bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3220: Lichen derived polyphenols as potential anticancer drugs
Authors: Shrestha Gajendra , Xiao Michael , Robison Richard , Clair Larry L. St. , O'Neill Kim 
Published: May 2015

Abstract
Polyphenols such as resveratrol, curcumin, (-)-epigallocatechin 3-gallate (EGCG) etc. have been shown to have anticancer properties. The anticancer activities of polyphenols include, but are not limited to, anti-oxidative effects, pro-apoptosis, DNA damage, anti-angiogenic effects, and immunostimulation. Lichens, symbiotic systems involving a fungus and an alga and/or cyanobacterium, are a rich source of polyphenols. Based on our previous research we have demonstrated that crude extracts of different lichen species affect cell proliferation, cell cycle dynamics, and cause apoptosis in Burkitt's lymphoma (Raji cells). This research examines the effects of a lichen-derived polyphenol compound, usnic acid, on human colon adenocarcinoma (HT-29) cells. We treated HT-29 cells with various concentrations (10, 30 and 50 µg/ml) of usnic acid for 24 hours. Although the viability was not affected by the treatment, there was a significant decrease in cell proliferation in dose-dependent manner. We also observed that after treatment, the morphology of treated cells was completely different from that of untreated control cells. Using transmission electron microscopy (TEM), we studied the morphological differences between control and treated HT-29 cells. The TEM micrographs clearly show that usnic acid damaged the mitochondria, reduced the amount of free ribosomes, and also distorted the shape of the nucleus. As the treatment of HT-29 with usnic acid reduced the rate of cell proliferation significantly, we investigated the effects of usnic acid on HT-29 cell cycle dynamics. Our results indicate that with the higher usnic acid concentrations (30 and 50 µg/ml) the cell cycle was stopped at the G0/G1 stage. These results further document the pattern of decreasing proliferation of HT-29 cells treated with usnic acid. With the distortion of the nucleus following exposure to usnic acid, we also investigated the effects of usnic acid on DNA the HT-29 cells. We performed a single cell gel electrophoresis (Comet Assay) to study the DNA damaging effects of various concentrations of usnic acid. Our results showed that there was a dose dependent increase in damage to the HT-29 cells' DNA resulting in 56.7% of the total DNA moving into the comet tail at 50 µg/ml concentration of usnic acid.
These preliminary results suggest that lichen derived polyphenols could be a potential source of anticancer drug therapies. However, additional research is needed to further validate these findings.
Citation Format: Gajendra Shrestha, Michael Xiao, Richard Robison, Larry L. St. Clair, Kim O'Neill. Lichen derived polyphenols as potential anticancer drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3220. doi:10.1158/1538-7445.AM2014-3220
Abstract 3232: Optimization of a potent stapled helix peptide that binds to Replication Protein A
Authors: Waterson Alex G. , Frank Andreas O. , Vandgamudi Bhavatarini , Feldkamp Michael D. , Souza-Fagundes Elaine M. , Luzwick Jessica W. , Cortez David , Olejniczak Edward T. , Rossanese Olivia W. , Chazin Walter J. , Fesik Stephen W. 
Published: May 2015

