular Therapy (2016)

dAd5GNE, an anti-cocaine vaccine based on a disrupted serotype 5 adenovirus gene transfer vector covalently conjugated to the cocaine analog GNE, evokes high titers of high affinity anti-cocaine antibodies that prevent cocaine from reaching its cognate receptor in the CNS. dAd5GNE has been shown to be effective in preclinical efficacy studies in mice, rats and nonhuman primates. In order to translate dAd5GNE to the clinic, this study focused on optimizing the choice of adjuvant, timing of vaccination regimen and dose. Adjuvant. To evaluate vaccine formulation, the adjuvants Adjuplex and Alum were assessed at a fixed dose to identify the formulation that evoked the fastest and highest titer response. BALB/c mice vaccinated with dAd5GNE/Adjuplex demonstrated high serum anti-cocaine antibody titers (>5×105) after a single administration while animals vaccinated with dAd5GNE/Alum required multiple injections to achieve high titers, and mice vaccinated with dAd5GNE/PBS plateaued at a lower titer. Therefore, a formulation based on the Adjuplex adjuvant was chosen for the clinical protocol. Timing. The measurement of titer half-life in nonhuman primates following individual vaccinations at variable intervals was used to inform the timing between vaccine boosts. The anti-cocaine antibody titer half-life in 8 dAd5GNE/Adjuplex vaccinated nonhuman primates was assayed regularly over the course of 1 yr and the titer half-life was calculated following each administration. The average half-life for all animals was 4.0 ± 0.2 wk. Continued cocaine use did not impact the titer half-life. These results indicate that a 4 wk interval for vaccinations is necessary to maintain the high titer anti-cocaine antibody levels. Dose. We measured the dose response in mice to provide the baseline for a phase I/II clinical trial and identified the range of doses that bracket the anticipated minimum effective dose and maximum tolerated dose. Doses from 0.04-40 μg of the vaccine were evaluated in BALB/c for the capacity to evoke antibody titers and to minimize access of radiolabelled cocaine to the CNS. Doses at and above 4 µg produced high anti-cocaine antibody titers above the threshold for efficacy (>5×105) which substantially reduced cocaine levels in the brain (p<0.0001 vs PBS). Using a modified weight adjusted dose from these results, the vaccine doses to be evaluated in the clinical trial were determined to be 100 to 1000 µg. The results of these studies combine to provide the specifications for critical vaccine design parameters required to translate the anti-cocaine vaccine to evaluation in a clinical trial. Based on these specifications the FDA has allowed the Adjuplex-formulated dAd5GNE vaccine to proceed to clinical study with a monthly vaccination regimen in recovering cocaine addicts.
Immunogenicity of Haemophilus Influenza and Pneumococcal Vaccines in Related and Unrelated Transplant Recipients.
Authors: Mary K. Pao, Esperanza B. Papadopoulos, Nancy A. Kernan, Ann A. Jakubowski, James W. Young, H.R. Castro-Malaspina, Miguel-Angel Perales, Richard J. O’Reilly, Farid Boulad, Susan Prockop, Trudy N. Small
Journal: Blood (2006)
569. Development of CRISPR Toolkit for Knock-In Transgene Targeting to the Rat Rosa26 Locus
Authors: Christopher T. Richie, Lowella V. Fortuno, YaJun Zhang, James Pickel, Brandon K. Harvey
Journal: Molecular Therapy (2015)

