tbuckley/cabot-search huggingface dataset:
Abstract LB-012: Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions
Authors: Rao V. Papineni, Shahid Umar, Alexey Goltsov, Ishfaq Ahmed
Journal: Cancer Research (2017)

Abstract We earlier showed with Systems Biology approach that the genotoxic stress response evoked by cancer, infection, and radiation injury have similarities, particularly at the gastrointestinal tract. This was made possible using biophotonics, and show promise in drug screening opportunities using each of these pathologies as a surrogate model for one another. Using similar molecular Imaging methodology, we showed for the first time binding of osteoporosis drug bisphosphonate to prostate and ovarian cancer tumors and potential drug repurposing candidature. Recently, we presented similar drug re-tasking potential of 2-Deoxyglucose (2-DG) in anti-infection. Here, our data demonstrating mitigation of citrobacter rodentium infection by dietary treatment by 2-DG (0.4%), were analyzed with the bisphosphonate anti-infection response to enteric bacterial pathogens data reported elsewhere. Based on these results, a systems approach analysis is developed and presented demonstrating cross-talk and communication between different cells and integrated responses to pathogens and disease by 2-DG and bisphosphonate in anticancer and anti-infection actions. A role in EGFR signaling and modulation in the infiltration immune response cells by these two dissimilar compounds play a profound bridging event in anticancer and anti-infection activities. These system biology strategies will provide opportunities for drug repurposing in personalized cancer therapy and in anti-microbial management during cancer treatment. Also pave way for safer drugs in prevention and therapy of HER family-driven cancers. Citation Format: Rao V. Papineni, Shahid Umar, Alexey Goltsov, Ishfaq Ahmed. Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-012. doi:10.1158/1538-7445.AM2017-LB-012
Abstract 3123: Identification of TIFA as a novel therapeutic target in acute myeloid leukemia
Authors: Pei-Yu Wu, Tong-You Wade Wei, Ting-Jung Wu, Ming-Daw Tsai
Journal: Cancer Research (2017)

Abstract Aurora A-dependent NF-κB signaling portends poor prognosis of cancers including acute myeloid leukemia (AML). Our previous study demonstrated that phosphorylation-dependent oligomerization of TRAF-interacting protein with FHA domain (TIFA) triggers the activation of NF-κB. The present study identifies that Aurora A is an essential kinase for the Thr9 phosphorylation of TIFA, and that TIFA functionally mediates the Aurora A-driven NF-κB survival pathway in AML. Overexpression of TIFA occurred concurrently with Aurora A and NF-κB signaling factors in de novo AML patients but not healthy individuals, and also correlated with poor prognosis. Silencing of TIFA specifically attenuated leukemic cell growth and enhanced chemosensitivity of AML cells via down-regulation of pro-survival factors Bcl-2 and Bcl-XL that support NF-κB-dependent anti-apoptotic events. In addition, molecular targeting of TIFA perturbed leukemic cytokine secretion and significantly lowered the IC50 of chemotherapeutic drugs to treat AML cells. Furthermore, in vivo delivery of TIFA-inhibitory fragments potentiates the clearance of leukemic myeloblasts in the bone marrow of xenograft-recipient mice via enhanced chemotoxicity, similar to the effect of anti-inflammatory drug treatments. Collectively, we proposed that TIFA functionally supports the positive feedback between TNF-α, Aurora A, and NF-κB to facilitate AML survival signaling, and impairment in this pathway can enhance the efficacy of AML treatments. Citation Format: Pei-Yu Wu, Tong-You Wade Wei, Ting-Jung Wu, Ming-Daw Tsai. Identification of TIFA as a novel therapeutic target in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3123. doi:10.1158/1538-7445.AM2017-3123
Abstract 5307: Analysis of volatile organic compounds for the diagnosis of lung cancer
Authors: Takuya Inoue, Hironori Takagi, Yuki Owada, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Satoshi Muto, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Takeda Manami, Atsushi Sato, Hiroyuki Suzuki
Journal: Cancer Research (2017)