Abstract
Replication Protein A (RPA) is a major regulator of checkpoint activation and enhanced DNA repair in cancer cells. In response to genotoxic stress, the RPA complex binds to and protects ssDNA while serving as a scaffold to recruit critical checkpoint and DNA-damage response proteins through the N-terminal region of the 70 kDa subunit of RPA (RPA70N). Specific disruption of the protein-protein interactions mediated by the RPA70N domain has the potential to produce selective killing of cancer cells without the risk of cytotoxicity due to interference in the ssDNA-binding function.
Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions. However, their utility can be limited due to difficulties often encountered during attempts to improve the binding affinity to the target. Here, we report the discovery and optimization of a potent stapled helix peptide probe, derived from the endogenous RPA binding partner ATRIP (ATR-interacting protein), that binds to and inhibits the RPA70N protein-protein interaction surface. Alanine scanning, charge abrogation, and rational sequence optimization resulted in a peptide with a 100-fold potency gain over the native sequence and improved physical characteristics.
In addition to the application of these traditional strategies, we describe a novel approach for efficiently designing peptides containing unnatural amino acids. This method involves the incorporation of an unnatural amino acid inspired by the structure activity relationships of small molecules that bind to the same site on the protein. Use of this approach produced stapled peptides with dramatic increases in binding affinity to RPA70N relative to aooIn al peptide containing only natural amino acids. The optimized peptides are cell penetrant, able to enter the nucleus, and co-localize with RPA in the nucleus at sites of DNA damage. Such a peptide may serve as a probe molecule to explore both the effects of RPA inhibition on the DNA damage response and the therapeutic potential of RPA inhibition as a cancer target.
Citation Format: Alex G. Waterson, Andreas O. Frank, Bhavatarini Vandgamudi, Michael D. Feldkamp, Elaine M. Souza-Fagundes, Jessica W. Luzwick, David Cortez, Edward T. Olejniczak, Olivia W. Rossanese, Walter J. Chazin, Stephen W. Fesik. Optimization of a potent stapled helix peptide that binds to Replication Protein A. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3232. doi:10.1158/1538-7445.AM2014-3232
Abstract 3235: Identification of the potential inhibitors of DNA polymerase kappa
Authors: Sullivan Christopher B. , Minko Irina G. , Yamanaka Kinrin , McCullough Amanda K. , Lloyd Stephen 
Published: May 2015

Abstract
Background and Purpose:
The therapeutic effect of many anticancer agents is due to induction of replication-blocking DNA lesions. Human DNA polymerase kappa (pol κ) is a trans-lesion synthesis polymerase that can catalyze direct replication past minor groove lesions, such as the one induced by mitomycin C. Pol κ has been found to be upregulated in ∼70% of gliomas and its upregulation associated with poorer prognosis in glioma patients. Therefore, small molecule inhibitors of pol κ in combination with chemotherapy may be useful in the treatment of cancer with upregulated pol κ expression.
Methodology:
Lead hits were initially identified from a screen of a library of ∼400,000 compounds at 5 different concentrations, using a strand-displacement DNA synthesis approach. From several thousand potential hits, these were systematically triaged, with 335 potential inhibitors of pol κ identified for further analyses.
A direct, gel-based primer extension assay was used to test for inhibitory effects of these 335 bioactive compounds. In this assay, pol κ was preincubated with individual compounds, and added to 32P-labeled DNA substrate to initiate primer extensions. The reactions were incubated for 30 minutes at room temperature and terminated by the addition of a DNA-denaturing solution. The products were then separated through a 15% acrylamide gel and visualized with a PhosphorImager screen. Compounds that significantly inhibited the polymerization activity of pol κ were further tested for the ability to intercalate into DNA by incubation with double-stranded DNA for 15 minutes at room temperature, followed by separation through a 1% agarose gel. DNA was stained with ethidium bromide and visualized by Alpha Innotech ChemiImager.
Results:
Through a series of rigorous triaging procedures, this investigation identified a total of 42 small molecule inhibitors of pol κ with the estimated potencies being the low micromolar range or less. All 42 compounds were confirmed not to exhibit their inhibitory effects through DNA intercalation. These compounds need to be further tested with other members of the Y family polymerase to ensure their specificity to pol κ and determine if they are amenable to medicinal chemistry.
Conclusion:
Further investigation and characterization of these compounds will allow for a more efficient therapeutic approach in patients who have upregulated pol κ receiving chemotherapy.
Citation Format: Christopher B. Sullivan, Irina G. Minko, Kinrin Yamanaka, Amanda K. McCullough, Stephen Lloyd. Identification of the potential inhibitors of DNA polymerase kappa. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3235. doi:10.1158/1538-7445.AM2014-3235
Abstract 3240: Proximal human aberrant crypt foci as surrogate markers of colorectal cancer risk
Authors: Drew David A. , Hanley Matthew P. , Mo Allen , Goh Gyuhyeong , Horelik Nicole A. , Devers Thomas J. , Levine Joel , Stevens Richard G. , Grady James J. , Rosenberg Daniel W. 
Published: May 2015

