tbuckley/cabot-search huggingface dataset:
Cardiovascular and respiratory assessment following IV administration of nanoparticle albumin-bound 17AAG (nab-17AAG) in conscious cynomolgus monkeys
Authors: Vuong Trieu, Jon Cordia, Andrew Yang, Bridget Beals, Sherry Ci, Leslie Louie, Neil Desai
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

5746 

Background: Nab technology when applied to hydrophobic molecules, such as paclitaxel, leads to improved drug safety and efficacy as well as enhanced drug delivery compared to surfactant-based drug formulations. Nab-17AAG is a nanoparticle albumin-bound, injectable form of the hydrophobic Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17AAG), a geldanamycin analogue that showed some clinical anti-tumor activity with MTD at 450 mg/m2 for weekly dosing and 650 mg/m2 for every 3-week dosing. Due to previously reported cardiovascular toxicities with alternative formulations of 17AAG, we evaluated the in vivo cardiovascular and respiratory effects of nab-17AAG in monkeys.    Methods: Based on a Latin Square design, telemetry-implanted, male cynomolgus monkeys (n = 4) were administered placebo (HSA, 600 mg/kg) or nab-17AAG IV at doses of 20, 40 and 55 mg/kg on day (d) 1, 8, 15 and 22. A range of hemodynamic and lead II-ECG variables were recorded from telemetry-data capture (Open A.R.T./PONEHMAH Physiological Platform) 2 hrs before (predose; PD) and 1, 2, 4, 8 and 14 hrs after administration of nab-17AAG. Blood gas samples were taken PD, 5 hrs after each scheduled dose, in addition to d7 and 21. Blood samples for hematology and serum chemistry were taken PD and d24. Treatment-related effects with telemetric and blood gas data were evaluated using statistical tests, rANOVA and ANCOVA respectively.    Results: Following IV administration of nab-17AAG at doses of 20, 40, and 55 mg/kg, there were no test article-related effects observed on hemodynamics (SBP, DBP, MAP), mean HR, respiration rate, lead II-ECG variables (PR interval, QRS duration, RR interval and QT interval), or HR-corrected QTcB interval. No test article-related changes were observed in arterial blood gas parameters (PO2, PCO2, oxyhemoglobin, and HbO2 saturation) or body weights. Treatment-related emesis was observed both during administration and post-dosing. However, emesis was more frequently associated with the mid- and high-dose cohorts. Therefore, using a Latin Square, multiple-dosage regimen, the no-observed-adverse-effect level (NOAEL) for the telemetry parameters, (including lead II QT interval and HR-corrected QTcB interval) for nab-17AAG in conscious male cynomolgus monkeys was 55 mg/kg.    Conclusions: The NOAEL for the telemetry parameters in conscious, male cynomolgus monkeys using a multiple-dosing, Latin Square-based regimen for nab-17AAG was 55 mg/kg. This value corresponds to a weekly nab-17AAG dose of 660 mg/m2 which is 44% higher than the reported MTD of 17-AAG (450 mg/m2). These data are strongly indicative of the cardiovascular and respiratory safety of nab-17AAG.
Abstract 3908: Periostin mediated TNFα and IL-17 induced collagen deposition: Potential role in liver fibrosis
Authors: Venkataswarup Tiriveedhi
Journal: Cancer Research (2015)