The advent of CRISPR-based genome modification has lowered the investment cost required for the creation of highly-customized model organisms. Here we describe the development of a Cas9-based genetic toolkit for the rat, which streamlines the targeted insertion of transgenes into the Rosa26 locus. We have constructed a set of plasmids which express the Cas9(D10A) nickase (Cas9n) and a pair of rat Rosa26-targeting guide RNAs (gRNAs) along with a selectable marker. When transfected into rat adrenal gland pheochromocytoma (PC-12) cells, these plasmids induce the formation of double-strand breaks and thereby lead to the accumulation of small insertion/deletions (InDels) between the gRNA binding sites. These plasmids also increase the efficiency of homology-directed insertion of a transgene (donor template) when delivered by cotransfection. The verified Rosa26-targeting gRNAs were transcribed and purified in vitro, and microinjected alongside Cas9n mRNA into Long-Evans rat embryos. InDel frequency at the Rosa26 locus in the resulting pups was assessed using a T7 endonuclease assay. For three rounds of injections, the frequency of InDels detected was (2 out of 16), (7 out of 12), and (10 out of 15). The ability to enhance homology-directed insertions in vivo was also validated by coinjecting these gRNAs with single-stranded oligonucleotides (ssODN) containing a novel loxP site flanked on each side by 72 basepairs of Rosa26 sequence. A single round of injections produced 15 pups, 4 of which carried the loxP allele. Next, a single round of injections employing a plasmid-based donor template with 1 kilobase homologous arms produced 7 pups, 1 of which carried the transgene. The use of this rat Rosa26 CRISPR toolkit will simplify the creation of "defined" transgenic rat models and should reduce the inconsistencies attributed to copy number- and position-effects when dealing with randomly integrated transgenes.
Abstract 2485: Novel monoclonal antibody targeting cancer stem cells
Authors: Jeff Holderness, Amy Turner, Sam dolezal, Steve Wolpe, Michael Pierce, Cohava Gelber
Journal: Cancer Research (2015)

Abstract Caerus Therapeutics (Caerus) is developing a monoclonal antibody directed to a cancer specific epitope on CD66c (CEACAM6) designated 109.12. CD66c has been shown in preclinical studies to be expressed on the colorectal cancer stem cell population but not on normal intestinal stem cells, making this a potential target for a therapeutic antibody. Previous attempts by other companies to develop anti-CD66c antibodies were unsuccessful due to cross-reactivity with CD66c on normal tissues. Caerus has developed a monoclonal antibody to a cancer-specific, glycan epitope that is only expressed in the adult during malignant transformation, enabling the targeting of CD66c on both cancer stem cells (CSCs) as well as bulk tumor without cross-reactivity with CD66c on normal cells. The glycan epitope recognized by the antibody has a novel structure not previously described that is highly protein-specific and site-specific. The specificity is due to a unique dual-recognition determinant for the site-specific glycosylation. In addition to its expression on colorectal tumorspheres, the epitope recognized by the 109.12 antibody is expressed by a wide variety of cancers including colon, pancreatic, lung stomach and a subtype of breast cancer. The biological role of CD66c in malignancy and tumor dissemination is well documented; the specificity of the antibody for a CD66c epitope only expressed in malignant cells offers multiple opportunities for immunotherapy and diagnosis of a diverse spectrum of cancers. Citation Format: Jeff Holderness, Amy Turner, Sam dolezal, Steve Wolpe, Michael Pierce, Cohava Gelber. Novel monoclonal antibody targeting cancer stem cells. [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 2485. doi:10.1158/1538-7445.AM2015-2485
Abstract 2005: Quantitative screening of serum protein biomarkers by reversed phase protein serum arrays
Authors: Zhizhou Kuang, Ruochun Huang, Shuhong Luo, Yun-Ru Chen, Zhiqiang Lv, Zhuo Zhang, Ruo-Pan Huang
Journal: Cancer Research (2015)