Abstract Background: Lung cancer is the leading cause of cancer-related deaths in the world. The prognosis of lung cancer depends on disease detection at an early stage. Recently, effectiveness of lung cancer screening by using low dose computed tomography scanning have been showing. However, it still has problems such as cost of screening and radiation exposure. Thus, less invasive and cost beneficial lung cancer screening procedure would be needed. In this context, several study to understand the efficacy of molecules from expiration of patients as a lung cancer screening were showing, but it was still controversial. In this study, we investigated to determine whether volatile organic compounds (VOC) from patients could be used for the detection for lung cancer by using novel small and unique absorbent material named MonoTrap . Method: The subjects’ gas was collected from skin and exhaled breath in a MonoTrap (GL sciences), and the VOCs were analyzed by gas chromatography/ mass spectrometry (GC/MS). First of all, we preliminary analyzed for both sample from skin and exhaled breath for 12 patients and 11 healthy volunteers to clarify which samples were more sensitive to diagnose lung cancer. Subsequently, each VOC was determined in detail for 7 healthy individuals and 4 lung cancer patients and these values were statistically analyzed. Results: By preliminary study, characteristics of VOC derived from skin were significantly correlated with cancer condition as compared with healthy volunteer by using comprehensive multivariate analysis. Therefore, we performed further quantitative analysis by targeting unique individual molecules derived from skin. In VOCs from skin, Mann-Whitney U test showed that 4-hydroxy-4-methyl-2-pentanone, hexadecane, and acetamide were significantly higher in lung cancer patients (p=0.036, p=0.006, p=0.036, respectively). Conclusion: In this study, we found that 3 kinds of VOCs could be a potential diagnostic biomarkers of lung cancer. Further prospective study is now planning to validate these data using large number samples. Citation Format: Takuya Inoue, Hironori Takagi, Yuki Owada, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Satoshi Muto, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Takeda Manami, Atsushi Sato, Hiroyuki Suzuki. Analysis of volatile organic compounds for the diagnosis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5307. doi:10.1158/1538-7445.AM2017-5307
Abstract 1960: Upregulation of MCP-1 regulates invasiveness in triple negative breast cancer
Authors: Pranabananda Dutta, Kimberly Paico, Inez Yuwanita, Yanyuan Wu, Marianna Sarkissyan, Jaydutt Vadgama
Journal: Cancer Research (2017)

Abstract Background: Triple negative breast cancer (TNBC) poses a critical problem for targeted therapy due to lack of significant expression of estrogen, progesterone receptor or Her2/neu oncogene. Hence, it is imperative to identify novel therapeutic strategies to target TNBC. Our study is aimed to examine whether Monocyte Chemoattractant Protein -1 (MCP-1) is a specific marker for TNBC metastasis. Experimental Design: We employed ELISA to determine secreted MCP-1 in cell conditioned media, as well as Real-time PCR to determine the status of MCP-1 in TNBC cell lines. Boyden chamber assay was used to determine the effect of recombinant MCP-1 on cellular metastasis. Cellular proliferation was measured with MTT assay. Immunofluorescence staining was utilized for protein of interest in breast cancer cells. MCP-1 knockdown was performed using lentiviral vector with shRNA targeting MCP-1 coding regions. Results: Our data show that the key inflammatory chemokine MCP-1 is upregulated in TNBC cell lines both transcriptionally as well as in terms of secretion compared to ER-positive cell line, MCF-7. MCP-1 stimulation in MDA-MB231 and MCF-7cells does not affect cellular proliferation. However, MCP-1 enhances metastatic properties of MDA-MB-231 cells along with BT-549 cells. Inhibiting Chemokine receptor 2/4 (CCR2/4), cognate receptor for MCP-1, with small molecule antagonists negatively affects invasiveness in MDA-MB-231 cells as evidenced by Boyden chamber assay. Knocking down MCP-1 by shRNA decreases cell invasion in TNBC cell line, BT-549 along with downregulation of key epithelial to mesenchymal transition markers, N-cadherin and Vimentin. MCP-1 induced cell invasion in TNBC may involve activation of p44/p42 MAPK Thr202/Tyr204. Conclusion: Our study suggests that high MCP-1 levels in TNBC is driving up metastasis potential in cells. Thus MCP-1 and its mediated pathways could be potential therapeutic targets for the treatment of TNBC. Citation Format: Pranabananda Dutta, Kimberly Paico, Inez Yuwanita, Yanyuan Wu, Marianna Sarkissyan, Jaydutt Vadgama. Upregulation of MCP-1 regulates invasiveness in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1960. doi:10.1158/1538-7445.AM2017-1960
Abstract 3135: Benzaldehyde suppresses the binding activity of overexpressed 14-3-3ζ to multiple signaling proteins in cancer cells
Authors: Jun Saitoh, Hideyuki Saya
Journal: Cancer Research (2017)

