tbuckley/cabot-search huggingface dataset:
Abstract 2733: Development of novel monoclonal antibodies for a cyclic DNA adduct derived from oxidation of ω-6 polyunsaturated fatty acids
Authors: Marcin Dyba, Brandon Da Silva, Jishen Pan, Fung-Lung Chung
Journal: Cancer Research (2015)

Abstract Dietary polyunsaturated fatty acids (ω-3 and ω-6 PUFAs) play a role in certain human cancers. The oxidation of PUFAs produces reactive α,β-unsaturated aldehydes (enals) that can modify DNA producing mutagenic lesions. Of particular interest, 7-(1′,2′-dihydroxyheptyl)-1,N6- ethenodeoxyadenosine (DHHϵdA) is a novel DNA adduct in vitro and in vivo derived from lipid peroxidation of ω-6 PUFAs. Despite its recent identification in vivo, the role of DHHϵdA in tumorigenesis is not yet known. Previously, the endogenously formed DHHϵdA was detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). Due to its low levels in vivo (1-30 adducts/109 DNA bases), a relatively high quantity of DNA is needed for its detection and quantification. In this study we developed a monoclonal antibody against DHHϵdA in order to detect and quantify this adduct in cells and tissues. Two antigens were synthesized by conjugating activated hapten: 5′-carboxy-7-(1′,2′-dihydroxyheptyl) adenosine (5′-carboxy DHHϵA) to BSA and KLH carrier proteins. KLH-conjugated hapten was used for mice immunization, whereas BSA-based hapten was used to test for an immune response. After immunization and several screenings, 6 monoclonal cell lines were chosen for further tests. Normal and competitive ELISA was performed to characterize the antibodies from all cell lines. Competitive ELISA revealed no cross-reactivity towards normal nucleosides and α- and γ-OHPdG, the cyclic 1,N2-propano adduct derived from acrolein, and 8-oxo-dG for all of the tested antibodies. However, we observed a weak (&amp;lt; 1:100) specificity for HNE-dG, an adduct derived from (E)-4-hydroxy-2-nonenal produced from oxidized ω-6 PUFAs. Because of the relatively low level of endogenous HNE-dG compared to DHHϵdA, this weak cross-reactivity should not affect the specificity of the developed antibody to detect DHHϵdA. Two cell lines were discarded after antibodies from them showed moderate competitive effects against 1,N6-etheno-2′-deoxyadenosine (ϵdA). From the remaining 4 cell lines the best one was chosen to produce purified antibody. We believe that this antibody will be a useful tool in the studies of the role of DHHϵdA as an endogenous DNA lesion in cancer development associated with ω-6 PUFAs. This work was supported by the NCI grant CA134892. Citation Format: Marcin Dyba, Brandon Da Silva, Jishen Pan, Fung-Lung Chung. Development of novel monoclonal antibodies for a cyclic DNA adduct derived from oxidation of ω-6 polyunsaturated fatty acids. [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 2733. doi:10.1158/1538-7445.AM2015-2733
353. New Insights of Microbubbles-Cell Interactions During Sonoporation Process
Authors: Anthony Delalande, Lucie Pigeon, Patrick Tauc, Eric Deprez, Patrick Midoux, Chantal Pichon
Journal: Molecular Therapy (2015)

Upon ultrasound (US) exposure, gas microbubbles (MBs) can be expanded, moved and even destroyed. These properties offer the opportunity of site-specific local drug/gene delivery. Activation of MB under specific US beams induces a transient cell membrane permeabilization with a process known as sonoporation. Transient pores formed at the plasma membrane are supposed to be responsible for the intracellular delivery of molecules but also the outward transport of intracellular molecules. Endocytosis process has been shown to be involved during sonoporation.
Interleukin 8 gene polymorphism in mastocytosis. A study of the European Competence Network on Mastocytosis (ECNM)
Authors: M. Niedoszytko, B. Nedoszytko, M. Lange, J. Glen, M. Zabotna, J. van Doormaal, J. Renke, J. Varkonyi, E. Jassem, J. Roszkiewicz, M. Marschalko, P. Valent
Journal: Allergy (2008)
Structure Function Analysis of Hematopoietic Specific Src Family Kinases Lyn, Hck and Fgr Reveal a Critical Role for Lyn’s Unique Domain in Regulating Growth of Myeloid Cells That Is Distinct from the Role of Hck and Fgr’s Unique Domain.
Authors: Jinbiao Chen, Sasidhar Vemula, Reuben Kapur
Journal: Blood (2005)
Abstract 1714: The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer
Authors: Ah-Rong Nam, Kyo Hwa Kang, Ji Eun Park, Ju-Hee Bang, Ling Jin, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang
Journal: Cancer Research (2015)