Abstract Protein biomarkers can be key indicators for cancer diagnosis, prediction, and selection of successful cancer treatments. Protein biomarkers can be identified by 2 methods: antibody arrays which profile protein expression levels from a patient's serum, or reversed phase protein arrays to measure single or limited sets of proteins from many patients’ sera. The reversed phase protein arrays have been widely used for detection of signaling molecules in cell lysates, however, this approach has been difficult to adapt to serum samples. Several years ago, we developed a sensitive method called the enhanced protein array to quantitatively measure serum protein levels from large numbers of patient samples. Here, we further refine the technology on several fronts: 1. simplifying the experimental procedure; 2. optimizing multiple parameters to make the assay more robust; 3. establishing a method for more accurate quantification. Using this technology, we quantitatively measured the protein expression levels of Nidogen-1 and CEACAM-1 from 164 serum samples from hepatocellular carcinoma (HCC) and equal number of control and found that both Nidogen-1 and CEACAM-1 expression levels are significantly increased in HCC patients. Our work reveals promise for using reversed phase protein serum arrays for biomarker discovery and validation. Citation Format: Zhizhou Kuang, Ruochun Huang, Shuhong Luo, Yun-Ru Chen, Zhiqiang Lv, Zhuo Zhang, Ruo-Pan Huang. Quantitative screening of serum protein biomarkers by reversed phase protein serum arrays. [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 2005. doi:10.1158/1538-7445.AM2015-2005
Abstract 4872: Improving bioinformatic analysis pipelines for calling somatic mutations in tumors and tumor derived cell lines
Authors: Bradley Wubbenhorst
Journal: Cancer Research (2015)

Abstract The use of massively parallel sequencing data (MPS) is a common technique for identifying genetic alterations in disease. A number of tools and resources have been developed to assist in variant identification, but most are not specifically designed for somatic cancer studies. Tumor samples often suffer from admixture and heterogeneity, and tumor DNA often is derived from formalin fixed paraffin embedded samples rather than fresh samples, which introduces artificial bias. These confounders require adjustments to variant quality filtering to ensure a confident call set, but no universal guidelines exist for bioinformatics analyses. In addition, no single tool characterizes the spectrum of possible DNA-based alterations in tumors, specifically single nucleotide variants, small to medium sized indels, large genomic rearrangements and copy number alterations. To address these issues, we compared several methods of bioinformatic analysis using whole exome and targeted high-throughput sequencing data from various tumor and tumor-derived cell line studies. Using a data sets with known somatic alterations, we developed modifications to best practices guidelines for the publically available Genome Analysis Toolkit (GATK) for use in tumor and cell line variant calling. The haplotype score annotation was removed from all filtering consideration due to its expectance of no more than two segregating haplotypes at a given site, which, for example, caused all known BRAF V600 mutations to be removed. Scores from the read position rank sum test required a reduced filter threshold due to presence of high alternate allele fractions, which may contribute an artificial bias for this annotation value. Where applicable, we combined GATK results with calls from MuTect to increase specificity of the somatic changes identified as well as further increase sensitivity to singleton mutations. Finally, we have analyzed three methods to detect large genomic rearrangements and copy number changes (Pindel, ngCGH, and Sequenza) from MPS data, and found inconsistent results which require further scrutiny. In conclusion, we have developed a somatic variant calling pipeline which includes several modifications to the best practices in standard variant calling algorithms to enhance the sensitivity and specificity for somatic variant calling of the entire range of DNA-based alterations in tumors. Citation Format: Bradley Wubbenhorst. Improving bioinformatic analysis pipelines for calling somatic mutations in tumors and tumor derived cell lines. [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 4872. doi:10.1158/1538-7445.AM2015-4872
Pharmacokinetic advantage of hipec using minimal extracorporeal circuit in patients with peritoneal carcinomatosis
Authors: Galina S. Kireeva, Valentin V. Alekseev, Ivan A. Solovyev, Alexey M. Belyaev, Konstantin Y. Senchik, Konstantin D. Guseinov, Maxim V. Vasilchenko, Vladimir G. Bespalov
Journal: Annals of Oncology (2015)
Abstract 2192: Stress-induced reprogramming of epithelial cancers toward a stem-like fate
Authors: Maricel C. Gozo, David A. Cheresh, Mayra Yebra, Laetitia Sequin
Journal: Cancer Research (2015)