Abstract
Despite effective use of screening colonoscopy, colorectal cancer (CRC) remains the second leading cause of cancer-related deaths. ‘Interval’ cancers, or those occurring between screening colonoscopy procedures, are often found within the proximal (right) colon, underscoring the need for advanced screening approaches using high-definition chromoendoscopy. To better define the colonic mucosa at-risk, we have focused considerable effort on identification and molecular analysis of aberrant crypt foci (ACF), an early macroscopically detectable lesion commonly found in the distal colon. ACF may serve as a surrogate marker of cancer risk, but have rarely been studied within context of the right colon. We hypothesize that proximal ACF may associate with risk factors for CRC and act as a surrogate marker for CRC risk. While distal ACF are frequent (approximately 13 per patient) proximal ACF are not (&lt;1 per patient). We report that subjects with at least one proximal ACF are significantly more likely to have higher ACF multiplicity (p = 0.0002) and more importantly, are more likely to harbor synchronous colonic neoplasia (OR=2.38 [1.24-4.59], p = 0.0087). Histologically, proximal ACF are more frequently dysplastic (41%) compared to distal colon ACF (8%). ACF (n=49) were analyzed for a panel of oncogenes and tumor suppressors using mass spectrometry (MS)-based genotyping (Sequenom). Among the 112 targets analyzed, after KRAS (20%) and BRAF (22%), APC mutations (12%) were most common and specifically associated with dysplasia. Due to their diminutive size and flat morphology, proximal ACF are almost certainly missed during routine colonoscopy. However, our findings suggest that the identification, removal and analysis of proximal ACF may be especially important during screening colonoscopy of high-risk individuals.
Citation Format: David A. Drew, Matthew P. Hanley, Allen Mo, Gyuhyeong Goh, Nicole A. Horelik, Thomas J. Devers, Joel Levine, Richard G. Stevens, James J. Grady, Daniel W. Rosenberg. Proximal human aberrant crypt foci as surrogate markers of colorectal cancer risk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3240. doi:10.1158/1538-7445.AM2014-3240
Abstract 325: TDP-43 promotes glioblalstoma cell survival under nutrient deprivation condition via activating autophagy
Authors: Chang Yun-Ching , Lin Tzu-Wei 
Published: May 2015

Abstract
Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults. TDP-43 (TARDBP), a DNA and RNA binding protein, is well known to play a key role in RNA processing, including involving in the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recent reports suggested that TDP-43 may participate to the regulation of metabolic glycolysis in cancer. Overcoming metabolic stress is critical for cancer cell survival and growth in nutrient deprivation condition. Herein we found TDP-43 overexpression promotes glioblastoma cell survival and suppressed the activated-form levels of caspase 3 protein under nutrient deprivation. Overexpression of TDP-43 increased the tumorigenicity as determined by anchorage-independent growth assay and xenografts in immunocompromised mice model. Under nutrient deprivation, we also found that TDP-43-overexpression induced autophagy. By this study, we presume TDP-43 enhanced GBM cells tumorigincity, activated autophagy and inhibited cell death under nutrient deprivation condition. TDP-43 is potentially the new aspects for understanding the tumorigenicity and metablolic regulation for malignant brain tumors and GBM.
Citation Format: Yun-Ching Chang, Tzu-Wei Lin. TDP-43 promotes glioblalstoma cell survival under nutrient deprivation condition via activating autophagy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 325. doi:10.1158/1538-7445.AM2014-325
Abstract 3255: Single oral dose pharmacokinetics of cancer chemopreventive phytochemicals from Angelica gigas Nakai in men and women
Authors: Zhang Jinhui , Li Li , Hale Thomas W. , Chee Wayne , Xing Chengguo , Jiang Cheng , Lü Junxuan 
Published: May 2015