Abstract Background: JAB1 (c-Jun activation domain binding protein-1) is a c-Jun coactivator, also known as COP9 signalosome subunit 5 (CSN5). Jab1 has an important role in cell proliferation and apoptosis. Overexpression of Jab1 is correlated with poor prognosis in various cancers. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. The role of Jab1 has not been studied in BTC. We investigated the role and mechanism of Jab1 as a potential therapeutic target in BTC. Methods: We used 8 kinds of BTC cells and designed Jab1 siRNA. MTT assay and colony formation assay were done to determine growth inhibitory effect of Jab1 knockdown. Cell cycle analysis was done by FACS Calibur flow cytometer and cell migration was evaluated by wound healing assay. We used cycloheximide chase assay for measuring of protein half-life. Results: BTC cell lines showed high level of Jab1 expression. Among them, SNU478, SNU869 and SNU 1196 were indicated with especially higher level of Jab1 expression. Cell growth and proliferation of BTC cells were decreased by Jab1 knockdown. Depletion of Jab1 induced G1 arrest, as well as decreased CyclinD/CyclinA and increased p27. Cell migration was also inhibited by Jab1 knockdown. Inhibition of Jab1 showed the decrease of pSrc, pAkt. Interestingly, depletion of Jab1 led to the elevation of PTEN protein levels without change of PTEN mRNA levels. PTEN half-life was longer in Jab1 siRNA-transfected cells. Suppression of Jab1 increased the sensitivity of BTC cells to the cytotoxic chemotherapeutic agent. Conclusion: Suppression of Jab1 shows antitumor effects in BTC cells by inhibiting cell proliferation, migration, cell cycle and increase of chemosensitivity. Taken together, Jab1 might be a potential therapeutic target in BTC. Citation Format: Ah-Rong Nam, Kyo Hwa Kang, Ji Eun Park, Ju-Hee Bang, Ling Jin, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. The role and mechanism of JAB1 as a therapeutic target in biliary tract 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 1714. doi:10.1158/1538-7445.AM2015-1714
Factors Predicting Early Mortality in Patients with Newly Diagnosed Multiple Myeloma,
Authors: Vishal Rana, Geetika Srivastava, Suzanne R Hayman, Francis K Buadi, Morie A Gertz, Martha Q Lacy, Philip R. Greipp, Steven R Zeldenrust, Angela Dispenzieri, Robert A Kyle, John A Lust, Kristen Detweiler Short, David Dingli, Stephen J. Russell, S. Vincent Rajkumar, Shaji Kumar
Journal: Blood (2011)
The chemoattractant chemerin as a natural tumor suppressive cytokine.
Authors: Russell Kent Pachynski, Brian Zabel, Nicole Tejeda, Justin Monnier, Alison K Holzer, Andrew Gentles, Holbrook Edwin Kohrt, Husein Hadeiba, Arash A. Alizadeh, Eugene Butcher
Journal: Journal of Clinical Oncology (2012)

e21071 Background: Infiltration of specialized immune cells regulates the growth and survival of neoplasia. In a survey of public whole genome expression datasets we found that the gene for chemerin, a widely expressed endogenous chemoattractant protein, is downregulated in melanoma as well as other human cancers. Moreover, high chemerin mRNA expression predicted improved outcomes in human melanoma. Methods: Forced re-expression of chemerin by tumor cells was achieved by transfection. An alternate strategy involved direct intratumoral injection of recombinant chemerin into tumors. Tumor line expression of chemerin was confirmed by ELISA and functionality of expressed, secreted chemerin confirmed by chemotaxis of CMKLR1 (the main receptor for chemerin) positive cells. Tumors were evaluated by FACS and immunofluorescence for presence of recruited leukocytes. Results: In studies of the B16 transplantable mouse melanoma, tumor-expressed chemerin inhibited in vivo tumor growth without altering in vitro proliferation. Growth inhibition was associated with an altered profile of tumor infiltrating cells with an increase in natural killers (NK cells), and a relative reduction in myeloid derived suppressor cells and putative immune inhibitory plasmacytoid DC. Tumor inhibition required host expression of CMKLR1, the chemoattractant receptor for chemerin, and was abrogated by NK cell depletion. Intratumoral injection of chemerin also inhibited tumors, suggesting the potential for therapeutic application. Conclusions: We therefore conclude that chemerin recruits anti-tumor immune effector cells, and that it may act as an endogenous tumor suppressor, whose downregulation in melanoma and potentially other neoplasia contributes to immune evasion and tumor growth.
Long-term responders to trastuzumab among patients with HER2-positive metastatic breast cancer.
Authors: J. Barrière, V. Mari, P. Follana, R. Largillier, E. Chamorey, W. Lescaut, B. Flipo, F. Ettore, I. Raoust, I. Peyrottes, A. Figl, M. Marcy, T. Ihrai, A. Courdi, J. Ferrero
Journal: Journal of Clinical Oncology (2011)