Abstract Cancer cell plasticity has become a focus of intense study as it impacts both therapy and drug resistance. Epigenetic changes contributing to cellular plasticity and stemness allow tumor cells to adapt to microenvironmental stress and or drug treatment. We recently reported that the heterodimer integrin receptor αvβ3 serves as a marker of stem-like breast, lung, and pancreatic carcinomas that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. In fact, αvβ3 was found to be both necessary and sufficient to drive stemness, drug resistance, and tumor progression. Here, we report that β3 expression is expressed in response to a range of cellular stresses, including nutrient deprivation, hypoxia, oxidative stress, and cancer therapy. Stress-induced β3 gene expression is enhanced by epigenetic histone modifications that promote an open chromatin state enabling binding of the HNF4A transcription factor to the β3 promoter. Once expressed, β3 induces reprogramming toward a stem-like fate by driving a subset of NFκB target genes, including FOXP1, a transcription factor that controls expression of pluripotency genes OCT4 and NANOG. Therefore, stress-induced chromatin remodeling and the HNF4A-mediated induction of β3 expression triggers a switch from an epithelial to a cancer stem-like phenotype. Evidence is provided that pharmacological blockade of this epigenetic change not only inhibits β3 expression but reverses tumor stem-like properties and enhances their response to therapeutic standard of care. These findings define a stress-induced but reversible epigenetic pathway leading to β3 expression on a range of epithelial cancers that drives cancer stemness, tumor progression and drug resistance. Citation Format: Maricel C. Gozo, David A. Cheresh, Mayra Yebra, Laetitia Sequin. Stress-induced reprogramming of epithelial cancers toward a stem-like fate. [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 2192. doi:10.1158/1538-7445.AM2015-2192
Abstract 1786: Role of Euphorbia tirucalli terpenes cocktail extracts in the regulation of molecular cell death: implications in gynecological cancer progression
Authors: Mpho Choene, Lesetja Motadi
Journal: Cancer Research (2015)

Abstract Gynaecological cancers are increasingly becoming the cause of death in females in developing countries. This type of cancers, especially cervical cancer is in the increase due to co-infection with HIV. Many of these people are solely dependent on traditional remedies, as conventional treatment might be expensive or inaccessible to them. In this study we characterised butanolic, hexane and methanolic extracts of Euphorbia tirucalli using both TLC and LC-MS spectroscopy. Following extract analysis, we looked at the effects of the extracts in regulating cell death in breast (MDA-MB 231), ovarian (RMG-1) and cervical (SiHa) cancer cell lines. The cells were treated with varying concentrations of the cocktailed extracts for up to 48 hours. A real time cell analyzer (xCELLigence) was used to monitor cell growth and to determine IC50. MTT assay was used to assess cell viability 24 hours post treatment with extracts. To determine if the extracts had an effect on cell cycle arrest, cell cycle distribution was determined by staining treated cancer cells with propidium iodide and the percentages of G0/G1, S, G2/M cell populations were analysed using flow cytometry. To determine the type of cell death induced, flow cytometry using annexin V was employed. At IC50, molecular analysis was performed to evaluate the effect cocktailed extracts had on apoptotic and cell cycle genes. Cocktailed extracts were found to inhibit cell proliferation in a concentration and cell type dependent manner. Cells were also found to have been arrested at G0/G1 and in some cases apoptosis induced. In general most pro-apoptotic genes like Bax and caspase-8 were upregulated this included the cell cycle gene p21 which was found to be significantly up-regulated in cells treated with extracts. These results suggest that the 3 cocktailed extracts might induce apoptosis or arrest cells at G0/G1 with the molecular mechanism that suggest activation of caspase-8 and Bax. Note: This abstract was not presented at the meeting. Citation Format: Mpho Choene, Lesetja Motadi. Role of Euphorbia tirucalli terpenes cocktail extracts in the regulation of molecular cell death: implications in gynecological cancer progression. [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 1786. doi:10.1158/1538-7445.AM2015-1786
CD8 + T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections
Authors: Bing He, Shaojun Xing, Changya Chen, Peng Gao, Li Teng, Qiang Shan, Jodi A. Gullicksrud, Matthew D. Martin, Shuyang Yu, John T. Harty, Vladimir P. Badovinac, Kai Tan, Hai-Hui Xue
Journal: Immunity (2016)
S97 Annual rate of fvc decline in various patient sub-groups with idiopathic pulmonary fibrosis treated with pirfenidone: pooled analysis from 3 pivotal studies
Authors: PW Noble, C Albera, W Chou, U Costabel, B Day, I Glaspole, MK Glassberg, L Lancaster, DJ Lederer, SD Nathan, CA Pereira, J Stauffer, JJ Swigris
Journal: Thorax (2016)