Abstract Background: The pro-inflammatory cytokines, tumor necrosis factor (TNF)-α, and interleukin (IL)-17, have been implicated in the pathogenesis of liver fibrosis. In this study, we investigated the role of TNFα and IL-17 towards induction of profibrotic factor, periostin. Methods: HepG2 cells were cultured and treated with inflammatory cytokines, TNFα and IL-17. Computational promoter sequence analysis of the periostin promoter was performed to define the putative binding sites for transcription factors. Transcription factors were analyzed by Western blot and Chromatin Immunoprecipitation. Periostin and transcription factor expression analysis was performed by RT-PCR, Western blot, and fluorescence microscopy. Type I collagen expression from fibroblast cultures was analyzed by Western blot and Sircol soluble collagen assay. Results: Activation of HepG2 Cells with TNFα and IL-17 enhanced the expression of periostin (3.5 and 4.4 fold, respectively p&amp;lt;0.05) compared to untreated cells. However, combined treatment with both TNFα and IL-17 at similar concentration demonstrated a 13.3 fold increase in periostin (p9.1 fold, p&amp;lt;0.01), indicative of a direct fibrogenic effect of TNFα and IL-17. Conclusion: TNFα and IL-17 induced fibrogenesis through cJun and STAT-3 mediated expression of profibrotic biomarker, periostin. Therefore, periostin might serve as a novel biomarker in early diagnosis of liver fibrosis. Note: This abstract was not presented at the meeting. Citation Format: Venkataswarup Tiriveedhi. Periostin mediated TNFα and IL-17 induced collagen deposition: Potential role in liver fibrosis. [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 3908. doi:10.1158/1538-7445.AM2015-3908
p90RSK2 as a Therapeutic Target in Treatment of FGFR3-Expressing t(4;14) Multiple Myeloma.
Authors: Sumin Kang, Shaozhong Dong, Tinglei Gu, Ailan Guo, Michael S. Cohen, Sagar Lonial, Petet Leif Bergsagel, Jack Taunton, Roberto D. Polakiewicz, Jing Chen
Journal: Blood (2007)
Abstract 5191: Missense mutants of p53 tumor suppressor contributes to drug-resistance and epithelial-mesenchymal transition in colon cancer cells
Authors: Salman B. Hosain, Yong Y. Liu
Journal: Cancer Research (2015)

Abstract The mutants of p53 tumor suppressor that have been detected in approximately 50% of tumors exhibit oncogenic function and promote tumor progression. Restoration of tumor suppression by introduction of wild-type p53 effectively eliminate cancers in preclinical studies; however, more than 80% of p53 mutations are missense mutants, those can form heterotetramers and diminish the therapeutic effect of p53 transgene. It is still unclear how missense mutants promote tumor progression, particularly in whether or not these mutants contribute to induced cancer stem cells during chemotherapy. We report herewith that R273 missense mutant contributes to drug-induced stem cell-like behavior in colorectal cancer cells. Heterozygous SW48 TP53 (R273H/+) cells presented the same sensitivity to doxorubicin and paclitaxel as its parental SW48 colon cancer cells. However, after exposure to lower concentrations of doxorubicin (10 nM) or paclitaxel (4 nM) for eight weeks, SW48 TP53 not only were resistant to anticancer drugs, but also displayed an epithelial-mesenchymal transition (EMT). With the overexpressed E-cadherin and down-expressed vimentin, SW48 TP53 cells that were exposed to doxorubicin displayed significantly EMT morphological changes and increased wound healing, compared to SW 48 cells. Interestingly, inhibition of ceramide glycosylation with PDMP to increase endogenous ceramide restored wild-type p53 expression in heterozygous SW48 TP53 cells exposed to doxorubicin and further sensitized these cells to anticancer drugs and reversed EMT. These findings indicate that a heterozygous missense p53 mutant promotes EMT and drug resistance of colon cancer cells in chemotherapy, and restoration of p53 expression with suppression ceramide glycosylation can improve therapeutic efficacy. Citation Format: Salman B. Hosain, Yong Y. Liu. Missense mutants of p53 tumor suppressor contributes to drug-resistance and epithelial-mesenchymal transition in colon cancer 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 5191. doi:10.1158/1538-7445.AM2015-5191
Abstract 650: A high-throughput conjugation strategy for the selection of THIOMAB™ antibodies with desired properties for antibody-drug conjugation
Authors: Rachana V. Ohri, Sunil Bhakta, Helga Raab, Richard Vandlen, Jagath Junutula, Hans Erickson
Journal: Cancer Research (2015)