e11062 Background: Since its approval in Europe in 2000, trastuzumab (T) has changed HER2-positive metastatic breast cancer (MBC) prognosis. After a durable controlled disease under T based therapy, no data are available about T maintenance duration and long-term potential side effects. The purpose of this retrospective study was to explore the pattern of outcome in a cohort of HER2-positive MBC patients (pts) with no disease progression after 3 years of T in a single institution. Methods: HER2-positive (IHC 3+ or FISH +) MBC women treated with T between 2001 to 2007 were identified from our database. We isolated long-term responders (LTR) defined as pts with a progression free survival (PFS) of more than 3 years under a first metastatic line with T. Results: We identified 124 HER2-positive MBC treated with T. There were 16 LTR (12.9%). Median age was 61.7 years (yrs). Median follow-up was 59.6 months (mths). Primary sites of metastases were bones (n=9), the liver (n=5), lungs (n=3), lymph nodes (n=3) and the skin (n=1). Five pts had 2 metastatic sites but none had more. T was associated with a taxane in first line chemotherapy (CT) in 14 pts and to an aromatase inhibitor (AI) in 2 pts. T maintenance began after a median number of CT cycles of 5 (range: 3-9), associated with AI in 5 cases. Best clinical response was 6 complete responses (CR), 3 partial responses, 5 stable diseases. Two pts had no measurable disease. The median PFS was 48.3 mths (38.4-83.3) with 9 pts (58.8%) who progressed (brain=4, bone=2, adrenal gland=1, lymph node=1, skin =1). The median overall survival was not reached with 3 deaths (3 progressions). Long-term administration of T was well tolerated with only 2 grade I reversible left ventricular dysfunction. One pt with initial bone metastases in CR stopped T after 7.5 years with no relapse after 2 yrs of follow-up. One pt in CR after 7 yrs of T has shown no will to stop by fear of progression. Conclusions: T should not be stopped after 3 years of durable response because late progression can occur, in particular in the brain. The question of T maintenance after a 5-year durable response is unsolved and may be a major source of anxiety among LTR if proposed. Regular brain imaging should be considered, even among LTR.
First-in-class inhibitor of the T cell receptor for the treatment of autoimmune diseases
Authors: Aldo Borroto, Diana Reyes-Garau, M. Angeles Jiménez, Esther Carrasco, Beatriz Moreno, Sara Martínez-Pasamar, José R. Cortés, Almudena Perona, David Abia, Soledad Blanco, Manuel Fuentes, Irene Arellano, Juan Lobo, Haleh Heidarieh, Javier Rueda, Pilar Esteve, Danay Cibrián, Ana Martinez-Riaño, Pilar Mendoza, Cristina Prieto, Enrique Calleja, Clara L. Oeste, Alberto Orfao, Manuel Fresno, Francisco Sánchez-Madrid, Antonio Alcamí, Paola Bovolenta, Pilar Martín, Pablo Villoslada, Antonio Morreale, Angel Messeguer, Balbino Alarcon
Journal: Science Translational Medicine (2016)

