tbuckley/cabot-search huggingface dataset:
Abstract 5333: Monoubiquitination inhibits the actin bundling activity of fascin
Authors: Shengchen Lin, Shuang Lu, Mentor Mulaj, Bin Fang, Tyler Keeley, Lixin Wan, Jihui Hao, Martin Muschol, Jianwei Sun, Shengyu Yang
Journal: Cancer Research (2017)

Abstract Fascin is the most frequently upregulated actin regulatory protein in metastatic tumors. The elevated expression levels of fascin universally correlate with poor clinical course and shorter survival across different cancer types. It is believed that fascin promotes cancer cell migration and invasion by crosslinking actin filaments into bundles. However, the molecular mehcanisms underlying the regulation of fascin bundling activity are not completely understood. In this study we examine the regulation of Fascin activity by monoubiquitination. IP and LC-MS/MS was used to identify the posttranslational modification of Fascin A novel chemical monoubiquitination method was employed to synthesize monoubiquitinated Fascin. The monoubiquitinated fascin was purified, and the effect of monoubiquitination on fascin bundling activity was determined using low speed sedimentation assay, fluorescence microscopy and transmission electron microscopy. Here we identified monoubiquitination as a novel mechanism that regulates fascin bundling activity and dynamics. The monoubiquitination sites were identified to be K247 and K250, two residues located in a positive charge patch at the actin binding site 2 (ABS2) of fascin. Using a chemical ubiquitination method, we synthesized chemically monoubiquitinated fascin (mUb-fascin) and determined the effects of monoubiquitination on fascin bundling activity and dynamics. Our data demonstrated that monoubiquitination decreased the fascin bundling EC50, delayed the initiation of bundle assembly and accelerated the disassembly of existing bundles. By analyzing the electrostatic properties on the solvent accessible surface of fascin, we proposed that monoubiquitination introduced steric hindrance to interfere with the interaction between actin filaments and the positively charged patch at ABS2. Mutation of the monoubiquitination sites (K247 and K 250) to arginine inhibited fascin monoubiquitination and enhanced pro-migration ability of fascin, supporting the notion that monoubiquitination inhibit fascin activity. We also identified Smurf1 as an E3 ligase regulating the monoubiquitination of fascin. Our findings revealed a previously unidentified regulatory mechanism for fascin, which will have important implications for the understanding of actin bundle regulation under physiological and pathological conditions. Citation Format: Shengchen Lin, Shuang Lu, Mentor Mulaj, Bin Fang, Tyler Keeley, Lixin Wan, Jihui Hao, Martin Muschol, Jianwei Sun, Shengyu Yang. Monoubiquitination inhibits the actin bundling activity of fascin [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 5333. doi:10.1158/1538-7445.AM2017-5333
Letter by Shi et al Regarding Article, “Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery: A Nationwide Study With a Systematic Review and Meta-Analysis”
Authors: Yu Shi, Hai Yu, Xiao-Yun Yang
Journal: Circulation (2017)

We read with great interest the article by Mariscalco et al. 1 It is an elegant research into the demonstration of the obesity paradox in cardiac surgery, which challenged the paradigm associating obesity with increased mortality.In this study, Mariscalco et al 1 further explored the relationship between body mass index (BMI) and mortality after cardiac surgery using a nationwide cohort and a well-established systematic review and meta-analysis.Notably, the authors made efforts to address residual confounding and reverse causation by multiple analyses.However, BMI provides a crude measurement of total adiposity without visceral fat or fat distribution.As mentioned by the authors, a single BMI measurement as an indicator of obesity has significant limitations and increased confounding.Thus, we suggest that adding measures of central obesity such as waist circumference (WC) or waist-to-hip ratio might provide additional information beyond BMI alone on mortality risk.For decades, epidemiological studies have shown that measures of central obesity such as WC or waist-to-hip ratio matter in assessing the risk of mortality.A large prospective cohort by Jacobs et al 2 emphasized the importance of WC as a risk factor for death in older patients despite BMI.Another pooled analysis similarly revealed that a higher WC was positively associated with higher mortality at all levels of BMI. 3 As for waist-to-hip ratio, Sahakyan et al 4 have indicated that US adults with normal weight but central obesity were linked to worse mortality than individuals with normal fat distribution.These reports may explain the imperfect accuracy of BMI in identifying patients with obesity, particularly in normal BMI range.However, the authors only used BMI to diagnose obesity.Therefore, we think that WC or waist-to-hip ratio in combination with BMI to identify obesity might increase the strength of their conclusion.In summary, using BMI as a unique marker of obesity may make the picture blurry among patients in this study.We would get confused regarding whether their article demonstrated obesity paradox or BMI paradox.More data elements, such as measures of central obesity, might improve our understanding of risk assessment for obesity-related mortality after cardiac surgery.
