tbuckley/cabot-search huggingface dataset:
Abstract 5336: Characterization of selective covalent inhibitors of USP7
Authors: Feng Wang, Jian Wu, Liqing Wang, Ivan Sokirniy, Hui Wang, Charles Grove, Phuong Nguyen, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Wayne Hancock, Irina Bezsonova, Suresh Kumar
Journal: Cancer Research (2017)

Abstract The ubiquitin-specific protease 7 (USP7) has emerged as an attractive therapeutic target owing to its critical roles in several cancer signaling pathways as well as its essential role in maintaining Foxp3+ T-regulatory cell (Treg) functions. Pharmacological inhibition of USP7 using Progenra’s small molecule inhibitors resulted in direct anti-tumor activity as well as the unleashing of anti-tumor immunity by suppressing Treg functions. However, the precise mechanism of action these compounds was not well characterized. Using a combination of NMR spectroscopy, mass spectrometry, and single amino acid substitution approaches, we have now demonstrated that our USP7 inhibitors specifically target the catalytic cleft of USP7 and covalently modify its active site cysteine (Cys223). Pharmacokinetic studies revealed sustained irreversible USP7 inhibition after short term inhibitor treatment as well as subsequent changes in the level and ubiquitylation of various pharmacodynamic markers, including the Treg lineage specific transcription factor Foxp3. Detailed knowledge of the mechanism of USP7 inhibition has allowed us to incorporate rational design strategies into the lead optimization to obtain improved molecules that will serve as the basis of a new class of anti-cancer immunotherapy agents. Citation Format: Feng Wang, Jian Wu, Liqing Wang, Ivan Sokirniy, Hui Wang, Charles Grove, Phuong Nguyen, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Wayne Hancock, Irina Bezsonova, Suresh Kumar. Characterization of selective covalent inhibitors of USP7 [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 5336. doi:10.1158/1538-7445.AM2017-5336
Abstract 5173: Discovery of a series of benzimidazoles as potent Wnt/β-catenin signaling inhibitors in colorectal cancer cells
Authors: Yonghe Li, Patsy G. Oliver, Wenyan Lu, Vibha Pathak, Corinne E. Augelli-Szafran, Donald J. Buchsbaum, Mark J. Suto
Journal: Cancer Research (2017)

Abstract Aberrant activation of Wnt/β-catenin signaling is a necessary initiating event in the genesis of most colorectal cancers. Loss-of-function mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are present in about 80% of all colorectal cancers, and gain-of-function mutations in the oncogene CTNNB1 (β-catenin encoding gene) exist in approximately 10% of colorectal cancers. Both APC and CTNNB1 mutations lead to cytosolic accumulation and nuclear translocation of β-catenin, and therefore constitutive activation of β-catenin/TCF4-mediated gene transcription. As such, the Wnt/β-catenin pathway has emerged as one of the most promising targets for colorectal cancer treatment. Despite tremendous efforts in the past decade, there are no small molecule Wnt inhibitors approved by the FDA for cancer treatment. Recent work in our laboratories has identified a series of benzimidazoles as potent Wnt/β-catenin inhibitors. Here, we show that several benzimidazoles displayed strong activities against Wnt/β-catenin signaling in colorectal cancer cells harboring mutations in CTNNB1 or APC. In particular, SRI36324, the lead compound in this series, inhibited Wnt/β-catenin signaling in colorectal cancer HCT116 and DLD-1 cells with IC50 values of 4.1 and 3.7 nM, respectively. Moreover, the benzimidazole compounds exhibited potent activities against colorectal cancer cell proliferation under both standard cell culture conditions (adherent cells in complete medium containing 10% FBS) and conditions designed to enrich for cancer initiating cells. In addition, the benzimidazole compounds had no off-target effects on other pathways (e.g., STAT3 and mTORC1 signaling) in colorectal cancer cells, and were less antiproliferative to non-cancerous cells. Together, our findings indicate that the benzimidazole compounds are promising candidates for development as novel therapeutic agents for colorectal cancer. Note: This abstract was not presented at the meeting. Citation Format: Yonghe Li, Patsy G. Oliver, Wenyan Lu, Vibha Pathak, Corinne E. Augelli-Szafran, Donald J. Buchsbaum, Mark J. Suto. Discovery of a series of benzimidazoles as potent Wnt/β-catenin signaling inhibitors in colorectal 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 5173. doi:10.1158/1538-7445.AM2017-5173
Abstract 16338: A Case-Crossover Study of Short Term Effects of Air Pollutants on Stroke in Gunma, Japan
Authors: Bing Zhao, Farhad Salimi, Fay Johnston, Kiyohiro Oshima, Masahiko Kurabayashi, Kazuaki Negishi
Journal: Circulation (2016)