Abstract THIOMAB™ antibody technology utilizes antibody engineering to replace endogenous amino acids of an antibody with cysteine to allow for site-selective conjugation. The technology enables the exploration of different drug attachment sites on the antibody thereby offering the potential to select antibody-drug conjugates (ADCs) with unique properties. Having a large number of antibody sites from which to choose may be desired for some applications. Many antibody sites are not suitable due to limited solvent accessibility or because drug attachment alters the native antibody properties. To identify those antibody sites most amenable to drug conjugation, we prepared 648 THIOMAB™ antibody variants of the anti-HER 2 antibody 4D5 by sequentially mutating every amino acid in the light and heavy chains to cysteine (excluding the endogenous cysteines). Each THIOMAB™ antibody variant was then conjugated to maleimido caproyl valine citrulline PABA MMAE and pyridyl disulfide MMAE in separate reactions. A high throughput on-bead Protein A conjugation and purification method was developed using a 96 well plate format. Complete reduction of the engineered cysteines and reoxidation of the endogenous cysteines, and drug to antibody ratios (DAR) were all determined by LC/MS. The concentration and aggregation status of each ADC were determined using automated liquid chromatography methods. Nearly 40% of the THIOMAB™ antibodies were found to be suitable for conjugation with DAR &amp;gt;1 and low aggregation levels. The other 60% failed due to a variety of factors including low drug incorporation, high aggregation levels, and incomplete re-oxidation of the endogenous cysteines. We found similar results with the maleimide and pyridyl disulfide derivatives suggesting our findings may be applicable to other auristatin derivatives with different sulfhydryl reactive chemistries. In summary, we have developed a high throughput conjugation strategy for THIOMAB™ antibodies and used it to identify the antibody sites most suitable for conjugation to auristatin derivatives. Citation Format: Rachana V. Ohri, Sunil Bhakta, Helga Raab, Richard Vandlen, Jagath Junutula, Hans Erickson. A high-throughput conjugation strategy for the selection of THIOMAB™ antibodies with desired properties for antibody-drug conjugation. [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 650. doi:10.1158/1538-7445.AM2015-650
Abstract 1083: Expression of an estrogen-regulated variant transcript of the peroxisomal branched chain fatty acid oxidase, ACOX2, in breast cancer
Authors: Sunniva Bjørklund, Vessela N. Kristensen, Michael Seiler, Grethe I. Grenaker Alnaes, Yao Ming, John Kerrigan, Bjørn Naume, Ravi Sachidanandam, Gyan Bhanot, Anne-Lise Børresen-Dale, Shridar Ganesan
Journal: Cancer Research (2015)

Abstract Alternate transcripts from a single gene locus greatly enhance the combinatorial flexibility of the human transcriptome. Different patterns of exon usage have been observed when comparing normal tissue to cancers, suggesting that variant transcripts may play a role in the tumor phenotype. In this study we show that an intronic start variant of ACOX2, peroxisomal Acyl-CoA oxidase 2 (ACOX2-i9), is expressed and translated into a 25kDa protein in HepG2 cells as well as in several breast cancer cell lines, where it is required for optimal cell proliferation. shRNA knock down of the ACOX2-i9 variant results in decreased cell viability as assessed by colony formation assay of T47D and MDA-MB 436 cells. Moreover, expression of ACOX2-i9 is estrogen regulated, being induced by estradiol and inhibited by tamoxifen in ER+ T47D and Mcf-7 cells, but not in the ER- MDA-MB 436 cell line. This variant transcript is present predominantly in breast tumors as assessed in our initial set of 53 breast cancers and further validated in 87 tumor/normal pairs from the TCGA Breast Cancer dataset. It is specifically enriched in ER+ breast cancers where it's expression is associated with improved outcome. These data identify variant ACOX2 as a potential novel therapeutic biomarker in ER+ breast cancer. Citation Format: Sunniva Bjørklund, Vessela N. Kristensen, Michael Seiler, Grethe I. Grenaker Alnaes, Yao Ming, John Kerrigan, Bjørn Naume, Ravi Sachidanandam, Gyan Bhanot, Anne-Lise Børresen-Dale, Shridar Ganesan. Expression of an estrogen-regulated variant transcript of the peroxisomal branched chain fatty acid oxidase, ACOX2, in breast 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 1083. doi:10.1158/1538-7445.AM2015-1083
The CD317-Targeted Immunotoxin HM1.24-ETA′ Efficiently Eliminates Malignant Plasma Cells in Vitro and in Vivo
Authors: Matthias Staudinger, Pia Glorius, Christian Kellner, Andreas Guenther, Roland Repp, Renate Burger, Martin Gramatzki, Matthias Peipp
Journal: Blood (2012)
Safety of Deferasirox (Exjade®) in Patients with Transfusion-Dependent Anemias and Iron Overload Who Achieve Serum Ferritin Levels &amp;lt;1000 Ng/Ml during Long-Term Treatment
Authors: John B Porter, Antonio Piga, Alan Cohen, John M Ford, Janet Bodner, Lisa Rojkjaer, Maria Domenica Cappellini
Journal: Blood (2008)
Developing a patient and public involvement intervention to enhance recruitment and retention in UK surgical trials (PIRRIST)
Authors: J.C. Crocker, S. Rees, L. Locock, S. Petit-Zeman, A. Chant, S. Treweek, J.A. Cook, N. Farrar, K. Woolfall, J. Bostock, L. Bowman, R. Bulbulia
Journal: International Journal of Surgery (2016)
Factors Influencing Prescription Drug Costs in the United States—Reply
Authors: Ameet Sarpatwari, Jerry Avorn, Aaron S. Kesselheim
Journal: JAMA (2016)