Abstract 1420: The endonuclease Metnase promotes base excision repair of Clustered abasic DNA lesions
Authors: Aruna S. Jaiswal, Elizabeth A. Williamson, Bhavita Patel, Gayathri Srinivasan, Satya Narayan, Robert A. Hromas
Journal: Cancer Research (2017)

Abstract Metnase, a human SET-transposase fusion protein contains two functional domains: a SET domain and transposase domain. Transposase domain exhibit strand transfer and end joining activity while set domain is responsible for histone lysine methyltransferase activity (KMT). Metnase also increases the efficiency of double strand break repair by non-homologous end joining (NHEJ); however, its role in the excision of clustered DNA damage remains to be investigated. We hypothesize that 5’-3’ endonuclease activity of metnase could possibly substitute for APE1 in BER and serve as an alternative initiator of BER in tumor cells lacking APE1. In the present study, we examined in vitro endonuclease activity of Metnase using abasic site containing artificial DNA, and describe its activity in BER. Its unique 5’ endonuclease activity was selective only for abasic lesions, but not other base modifications such as 8-oxoguanine, uracil, hypoxanthine or xanthenes. Metnase specifically initiates removal of reduced abasic lesions from DNA, and allows completion of short-patch or long-patch BER. APE1 has difficulty cleaving 5’ of clustered abasic lesions. This endonuclease that promotes BER in clustered oxidative DNA damage is not known. Metnase also cleaves multiple abasic lesions (clustered DNA damage) and facilitates the repair of DNA if the multiple DNA damages are 3 or more nucleotides apart on the opposing strands. However, repair of multiple DNA damages remains inefficient if these are in close proximity of each other (&amp;lt; 3nt apart on the opposing strands) and results in DNA double strand break (DSB). These results suggest that Metnase can promote BER of oxidative nucleotides, where APE1 is unable to function. Citation Format: Aruna S. Jaiswal, Elizabeth A. Williamson, Bhavita Patel, Gayathri Srinivasan, Satya Narayan, Robert A. Hromas. The endonuclease Metnase promotes base excision repair of Clustered abasic DNA lesions [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 1420. doi:10.1158/1538-7445.AM2017-1420
Abstract 5534: Runx1 possesses anti-tumor activity and inhibits stemness in breast cancer cells
Authors: Deli Hong, Andrew J, Fritz, Kristiaan Finstad, Mark P. Fitzgerald, Janet L. Stein, Jane Lian, Gary S. Stein
Journal: Cancer Research (2017)

Abstract Background: Despite advances in detection and therapies, breast cancer is still the most common malignant disease in women worldwide. Cancer stem cells (CSC) play an important role in formation, growth, drug-resistance and recurrence of tumors. Transcription factor Runx1 has received recent attention for its potential tumor suppressor activity in solid tumors. We previously showed that Runx1 represses the epithelial to mesenchymal transition in breast cancer cells. The objective of the present study is to investigate Runx1 functional effects on cellular activities, and its contribution to inhibiting CSC-like properties in breast cancer cells. Methods: We generated Runx1 overexpression and Runx1 knockdown stable cell lines in both malignant MCF10AT1 and metastatic MCF10CA1a cells. Cells were analyzed for tumorsphere formation, protein (Western) and RNA (RT-qPCR) expression analysis. Cellular activity assays (cell proliferation, migration, and invasion) were performed to measure the tumorigenic potential of the cells. Xenograft studies were used to determine whether Runx1 overexpression in breast cancer cells represses tumor growth in vivo. Results: Upon overexpressing Runx1, both MCF10AT1 and MCF10CA1a cells reduce their proliferation, migration and invasion, which support the concept that Runx1 acts as a tumor