Abstract Benzaldehyde is the simplest aromatic aldehyde constituent of almonds and many fruits. Anticancer effect of Benzaldehyde was first reported in 1980, and multi-institutional clinical trials were performed in those days in Japan. However, trial was over without determination of effectiveness, only its’ safety was confirmed. The underlying mechanism why Benzaldehyde specifically suppresses growth of some particular cancer cells but not that of normal cells has not been elucidated. Therefore, we attempted to clarify the mechanism of anticancer effect of Benzaldehyde. We have previously reported that, in pancreatic cancer cell BxPC3 and in non-small cell lung cancer cell A549, Benzaldehyde inhibits PI3K/AKT/mTOR, STAT3, NFκB and ERK pathways, those are major signaling pathways activated in cancer cells. Effects of Benzaldehyde on multiple signaling pathways are found to be derived from regulation of 14-3-3 family proteins which interact with phosphorylation sites of various proteins of multiple signals. In BxPC3 cells, Benzaldehyde treatment reduced the phosphorylation levels of 14-3-3-binding sites. Moreover, we ectopically expressed seven isoforms of 14-3-3 in HEK293T cells and found that Benzaldehyde treatment significantly suppressed association of 14-3-3ζ with client proteins such as mTOR, Rictor, cRaf, STAT3 and FOXOs. The interaction of other isoforms of 14-3-3 with their client proteins was also partially reduced. But, the expression levels of those seven 14-3-3 isoforms were not significantly changed. Here we further analysis the Benzaldehyde-mediated 14-3-3ζ regulation, in HEK293 cells overexpressing 14-3-3ζ. Benzaldehyde significantly suppressed mTOR pathway while it was not observed in parental HEK293 cells. Furthermore, we performed pull down assay by using 14-3-3ζ GST tagged recombinant proteins and lysates of HEK293T and BxPC3 and found that Benzaldehyde treatment suppressed the interaction of 14-3-3ζ with cRaf, TSC2 and other 14-3-3ζ client proteins. From these data, we confirmed that Benzaldehyde is an inhibitor of the overexpressed 14-3-3ζ. Recent reports have shown that 14-3-3ζ is overexpressed in many cancers and acts as a signaling hub controlling the network of oncogenic pathways, suggesting that overexpressed 14-3-3ζ associates with carcinogenesis, metastasis and resistance for chemotherapy and radiation. Hence, Benzaldehyde is considered to be a new molecular target agent of 14-3-3ζ which promote and maintain cancer signals. Citation Format: Jun Saitoh, Hideyuki Saya. Benzaldehyde suppresses the binding activity of overexpressed 14-3-3ζ to multiple signaling proteins in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3135. doi:10.1158/1538-7445.AM2017-3135
The warm water in Langkawi awaits, but first…
Authors: Ebonie Kendra Rio, David Opar
Journal: British Journal of Sports Medicine (2017)

Welcome to another edition of BJSM that is jam-packed cover to cover with something for everyone. Let’s start with a great overview of the work by Faltstrom, ‘One Anterior Cruciate Ligament injury is enough! Focus on female football players’, as part of the PhD Academy Award series ( see page 1227 ). From there we move (pardon the pun) with the MapMyFitness app user guidelines ( see page 1223 ). Staying in the app world for just a moment, the republished BMJ article by Armstrong highlights considerations around the use of apps in the healthcare system ( see page 1229 ). In an area that is evolving rapidly, efforts to improve the endorsement of apps for healthcare have begun in earnest.

Interested in learning more about calf injury? Want to know who in the team …
Retinoic acid improves nephrotoxic serum–induced glomerulonephritis through activation of podocyte retinoic acid receptor α
Authors: Yan Dai, Anqun Chen, Ruijie Liu, Leyi Gu, Shuchita Sharma, Weijing Cai, Fadi Salem, David J. Salant, Jeffrey W. Pippin, Stuart J. Shankland, Marcus J. Moeller, Norbert B. Ghyselinck, Xiaoqiang Ding, Peter Y. Chuang, Kyung Lee, John Cijiang He
Journal: Kidney International (2017)
Abstract P270: Resin-Assisted Capture Reveals Unique Targets of Oxidation in Ischemic Preconditioning
Authors: Mark J Kohr, Junhui Sun, Angel Aponte, Guanghui Wang, Marjan Gucek, Charles Steenbergen, Elizabeth Murphy
Journal: Circulation Research (2011)