Modulating T cell activation is critical for treating autoimmune diseases but requires avoiding concomitant opportunistic infections. Antigen binding to the T cell receptor (TCR) triggers the recruitment of the cytosolic adaptor protein Nck to a proline-rich sequence in the cytoplasmic tail of the TCR's CD3ε subunit. Through virtual screening and using combinatorial chemistry, we have generated an orally available, low-molecular weight inhibitor of the TCR-Nck interaction that selectively inhibits TCR-triggered T cell activation with an IC50 (median inhibitory concentration) ~1 nM. By modulating TCR signaling, the inhibitor prevented the development of psoriasis and asthma and, furthermore, exerted a long-lasting therapeutic effect in a model of autoimmune encephalomyelitis. However, it did not prevent the generation of a protective memory response against a mouse pathogen, suggesting that the compound might not exert its effects through immunosuppression. These results suggest that inhibiting an immediate TCR signal has promise for treating a broad spectrum of human T cell-mediated autoimmune and inflammatory diseases.
Exome Sequencing Identifies Somatic Mutations of DDX3X in Natural Killer/T-Cell Lymphoma
Authors: Lu Jiang, Zhao-Hui Gu, Zi-Xun Yan, Xia Zhao, Yin-Yin Xie, Zi-Guan Zhang, Chun-Ming Pan, Yuan Hu, Chang-Ping Cai, Ying Dong, Li Wang, Yang Shen, Guoyu Meng, Jian-Feng Zhou, Jian-Da Hu, Jin-Fen Wang, Lin-Hua Yang, Feng Zhang, Jian-Min Wang, Zhao Wang, Zhi-Gang Peng, Fang-Yuan Chen, Zi-Min Sun, Hao Ding, Jin-Yan Huang, Yuan-Hua Liu, Jumei Shi, Jian Hou, Jin-Song Yan, Jing-Yi Shi, Lan Xu, Yang Li, Jing Lu, Zhong Zheng, Wen Xue, Wei-Li Zhao, Zhu Chen, Sai-Juan Chen
Journal: Blood (2014)
Vitamin A Supplementation and Child Mortality
Authors: Wafaie W. Fawzi
Journal: JAMA (1993)

<h3>Objective.</h3> —A two-part meta-analysis of studies examining the relationship of vitamin A supplementation and child mortality. <h3>Data Sources.</h3> —We identified studies by searching the MEDLARS database from 1966 through 1992 and by scanning<i>Current Contents</i>and bibliographies of pertinent articles. <h3>Study Selection.</h3> —All 12 vitamin A controlled trials with data on mortality identified in the search were used in the analysis. <h3>Data Extraction.</h3> —Data were independently extracted by two investigators who also assessed the quality of each study using a previously described method. <h3>Data Synthesis.</h3> —We formally tested for heterogeneity across studies. We pooled studies using the Mantel-Haenszel and the DerSimonian and Laird methods and adjusted for the effect of cluster assignment of treatment groups in community-based studies. Vitamin A supplementation to hospitalized measles patients was highly protective against mortality (DerSimonian and Laird odds ratio, 0.39; 95% confidence interval, 0.22 to 0.66;<i>P</i>=.0004) (part 1 of the meta-analysis). Supplementation was also protective against overall mortality in community-based studies (DerSimonian and Laird odds ratio, 0.70; clustering-adjusted 95% confidence interval, 0.56 to 0.87;<i>P</i>=.001) (part 2 of the meta-analysis). <h3>Conclusions.</h3> —Vitamin A supplements are associated with a significant reduction in mortality when given periodically to children at the community level. Factors that affect the bioavailability of large doses of vitamin A need to be studied further. Vitamin A supplements should be given to all measles patients in developing countries whether or not they have symptoms of vitamin A deficiency. (<i>JAMA</i>. 1993;269:898-903)
OC-088 Investigation of asymptomatic iron deficiency anaemia consistently yields high rates of underlying pathology: 5-year results from our nurse-led clinic: Abstract OC-088
Authors: S L Surgenor, J A Snook, E J Williams
Journal: Gut (2010)

<h3>Introduction</h3> Iron deficiency anaemia (IDA) is a common mode of presentation of GI disease, with 50% of symptomatic individuals having underlying GI pathology of whom a third have evidence of an underlying neoplastic process.1 The management of IDA is frequently haphazard with a myriad of referral routes and consequently random and sometimes inappropriate investigations, often with significant delays.2 <h3>Methods</h3> In 2005, following a retrospective audit which demonstrated our existing service to be suboptimal, we established a nurse-led IDA clinic to streamline, rationalise and accelerate the appropriate investigation and management of patients with asymptomatic (ie, without any GI symptoms) but proven IDA. Subsequently we prospectively collected data on all patients seen by this service. <h3>Results</h3> To date we have seen 435 patients, with a complete data set being available in 347. 329 were investigated with bi-directional endoscopy (16 declined and two were unfit for investigation). There were 130 men and 217 women, including a proportion of pre-menopausal women predominantly over the age of 40. The median age was 75 years (IQR 62-82 years). 148 patients had underlying pathology (45%), with 50 of these (34%) having an underlying neoplastic process (see Abstract 088). Furthermore, the time from assessment of IDA to investigation reduced from a median of 51 days (IQR 34–86 days) before the introduction of our nurse-led clinic, to a median of 16 days (IQR 13–24 days). However, in some patients there remained a significant delay from diagnosis of anaemia to confirmation of iron deficiency and onward referral to secondary care. <h3>Conclusion</h3> Our nurse led IDA service has optimised the management of patients referred with asymptomatic IDA. Interestingly, our findings in this asymptomatic cohort are consistent with the literature and promote the ideal that IDA should always be investigated in a timely fashion in line with the National Cancer Targets.
CSIG-21. CELL DEATH MECHANISMS OF ANTI-TUMOR THIOBARBITURIC ACID COMPOUND FOR CANCERS
Authors: Sang Lee, James Connor
Journal: Neuro-Oncology (2016)