suppressor in breast cancer cells. Notably, overexpressing Runx1 inhibited the formation of tumorspheres and effectively reduced the stem-like population in these two breast cancer cells. These observations are consistent with the results of Runx1 knock-down in early stage ER positive MCF7 breast cancer cells which showed increased tumorsphere formation efficiency. Furthermore, Runx1 tumor suppressor activity was confirmed in mouse xenograft by showing that Runx1 overexpression inhibits tumor growth. Conclusion: Our studies show that Runx1 inhibits proliferation, migration, and invasion, reflecting its tumor suppressor activity. Runx1 mediated reduction of tumorsphere formation suggests that Runx1 also contributes significantly to inhibit the population of the breast cancer stem cells. Therefore these studies offer Runx1 as a novel bio-therapeutic molecule for breast cancer intervention. Citation Format: Deli Hong, Andrew J, Fritz, Kristiaan Finstad, Mark P. Fitzgerald, Janet L. Stein, Jane Lian, Gary S. Stein. Runx1 possesses anti-tumor activity and inhibits stemness in breast 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 5534. doi:10.1158/1538-7445.AM2017-5534
Abstract 5508: Histone modifications affect differential regulation of TGF-beta-induced Nox4 by p53
Authors: Howard E. Boudreau, Wei Feng MA, Agnieszka Korzeniowska, Jonathan J. Park, Thomas L. Leto
Journal: Cancer Research (2017)

Abstract Recent studies suggest p53 plays an important role in TGF-β-mediated cell signaling and migration. Previously, we showed wild-type (WT) and mutant (mt) forms of p53 differentially regulate reactive oxygen species (ROS) generation by NADPH oxidase-4 (NOX4). We found that WT-p53 suppresses TGF-β-induced NOX4, ROS production, and cell migration, whereas tumor-associated p53-mt proteins enhance NOX4 expression and cell migration by TGF-β/SMAD3-dependent mechanisms. In this study, we utilized The Cancer Genome Atlas (TCGA) to perform statistical analysis on gene expression data from primary tumor samples and found a correlation between tumors with p53 “hotspot” mutations and increased NOX4 mRNA expression. Furthermore, we examined the basis of human NOX4 promoter regulation by p53 and SMAD3. By deletion analysis of the NOX4 promoter, we found two critical SMAD3 binding elements (SBE) are also required for p53-dependent promoter activity. Conversely, promoter activity was abolished by dose-dependent heterologous expression of p53-WT. Moreover, expression of active SMAD3 resulted in robust NOX4 promoter activity, which was abolished when co-expressed with p53-WT. Chromatin immunoprecipitation (ChIP) analysis revealed SMAD3 and p53-WT or p53-mt were associated with specific SBEs and p53 response elements (p53-RE) in a TGF-β-dependent manner. Interestingly, the repressive effect by p53- WT on NOX4 was relieved upon treatment with histone deacetylase (HDAC) inhibitors or mutation of the transactivation domain. Overexpression of p300, a known p53-mt-binding transcriptional co-regulator and histone acetyltranserfase (HAT), enhanced p53-mt-mediated NOX4 promoter activity, whereas the HAT-inactive p300-mt reduced promoter activity. Furthermore, overexpression of p53-mt augmented TGF-β-mediated acetylation of histones associated with the NOX4 promoter. Finally, scratch wound assays demonstrated NOX4 and p300 promote TGF-β/mutant p53-mediated cell migration. Collectively, these data and provide new insight on TGF-β/SMAD3 and mutant p53-mediated NOX4 induction involving epigenetic control of NOX4 in tumor cell migration. Citation Format: Howard E. Boudreau, Wei Feng MA, Agnieszka Korzeniowska, Jonathan J. Park, Thomas L. Leto. Histone modifications affect differential regulation of TGF-beta-induced Nox4 by p53 [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 5508. doi:10.1158/1538-7445.AM2017-5508