Introduction: Accumulating evidence links the elevated risk for cardiovascular mortality or hospitalization with exposure to air pollution, such as: fine particles <2.5μm in aerodynamic diameter (P...
Abstract 4135: Inactivation/loss of PTPRS promotes ERK activation that sensitizes colorectal cancer cells to ERK inhibitors
Authors: Thomas B. Davis, Mingli Yang, Michael J. Schell, Heiman Wang, Le Ma, W. Jack Pledger, Timothy J. Yeatman
Journal: Cancer Research (2017)

Abstract The RAS pathway is a driver of many cancers, and has been targeted for the development of a variety of therapeutic inhibitors of BRAF, MEK, and more recently ERK. One of challenging issues is to predict response to targeted therapies. Here we report identification of PTPRS, a receptor-type protein tyrosine phosphatase, as a regulator/biomarker of ERK activation and inhibitor response in colorectal cancer. To identify the genes with high frequency mutations that might be predictive of RAS pathway dependence (“addiction”), we used a gene expression signature score to stratify 468 colorectal cancer tumors that also underwent targeted exome sequencing for 1321 cancer-associated genes. We found that, when the masking effects caused by mutant KRAS, BRAF and NRAS was iteratively removed, mutant PTPRS was strongly correlated with RAS pathway activation, with a mutation rate of 10.4% (22 out of 211 remaining tumors). This led us to inactivate PTPRS in vitro using a specific peptide inhibitor, siRNA or CRISPR approaches in various colorectal cancer cell lines. Inhibition/loss of PTPRS significantly elevated phosphorylation of ERK and AKT and substantially sensitized cancer cells to the treatment of ERK inhibitors, which was enhanced by an AKT inhibitor. Surprisingly, PTPRS did not modulate the activity of EGFR and the ERK kinase, MEK. Our data indicate that PTPRS negatively regulates ERK signaling downstream of the EGFR/RAS/RAF/MEK pathway in a mechanism independent of AKT and DUSP6. As a result, inactivation/loss of PTPRS promotes ERK activation and “addiction”, thereby contributing to increased sensitivity to ERK inhibitors. Citation Format: Thomas B. Davis, Mingli Yang, Michael J. Schell, Heiman Wang, Le Ma, W. Jack Pledger, Timothy J. Yeatman. Inactivation/loss of PTPRS promotes ERK activation that sensitizes colorectal cancer cells to ERK inhibitors [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 4135. doi:10.1158/1538-7445.AM2017-4135
What is the precise role of cognitive control in the development of a sense of number?
Authors: Rebecca Merkley, Gaia Scerif, Daniel Ansari
Journal: Behavioral and Brain Sciences (2017)

Abstract The theory put forward by Leibovich et al. of how children acquire a sense of number does not specify the mechanisms through which cognitive control plays a role in this process. We argue that visual attention and number word knowledge influence each other over development and contribute to the development of the concept of number.
Abstract 4495: Elucidating BCL11A’s function in triple negative breast cancer
Authors: Nicholas O. Stevers, Samantha L. Tinsley, Rebecca Moody, Chang-Ching Lin, Jennifer Meagher, Jeanne A. Stuckey, Miao-Chia Lo, Duxin Sun
Journal: Cancer Research (2017)