Previously, we reported that a derivative of thiobarbituric acid compound (CC-I) is an effective agent for chemotherapy resistant gliomas and neuroblastoma. In this study, we studied the mechanism of action of this compound. CC-I induced apoptosis in a dose dependent manner in CCF-STTG1 GBM cell lines, but CC-I induced necrotic cell death in a dose dependent manner in neuroblastoma cells. CC-I exposure was also associated with cell cycle arrest in S and G2/M phase in GBM and neuroblastoma cells. The Human Apoptosis Microarray revealed that tumor necrosis factor (TNF) pathway genes have the greatest changes in gene expression in the CCF-STTG1 cells compared to the vehicle treated cells. Among caspase pathway genes, caspase 10 and caspase 14 but not caspase 3 were over 16 fold induced. Moreover, CC-I activated AKT in a dose and time dependent manner in glioma cells. According to Human Phospho-Kinase array, in addition to the activation of AKT, all three MAPKs (ERK, JNK, p38) were activated by CC-I. While phospho-AKT (S473) increased 2 fold, phospho c-jun (S63) was elevated 38 fold and phospho JNK (p-JNK) (T183/Y185, T221/Y223) was increased 8 fold compared to vehicle treated controls. The western blot and Kinase array data also indicated that CC-I mediated apoptosis is p53 independent, at least in CCF-STTG1 GBM cells. In summary, the present results and our previous findings provide compelling evidence that CC-I induced cell death in GBM cells occur via a TNF-JNK mediated cell death mechanism.
Abstract 3972: MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373
Authors: Patricia A. Toniolo, Patrick M. Pilarski, Christian Bach, James D. Griffin, Sophia Adamia
Journal: Cancer Research (2015)

Abstract Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the accumulation of poorly differentiated myeloid cells in the bone marrow and blood of patients. Differentiation therapy is an attractive therapeutic approach for treating patients with AML. All-Trans Retionic Acid, induces differentiation of patients with the PML/RARa oncogene, but is ineffective in treating other more frequent types of AML. Here we describe the use of microRNAs to target the oncogene formed as a result of the (8;21) translocation, The goals was to identify miRNAs that could target the breakpoint region of the fusion protein, and determine if this would reduce expression of AML1-ETO and promote differentiation and/or apoptosis. Bioinformatics analysis was used to identify 28 different miRNAs that could potentially target AML1-ETO transcripts. Among those, miRNA-520 and -373 showed the highest degree of complimentary to AML1-ETO transcripts at the braikpoint. To look for miR-520 and -373 efficacy, we transfected two AML cell lines, Kasumi 1 and SKNO1, which have AML1-ETO translocation, with pre-miR-520 and -373 LNA probes, as well as HL60 cells which lack AML1-ETO. Expression of the LNA pre-miR-520/373 in Kasumi-1 and SKNO-1 cell lines decreased AML1-ETO transcripts and led to a significant reduction of AML1-ETO protein levels. The inhibition of AML1-ETO fusion protein also induced apoptosis of leukemic cells in vitro, but had no effect on HL60 cells. Moreover, the administration of LNA pre-miR-520 in an AML xenografts murine model increased apoptosis of leukemic cells and reduced tumor burden without obvious toxicity. We are currently testing the effects of miR-520 and -373 on differentiation and proliferation of primary blasts from patients with the AML1-ETO translocation. Our results suggest that small molecules such as miRNAs can be identified that directly target a frequent AML oncogene. miRNAs are naturally accruing molecules and have the potential advantage of producing modest side effects, with highly significant specificity. The approaches we developed in this study can be used to evaluate and optimize other pre-miRs and anti-miRs as therapeutic agents to target other types oncogenes not currently amenable to small molecule drugs. Citation Format: Patricia A. Toniolo, Patrick M. Pilarski, Christian Bach, James D. Griffin, Sophia Adamia. MicroRNAs as potential therapeutic agents for AML: Targeting the AML1-ETO Oncogene by pre-miR-520 and -373. [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 3972. doi:10.1158/1538-7445.AM2015-3972