Abstract 2393: Decreased expression of 5-hydroxymethylcytosine is associated with grade of malignancy in lung cancer
Authors: Yoshiaki Tominaga, Ken-ichi Ito, Jun Nakayama
Journal: Cancer Research (2017)

Abstract Purpose: The ten-eleven translocation (TET) proteins are critical regulators in epigenetic modification. It is well known that TET proteins catalyze the oxidation of 5-methylcytosine (5-mC) to generate 5-hydroxymethylcytosine (5-hmC), and 5-hmC levels reflect diverse functions of TET proteins. It has been reported that the expression of 5-hmC in cancer tissues is decreased compared with that in normal tissues in several organs. However, 5-hmC expression in lung cancer has not been fully analyzed. To examine whether or not 5-hmC was associated with phenotypes or progression of lung cancer, we evaluated 5-hmC expression in a variety of histological types of lung cancers. Materials and methods: The expression of 5-hmC was analyzed by immunohistochemistry in 109 paired specimens of lung cancer and adjacent normal tissues obtained from the patients underwent operation at Shinshu University Hospital. Eighty-nine adenocarcinomas, 17 squamous cell carcinomas, two large cell carcinomas, and one small cell carcinoma were analyzed in the study. Results: 5-hmC expression in female was significantly lower than that in male, and was lower in smokers than non-smokers. 5-hmC expression was positive in 34.1±22.0% of lung cancer tissues and 69.4±18.8% of normal tissues. The expression of 5-hmC was significantly decreased in the lung cancer tissues compared with that in the adjacent normal tissues (p&amp;lt;0.001). With regard to the histological types, the positive ratios of 5-hmC expression were 36.0±21.7% in adenocarcinoma, 24.0±20.3% in squamous cell carcinoma, 8.0±7.3% in large cell carcinoma, and 13.0% in small cell carcinoma. Thus, the frequency of positive expression of 5-hmC was decreased in accordance with the increase of grade of malignancy of lung cancer, and a negative correlation between 5-hmC expression and the grade of malignancy of lung cancer was observed. On the other hand, no difference of the expression of 5-mC was observed between lung cancer tissues and normal tissues. Conclusions: Our results indicate a possibility that 5-hmC may be related to carcinogenesis and progression or differentiation of lung cancer. Citation Format: Yoshiaki Tominaga, Ken-ichi Ito, Jun Nakayama. Decreased expression of 5-hydroxymethylcytosine is associated with grade of malignancy in 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 2393. doi:10.1158/1538-7445.AM2017-2393
Abstract 3398: The genomic and transcriptomic analysis of nine widely invasive follicular thyroid carcinomas (wiFTC) in Korean patients
Authors: Angela Byuri Cho, Seong-Keun Yoo, Min-Hwan Sohn, Jong-Yeon Shin, Su-jin Kim, Eun Kyung Lee, Young Joo Park, Jeong-Sun Seo
Journal: Cancer Research (2017)

Abstract Widely invasive follicular thyroid carcinoma (wiFTC) can be characterized from minimally invasive follicular thyroid carcinoma (miFTC) as it exhibits poor prognosis with frequent distant metastasis. We have reported that miFTC shows similar mutational and transcriptional spectrum when compared to follicular adenoma (FA). Here, we performed whole-exome and transcriptome sequencing on wiFTC samples to define their aggressive biological features by comparing with 30 miFTCs and 26 FAs. Well-known miFTC and FA driver genes, NRAS (66.67%), HRAS (11.11%), and EIF1AX (11.11%), were identified in wiFTC. TERT mutation was found in all samples which can explain its aggressive feature. Chromosome 17p/q amplification was found in most wiFTC samples as well as 22q deletion that is frequently aberrant in H/K/NRAS mutated thyroid cancers. Most of wiFTCs were classified as RAS-like (66.67%) and a few were BRAF-like (22.22%) and NBNR (11.11%) molecular subtypes. From differentially expressed gene analysis, we