Abstract
The ethanol extracts of the root of Korean herb Angelica gigas Nakai (AGN) have promising anti-cancer, anti-nociceptive and other activities in rodent models. It is currently believed that the pyranocoumarin decursin and its structural isomer decursinol angelate (DA) in such extracts contribute to the in vitro anti-cancer activity.
We and others have demonstrated that both decursin and DA were extensively converted to decursinol (DOH) in rodents. However, our in vitro experiments using human and rodent S9 fractions suggested the hypothesis that decursin and/or DA might be metabolized differently in humans. Given the notable difference in the biological activities between decursin/DA and
DOH, we conducted a single oral dose pharmacokinetic study of these phytochemicals in healthy volunteers to address a key question for human translatability of preclinical animal studies of decursin, DA or AGN extract. Knowing that chemicals other than decursin and DA in AGN had minimal effect on their absorption and metabolism in rodents, we used an AGN-based dietary supplement as the study drug in compliance with the FDA and institutional requirements. In all, 20 healthy subjects (10 men and 10 women) had completed the study in full.
AGN product was very well tolerated by all subjects as evidenced by plasma biochemistry, complete blood cell count and physical examination. Analyzing plasma samples using UHPLC-MS/MS showed that, though humans metabolized DA slightly slower than rodents, both decursin and DA were extensively converted to DOH. Gender and racial/ethnicity do not appear to dramatically affect the PK parameters. Since we show here that humans metabolize decursin and DA in similar pattern with rodents, the anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarker data generated in rodent models will likely be relevant for human translation. In spite of the limited number of healthy individuals in the trial, this project demonstrated feasibility for our team to consider translational research in disease-oriented populations.
Citation Format: Jinhui Zhang, Li Li, Thomas W. Hale, Wayne Chee, Chengguo Xing, Cheng Jiang, Junxuan Lü. Single oral dose pharmacokinetics of cancer chemopreventive phytochemicals from Angelica gigas Nakai in men and women. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3255. doi:10.1158/1538-7445.AM2014-3255
Abstract 3257: ERC/mesothelin is expressed in human gastric cancer tissues and cell lines
Authors: Ito Tomoaki , Kajino Kazunori , Abe Masaaki , Sato Koichi , Maekawa Hiroshi , Sakurada Mutsumi , Orita Hajime , Wada Ryo , Kajiyama Yoshiaki , Hino Okio 
Published: May 2015

Abstract
Background: ERC/mesothelin is expressed in mesothelioma and other malignancies. The ERC/mesothelin gene (MSLN) encodes a 71 kDa precursor protein, which is cleaved to yield 31 kDa N-terminal (N-ERC/mesothelin) and 40 kDa C-terminal (C-ERC/mesothelin) proteins. N-ERC/mesothelin is a soluble protein and has been reported to be a diagnostic serum marker of mesothelioma and ovarian cancer. Gastric cancer tissue also expresses C-ERC/mesothelin, but the significance of serum N-ERC levels for diagnosing gastric cancer has not yet been studied. We examined the latter issue in this study as well as C-ERC/mesothelin expression in human gastric cancer tissues and cell lines.
Methods: We immunohistochemically examined C-ERC/mesothelin expression in tissue samples from 50 cases of gastric cancer, and we also assessed the C-ERC/mesothelin expression of 6 cancer cell lines (MKN-1, MKN-7, MKN-74, NUGC-3, NUGC-4 and TMK-1) using the reverse transcription-polymerase chain reaction, flow cytometry, immunohistochemistry, and immunoblotting. We also examined the N-ERC/mesothelin concentrations of the supernatants of cultured cells and the sera of gastric cancer patients using an ELISA.
Results: N-ERC/mesothelin was detected in the supernatants of 3 cell lines (MKN-1, NUGC-4, and TMK-1) by ELISA, but its concentration in the sera of gastric cancer patients was almost same as that observed in the sera of the normal controls. In the gastric cancer tissues, C-ERC/mesothelin expression was associated with lymphatic invasion, as reported by Einama et al.
Conclusion: N-ERC/mesothelin was secreted into the supernatants of gastric cancer cell lines, but did not appear to be a useful serum marker of gastric cancer.
Citation Format: Tomoaki Ito, Kazunori Kajino, Masaaki Abe, Koichi Sato, Hiroshi Maekawa, Mutsumi Sakurada, Hajime Orita, Ryo Wada, Yoshiaki Kajiyama, Okio Hino. ERC/mesothelin is expressed in human gastric cancer tissues and cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3257. doi:10.1158/1538-7445.AM2014-3257
Abstract 3260: Male pattern baldness increases the risk of aggressive prostate cancer: A prospective analysis of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial
Authors: Zhou Cindy K. , Pfeiffer Ruth M. , Cleary Sean D. , Hoffman Heather J. , Levine Paul H. , Chu Lisa W. , Hsing Ann W. , Cook Michael B. 
Published: May 2015