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Abstract 2174: Identification of genetic factors contributing to development of common cancers through tissue-specific protein interaction analysis
Authors: David C. Qian, Jinyoung Byun, Younghun Han, David J. Hunter, Brian E. Henderson, Rosalind Eeles, Christopher A. Haiman, Douglas F. Easton, Rayjean J. Hung, Christopher I. Amos
Journal: Cancer Research (2015)

Abstract In the genetic study of diseases, pathway based analysis captures more of the variability in risk than single-variant analysis, and also provides a meaningful framework for organizing and interpreting findings. Here, we augment the biologic insights provided by pathway based analysis of GWAS results by incorporating tissue-specific protein interactions. From large GWAS meta-analyses of lung cancer (12,160 cases/16,838 controls), breast cancer (15,748 cases/18,084 controls), and prostate cancer (14,160 cases/12,724 controls), we determined the tissue-specific interactomes of proteins expressed from genes containing independently associated variants. The pathways with statistical overrepresentation of proteins in each network were evaluated across the three cancers. Our results show that pathways implicated in the development of all three cancers or two out of the three cancers tend to be broad, essential cellular processes required for growth and survival. The most significant examples include the nerve growth factor (P = 1.65 × 10^-47), epidermal growth factor (P = 1.22 × 10^-37), and stem cell factor/Kit (P = 4.47 × 10^-35) signaling cascades. However, within these shared pathways, the proteins encoded by genes with risk-conferring variants generally differ from cancer to cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as leptin signaling in breast cancer (P = 1.24 × 10^-6) and platelet sensitization by low-density lipoprotein in prostate cancer (P = 3.80 × 10^-6). Taken together, we demonstrate a new method of pathway based analysis following GWAS that considers tissue-specific protein interactions. For cancers of the lung, breast, and prostate, we validate known susceptibility pathways and identify previously unexplored ones, as well as characterize each cancer by its unique pathways. Citation Format: David C. Qian, Jinyoung Byun, Younghun Han, David J. Hunter, Brian E. Henderson, Rosalind Eeles, Christopher A. Haiman, Douglas F. Easton, Rayjean J. Hung, Christopher I. Amos. Identification of genetic factors contributing to development of common cancers through tissue-specific protein interaction analysis. [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 2174. doi:10.1158/1538-7445.AM2015-2174
Reservoir computing and the Sooner-is-Better bottleneck
Authors: Stefan L Frank, Hartmut Fitz
Journal: Behavioral and Brain Sciences (2016)

Abstract Prior language input is not lost but integrated with the current input. This principle is demonstrated by “reservoir computing”: Untrained recurrent neural networks project input sequences onto a random point in high-dimensional state space. Earlier inputs can be retrieved from this projection, albeit less reliably so as more input is received. The bottleneck is therefore not “Now-or-Never” but “Sooner-is-Better.”
Abstract 3843: Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids
Authors: Angelo Sparaneo, Annamaria la Torre, Domenico Trombetta, Leonarda Di Candia, Massimiliano Copetti, Teresa Balsamo, Evaristo Maiello, Paolo Graziano, Vito M. Fazio, Lucia A. Muscarella, Montse Sanchez-Cespedes
Journal: Cancer Research (2015)