Proper maintenance of cellular thiol redox status is critical in the regulation of many processes that dictate normal myocardial function. Cell death signaling, in particular, is especially susceptible to alterations in thiol redox state. Myocardial ischemic preconditioning (IPC) is a redox sensitive process that is thought to provide protection from ischemia-reperfusion (IR) injury, in part, via reversible oxidative signaling. Protein S -nitrosylation (SNO) is a reversible, thiol-based modification that we and others have shown to provide cardioprotection by modulating the activity of target proteins and by shielding cysteine residues from irreversible oxidation. Additional thiol-based modifications are also thought to play an important role in cardioprotection, and these include disulfide bridges and glutathiolation. Therefore, it is of interest to identify these redox sensitive targets that are unique to IPC. Langendorff perfused mouse hearts were subjected to various perfusion protocols (control, IPC, IR, IPC-IR) and homogenized. Specific sites of oxidation were identified using oxidation-resin assisted capture (Ox-RAC) with mass spectrometry. Consistent with a role for oxidative signaling in cardioprotection, Ox-RAC analysis identified 56 proteins that were oxidized with IPC, but not IR or IPC-IR. These proteins are likely to be reversibly oxidized, as evidenced by the fact that they are oxidized with IPC, but are no longer oxidized following reperfusion (IPC-IR). These proteins may represent important targets in cardioprotective signaling and include F-actin-capping protein β, Egl nine homolog 1, and numerous members of the heat shock family (HSP60, HSP70, HSP90β). Heat shock proteins are important in the cellular stress response and have been shown to play an important role in cardioprotection. Pathway analysis also revealed that more than 30% (19 of 56) of the proteins uniquely oxidized following IPC were involved with cell death pathways. These proteins include Aminoacyl tRNA synthase complex-interacting multifunctional protein 1, Charged multivesicular body protein 5, and Lamin-A/C. These results indicate that the cardioprotective effects of IPC may occur, in part, through the reversible oxidation of key protein targets.
Abstract LB-035: Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis
Authors: Seung-Hyun Ro, Xiang Xue, Yatrik Shah, Jun Hee Lee
Journal: Cancer Research (2017)

Abstract The mTOR complex 1 (mTORC1) and endoplasmic reticulum (ER) stress pathways are critical regulators of intestinal inflammation and colon cancer growth. Sestrins are stress-inducible proteins, which suppress both mTORC1 and ER stress; however, the role of Sestrins in colon physiology and tumorigenesis has been elusive due to the lack of studies in human tissues or in appropriate animal models. In this study, we show that human SESN2 expression is elevated in the colon of ulcerative colitis patients but is lost upon p53 inactivation during colon carcinogenesis. In mouse colon, Sestrin2 was critical for limiting ER stress and promoting the recovery of epithelial cells after inflammatory injury. During colitis-promoted tumorigenesis, Sestrin2 was shown to be an important mediator of p53's control over mTORC1 signaling and tumor cell growth. These results highlight Sestrin2 as a novel tumor suppressor, whose downregulation can accelerate both colitis and colon carcinogenesis. Citation Format: Seung-Hyun Ro, Xiang Xue, Yatrik Shah, Jun Hee Lee. Tumor suppressive role of sestrin2 during colitis and colon carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-035. doi:10.1158/1538-7445.AM2017-LB-035
Risks of Medical Metaphors—Reply
Authors: Brit Trogen
Journal: JAMA (2017)

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Abstract 2273: Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations
Authors: Joyce Huang, Lesley Butler, Øivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan
Journal: Cancer Research (2017)

Abstract Background: Choline, methionine, and betaine are methyl group donors associated with DNA methylation. Diets deficient in choline and methionine have been shown to promote pancreatic carcinogenesis in experimental animals. We have previously reported an inverse association between dietary intake of choline and pancreatic cancer risk in a prospective cohort of Singapore Chinese. In the present study biomarkers of dietary choline and other methyl donor nutrients were evaluated in relation to pancreatic cancer risk. Method: Two case-control studies were nested within the Shanghai Cohort Study (129 cases and 258 matched controls) and the Singapore Chinese Health Study (58 cases and 104 matched controls). Concentrations of choline, methionine, betaine, dimethylglycine (DMG), and trimethylamine-N-oxide (TMAO) were measured by LC-MS/MS in pre-diagnostic serum samples. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression method with adjustment for potential confounders. Results: Choline, methionine, and betaine were moderately associated with each other (spearman correlation coefficient: 0.28 ~0.43). In the pooled analysis, serum choline, betaine, and methionine were inversely associated with risk of pancreatic cancer, while TMAO, an oxidative metabolite of choline produced by gut microbiota, was positively associated with risk of pancreatic cancer. Compared with the lowest quartile, ORs (95%CIs) of pancreatic cancer for the highest quartiles of choline, methionine, betaine, and TMAO were 0.37 (0.17-0.80), 0.39 (0.22-0.69), 0.49 (0.28-0.85), and 1.60 (0.94-2.74), respectively (all Ps for trend &amp;lt; 0.05). DMG was not associated with pancreatic cancer risk. Conclusion: The novel inverse associations of serum choline, methionine, and betaine with risk of pancreatic cancer support the notion that methyl groups related to DNA methylation may modulate the risk of pancreatic cancer development. The positive association between TMAO and pancreatic cancer risk suggested gut microbiota may play an important role in pancreatic carcinogenesis. Citation Format: Joyce Huang, Lesley Butler, Øivind Midttun, Renwei Wang, Aizhen Jin, Yu-Tang Gao, Per Ueland, Woon-Puay Koh, Jian-Min Yuan. Serum choline, methionine, betaine, dimethylglycine, and trimethylamine-N-oxide in relation to pancreatic cancer risk in two nested case-control studies in Asian populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2017-2273