Abstract
Purpose: Androgenic actions are thought to underlie the development of both male pattern baldness and prostate cancer. However, results from previous studies of the relationship between these two phenotypes have been inconsistent. Therefore, we investigated the association of male pattern baldness at age 45 years with overall and aggressive prostate cancer risk in a large, prospective cohort–the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.
Methods: We included 39,070 men, from the usual care and screening arms of the trial, who were cancer-free at start of follow-up. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazards regression models with age as the underlying time-scale.
Results: During follow-up (median=2.78 years), 1,138 incident prostate cancer cases were diagnosed, 578 of which were aggressive (Gleason score ≥ 7, stage ≥ III, or fatal). Frontal + vertex balding at age 45 years, compared with no balding, was not associated with overall prostate cancer risk (HR=1.19, 95%CI: 0.98, 1.45), but was associated with increased risk of aggressive prostate cancer (HR=1.42, 95%CI: 1.10, 1.83). Adjustment for covariates did not significantly alter these estimates. Other classes of male pattern baldness were not associated with the overall or aggressive prostate cancer.
Conclusion: Our analysis indicates that frontal + vertex balding at age 45 years increases the risk for future development of aggressive prostate cancer, and supports the possibility of overlapping pathogenesis.
Citation Format: Cindy Ke Zhou, Ruth M. Pfeiffer, Sean D. Cleary, Heather J. Hoffman, Paul H. Levine, Lisa W. Chu, Ann W. Hsing, Michael B. Cook. Male pattern baldness increases the risk of aggressive prostate cancer: A prospective analysis of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3260. doi:10.1158/1538-7445.AM2014-3260
Abstract 3265: Dual specificity phosphatase 4 gene expression in triple negative breast cancer
Authors: Baglia Michelle L. , Cai Qiuyin , Zheng Ying , Wu Jie , Su Yinghao , Ye Fei , Bao Ping-Ping , Cai Hui , Zhao Zhiguo , Zheng Wei , Lu Wei , Shu Xiao-Ou 
Published: May 2015

Abstract
Background
Triple negative breast cancer (TNBC) is an aggressive cancer with limited treatment options. A recent report suggested that dual specificity phosphatase 4 (DUSP4) may be a potential marker of chemotherapy resistance for TNBC.
Methods
We measured the DUSP4 gene expression levels in breast cancer tissue from 469 TNBC patients who participated in the Shanghai Breast Cancer Survival Study and evaluated their association with breast cancer recurrence/breast cancer mortality and total mortality. Study participants were diagnosed with incident breast cancer between March 2002 and April 2006 and aged between 20 and 75 years. Information on breast cancer diagnosis and treatment, as well as demographic, lifestyle, and disease progression information, were collected approximately 6 months after cancer diagnosis and reassessed at 18, 36, and 60 months after diagnosis in follow-up interviews. Expression levels of transcript variant 1 (NM_001394) and transcript variant 2 (NM_057158) of DUSP4 gene were measured by the NanoString nCounter assay using RNA obtained from formalin-fixed, paraffin-embedded tissue sections. Cox regression analysis was applied in the data analyses with adjustment for clinical and demographic factors.
Results
Of the 469 TNBC participants in this study, 100 deaths and 92 recurrences/breast cancer deaths were documented over a median follow-up of 5.3 years (range, 0.7-8.9 years). The expression of the two DUSP4 isoforms were highly correlated (r=0.76). Low DUSP4, particularly variant 1 (NM_001394), expression levels were associated with increased recurrence/breast cancer mortality and overall mortality. After adjustment for age at diagnosis and TNM stage, the hazard ratios comparing those with DUSP4 (variant 1) expression levels below the median to those above the median were 1.97 (95% confidence interval (CI): 1.27, 3.05) for recurrence/breast cancer mortality and 2.09 (95% CI: 1.38, 3.17) for overall mortality. Adjustment for expression levels of MKI67 and TP53, common treatment types, breast cancer subtype, or grade did not materially alter the observed association.
Conclusion
Low DUSP4 expression levels predict recurrence and mortality in TNBC patients independently from known clinical and molecular predictors.
Citation Format: Michelle L. Baglia, Qiuyin Cai, Ying Zheng, Jie Wu, Yinghao Su, Fei Ye, Ping-Ping Bao, Hui Cai, Zhiguo Zhao, Wei Zheng, Wei Lu, Xiao-Ou Shu. Dual specificity phosphatase 4 gene expression in triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3265. doi:10.1158/1538-7445.AM2014-3265