Abstract Introduction. The Keap1/Nrf2 pathway is a master regulator of antioxidants and cellular stress re-sponses implicated in resistance of tumour cells against chemotherapeutic drugs. Recent data suggest that genetic and epigenetic mechanisms may play a pivotal role in the regulation of KEAP1 expression in Non Small Cell Lung Cancer. At present, the data concerning the mechanism of alteration of Nrf2-Keap1 pathway in the Carcinoids of the lung remain almost incomplete. Materials and methods. Here we report a comprehensive molecular characterization of Keap1/Nrf2 axis in cell lines and 48 tissues from Lung Carcinoid affected patients by integrating data from altera-tions at DNA, transcript and protein levels. Results. An hypermethylation of the CpGs island located into the P1 promoter region of the KEAP1 was detected in 16 out of the 32 Typical Carcinoids (50%) and 8 out of the 16 Atypical Carcinoids (50%). No somatic mutations were detected both in the kelch-repeats region of the KEAP1 gene and in the Nhe2 domain of NFE2L2 gene, whereas LOH at the KEAP1 locus (19p13.2) was found in more than 50% of cases, suggesting that biallelic inactivation of KEAP1 in lung cancer is a common event in lung carcinoids. Decreased of the KEAP1 expression in methylated cancer cells induced greater nuclear accumulation of Nrf2, causing enhanced transcriptional xenobiotic metabolism enzymes. Conclusions. This is the first study to our knowledge that provides new insights into the mechanism of deregulation of Nrf2/Keap1 detoxification pathway in lung carcinoids. Loss of KEAP1 function leading to constitutive activation of Nrf2-mediated gene expression in cancer suggests that deregulation of the Keap1/Nrf2 system could play a pivotal role in the pathogenesis of carcinoids. Citation Format: Angelo Sparaneo, Annamaria la Torre, Domenico Trombetta, Leonarda Di Candia, Massimiliano Copetti, Teresa Balsamo, Evaristo Maiello, Paolo Graziano, Vito M. Fazio, Lucia A. Muscarella, Montse Sanchez-Cespedes. Nrf2-keap1 axis: uncovers molecular profile in lung carcinoids. [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 3843. doi:10.1158/1538-7445.AM2015-3843
BMET-06. IMPROVED SURVIVAL AND PROGNOSTIC ABILITY IN LUNG CANCER PATIENTS WITH BRAIN METASTASES: AN UPDATE OF THE GRADED PROGNOSTIC ASSESSMENT FOR LUNG CANCER USING MOLECULAR MARKERS (LUNG-molGPA)
Authors: Paul Sperduto, T. Jonathan Yang, Kathryn Beal, Hubert Pan, Paul Brown, Ananta Bangdiwala, Ryan Shanley, Norman Yeh, Laurie E. Gaspar, Steve Braunstein, Penny Sneed, John M. Boyle, John Kirkpatrick, Kimberley Mak, Helen Shih, Alex Engelman, David Roberge, Nils Arvold, Brian Alexander, Mark Awad, Joseph Contessa, Veronica Chiang, John Hardie, Daniel Ma, Emil Lou, William Sperduto, Minesh Mehta
Journal: Neuro-Oncology (2016)

Lung cancer is the leading worldwide cause of cancer and cancer-related mortality. With improving, molecularly-targeted systemic therapies, lung cancer patients are living longer and are at increased risk for brain metastases. Understanding how prognosis varies across this heterogeneous population is essential to individualizing care and designing future clinical trials. Our original Lung-GPA prognostic index was based on four factors (age, Karnofsky Performance Status, extracranial metastases and number of brain metastases) found to be significant for survival and weighted by magnitude, such that patients with the best/worst prognosis would have a Lung GPA score of 4.0/0.0, respectively. The purpose of this study is to update the Lung-GPA, incorporating that gene/molecular alteration data, to create the new Lung-molGPA. A multi-institutional retrospective database (2006-2014) of 2186 patients with NSCLC and newly diagnosed brain metastases was utilized for this analysis. Prognostic factors reaching statistical significance on multivariate analysis were weighted by Hazard Ratio and an updated Lung-molGPA was designed. Significant prognostic factors included the four original factors and two new factors (EGFR and ALK alterations in adenocarcinoma patients). Notably, the overall median survival for the group increased from 7 to 12 months between the two study periods (1985-2005 and 2006-2014). NSCLC-adenocarcinoma patients with Lung-molGPA of 3.5-4.0 exhibited a median survival of nearly 4 years. This best prognosis group (Lung-molGPA 3.5-4.0) would require all of the following: EGFR or ALK alterations, KPS > 90, age < 70, no extracranial metastases and < 5 brain metastases. The updated Lung-molGPA incorporates gene alteration data. Survival and the ability to predict survival duration for NSCLC patients with brain metastases has improved significantly. This free user-friendly tool (BrainMetGPA.com) will facilitate clinical decision-making and appropriate stratification of future clinical trials.