found 1,832 and 1,384 up-regulated and down-regulated genes when wiFTC was compared to miFTC and FA together. wiFTC had many overlapped down-regulated genes as poorly differentiated and anaplastic thyroid carcinoma which also supports its aggressiveness. Through weighted correlation network analysis we have established gene expression networks, highly associated with wiFTC, that have SIRT6 and TGFBR2 as the central nodes. In this study, we demonstrated the distinctive mutational and transcriptional characteristics of wiFTC hence found the underlying molecular mechanism for its aggressiveness. Citation Format: Angela Byuri Cho, Seong-Keun Yoo, Min-Hwan Sohn, Jong-Yeon Shin, Su-jin Kim, Eun Kyung Lee, Young Joo Park, Jeong-Sun Seo. The genomic and transcriptomic analysis of nine widely invasive follicular thyroid carcinomas (wiFTC) in Korean patients [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 3398. doi:10.1158/1538-7445.AM2017-3398
Abstract 2230: Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate cancer cells
Authors: Rajnee Kanwal, Xiaoping Yang, Eswar Shankar, Sanjay Gupta
Journal: Cancer Research (2017)

Abstract The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex (PRC2) and is involved in chromatin remodeling and gene silencing through its methylation of histone H3 on lysine 27 (H3K27). Specifically, trimethylation of H3K27 is associated with gene silencing and plays critical role in cancer initiation and progression. Therefore, blocking EZH2 catalytic activity may present a valid preventive and/or therapeutic strategy for the treatment of cancers with EZH2 overexpression including prostate cancer. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone luteolin (3’, 4’, 5, 7-tetrahydroxyflavone) as a specific inhibitor of EZH2 with preferential blocking of its catalytic site. Here we report luteolin, in micro molar range, inhibits EZH2 catalytic activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays. Treatment of human prostate cancer DU145 and 22Rv1 cells, which possess high constitutive EZH2 expression, with 5-20 μM luteolin significantly inhibits EZH2 and SUZ12 protein expression in dose and time dependent manner, although luteolin treatment did not affect protein expression of EED and RbAp46/48 protein, other members of PRC2 complex. Treatment of both cell lines with luteolin also reduced H3K27me3 and H3K27me2 protein and its enzymatic activity in dose and time dependent manner without affecting total H3 protein. In addition, luteolin was also effective in suppressing in vitro methylation performed using recombinant PCR2 complex. These events led to increase in the expression of downstream tumor suppressor genes including E-cadherin, SLIT2 and TIMP3, respectively. Interestingly, treatment of cells with proteasome inhibitor, MG132 together with luteolin did not prevent EZH2 degradation indicating that proteasomal degradation might not contribute to EZH2 inhibition. Taken together, our study suggest that luteolin acts on the catalytic binding site of EZH2 to exhibit downregulation of histone H3 methylation and could be developed as a potential promising agent for the prevention and/or treatment of various human cancers including prostate cancer with EZH2 overexpression. Citation Format: Rajnee Kanwal, Xiaoping Yang, Eswar Shankar, Sanjay Gupta. Luteolin selectively inhibits EZH2 and blocks H3K27 methylation in prostate 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 2230. doi:10.1158/1538-7445.AM2017-2230
Optimum support by high-flow nasal cannula in acute hypoxemic respiratory failure: effects of increasing flow rates
Authors: Tommaso Mauri, Laura Alban, Cecilia Turrini, Barbara Cambiaghi, Eleonora Carlesso, Paolo Taccone, Nicola Bottino, Alfredo Lissoni, Savino Spadaro, Carlo Alberto Volta, Luciano Gattinoni, Antonio Pesenti, Giacomo Grasselli
Journal: Intensive Care Medicine (2017)