<h3>Introduction</h3> Pirfenidone has been shown to decrease the annual rate of decline in forced vital capacity (FVC) volume in patients with idiopathic pulmonary fibrosis (IPF). This analysis explored this effect in various patient subgroups. <h3>Methods</h3> Patients randomised to pirfenidone 2403 mg/d or placebo in the CAPACITY or ASCEND studies were included. The annualised rate of decline in FVC volume from baseline through 12 months was estimated using a mixed-effects model, with study, time-by-treatment, age-by-sex and height-by-sex as fixed effects and patients and time-by-patient (slope) as random effects. The annual rate of FVC decline was estimated from the slope within the subgroups, defined by demographics and baseline disease activity measures. <h3>Results</h3> A total of 623 patients in the pirfenidone group and 624 in the placebo group were included in the pooled analysis. Overall, the adjusted annual rate (SE) of FVC decline from baseline to 12 months was −109.0 (13.6) mL for pirfenidone vs −207.5 (13.7) mL for placebo, a difference of 98.5 (17.5) mL. The annual rate of FVC decline favoured pirfenidone over placebo across various baseline demographic and lung function subgroups (<b>Figure 1</b>). <h3>Conclusions</h3> Patients with IPF treated with pirfenidone, regardless of baseline demographic or lung function, had a significantly lower annual rate of decline in FVC volume vs those treated with placebo after 12 months.
Weekly Low-Dose Rituximab As the Preemptive Management of Epstein-Barr Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: A Novel Strategy?
Authors: Feng Chen, Wu Depei, Tao Tao, Wei Gong, Chunmei Ye, XiaoWen Tang, Yue Han, Huiying Qiu
Journal: Blood (2015)
SGN-70, a Humanized Anti-CD70 Antibody, Targets CD70-Expressing Hematologic Tumors.
Authors: Julie A. McEarchern, Charlotte F. McDonagh, Leia M. Smith, Kerry Klussman, Ezogelin Oflazoglu, Carol Morris-Tilden, Ivan Stone, Renee McCormick, Paul Carter, Hanspeter Gerber, Iqbal S. Grewal, Che-Leung Law
Journal: Blood (2006)
MRI-Detectable Focal Lesions (FL) in Multiple Myeloma (MM) at Relapse Frequently Involve Novel Sites Not Involved at Diagnosis.
Authors: Ronald Walker, L. Jones-Jackson, Eric Rasmussen, M. Miceli, Elias Anaissie, Joshua Epstein, Guido Tricot, John Shaughnessy, Bart Barlogie
Journal: Blood (2004)
FOLFIRINOX with modified regimen therapy for advanced pancreatic cancer in Okayama university hospital
Authors: Shigeru Horiguchi, Hironari Kato, Yutaka Akimoto, Daisuke Uchida, Takeshi Tomoda, Kazuyuki Matsumoto, Naoki Yamamoto, Koichiro Tsutsumi, Junichiro Nasu, Kazuhide Yamamoto
Journal: Annals of Oncology (2015)
Abstract 4772: Aberrantly hypermethylated Homeobox A2 derepresses metalloproteinase-9 through TBP and promotes invasion in nasopharyngeal carcinoma
Authors: CHEN-CHING PENG
Journal: Cancer Research (2015)

Abstract Nasopharyngeal carcinoma (NPC) is notorious for its high invasiveness and metastatic ability. In this study, we identified a differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), which helps explain such observation. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5′Aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptional repression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 was correlated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Our results reveal a novel mechanism wherein HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels. Plasma EBV DNA and methylated cell-free HOXA2 may use as biomarkers for monitoring NPC treatment. Citation Format: CHEN-CHING PENG. Aberrantly hypermethylated Homeobox A2 derepresses metalloproteinase-9 through TBP and promotes invasion in nasopharyngeal 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 4772. doi:10.1158/1538-7445.AM2015-4772