Abstract It has been recently shown that the B-cell CLL/lymphoma 11A (BCL11A) transcription factor is highly expressed in triple-negative breast cancer (TNBC) and has critical functions in promoting tumor growth and mammary stem cell maintenance. Studies in our group have found that the first twelve amino acids (aa 1-12) of BCL11A are a conserved sequence that allows binding to retinoblastoma binding protein 4 (RBBP4). RBBP4, a histone binding protein, is involved in many epigenetic complexes, including the Polycomb repressive complex 2 (PRC2), the nucleosome remodeling and deacetylase (NuRD) complex, and SIN3A complex. Through these interactions BCL11A may exert transcriptional and epigenetic regulation. Herein we investigate the importance of BCL11A’s interaction with RBBP4 and its function in TNBC. BCL11A-complex interactions were observed through pull-down experiments of TNBC cell lysate utilizing aa 2-16 of BCL11A and a scramble control sequence. Our results demonstrate that this 16-amino acid sequence is sufficient to bind to RBBP4 and pull down the PRC2, NuRD, and SIN3A complexes. Furthermore, the NuRD and Sin3a complexes pulled down by BCL11A aa 2-16 retained their functionality as observed through post pull-down histone deacetylase (HDAC) activity assays. These results indicate significantly higher HDAC activity in the wildtype sequence as compared to the scrambled sequence. To further investigate this interaction, protein crystallization was conducted, the results of which validate the binding between BCL11A and RBBP4. Additionally, a BCL11A peptide (aa 2-12) and a scramble control were transfected into the TNBC cell line SUM149. Analysis via flow cytometry shows a reduction of the ALDH+ cell population in the BCL11A peptide transfected cells versus scramble control. We are currently investigating the necessity of this 12-amino acid sequence in interactions with RBBP4, PRC2, NuRD and SIN3A via co-Immunoprecipitation experiments using an N-terminal truncated BCL11A protein (del 2-12). The effects of full-length BCL11A and del 2-12 on the ALDH+ cell population are also being examined. These experiments will further delineate this sequence’s importance in BCL11A-RBBP4 interactions. Citation Format: Nicholas O. Stevers, Samantha L. Tinsley, Rebecca Moody, Chang-Ching Lin, Jennifer Meagher, Jeanne A. Stuckey, Miao-Chia Lo, Duxin Sun. Elucidating BCL11A’s function 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 4495. doi:10.1158/1538-7445.AM2017-4495
Abstract 4241: Circulating microRNAs in plasma of men screened for prostate cancer
Authors: Alicia C. Mcdonald, Jing Shen, Manish Vira, Martin Sanda, Jason Liao, Martin L. Lesser, Dattatraya Patil, Jay D. Raman, Emanuela Taioli
Journal: Cancer Research (2017)

Abstract Introduction: Although microRNAs (miRNAs) have been linked to prostate cancer risk, their role as a screening biomarker for prostate cancer (PC) has yet to be determined. We examined whether circulating miRNAs in plasma could be potential biomarkers for the early detection of PC among men undergoing prostate needle biopsy. Methods: Men who had a prostate biopsy due to an abnormal screening test were recruited. Demographics, medical history, clinical information, and blood processed into plasma were collected. TaqMan Low Density Arrays were used for the expression profiling of 733 miRNAs in plasma. Wilcoxon test was used to compare expression levels between men with and without a PC diagnosis. Logistic regression was used to examine the association between miRNAs and PC status, after adjusting for age and Bonferroni-correction. Results: There were 131 men, aged 46 to 86 years, included in the final analysis, with 66 men diagnosed with PC on prostate biopsy and 65 men without a PC diagnosis. Majority were white (72.5%) followed by black race (13.5%). Men with PC were older (median: 64 vs. 62 years; p-value = 0.16) and had statistically significantly higher serum PSA (median: 5.8 vs. 5.1 ng/mL; p-value = 0.01) compared to men without a PC diagnosis. The most statistically significant PC circulating miRNAs in plasma were miR-381, miR-523, miR-450B-5p, miR-34a, miR-34b, miR-639, and miR-365, after adjusting for age (p-values ≤ 0.05). The detection rate of these miRNAs in plasma ranged from 23.7% to 83.2%. These miRNAs were no longer statistically significant with PC diagnosis, after adjusting for multiple comparison (FDR q-value = 1.00). Conclusion: Among the 733 miRNAs evaluated, there was no miRNA found to be associated with PC diagnosis after adjusting for multiple comparison. Studies that examine a larger number of miRNAs which include the discovery of new miRNAs and their relationship with PC risk are warranted. Citation Format: Alicia C. Mcdonald, Jing Shen, Manish Vira, Martin Sanda, Jason Liao, Martin L. Lesser, Dattatraya Patil, Jay D. Raman, Emanuela Taioli. Circulating microRNAs in plasma of men screened for prostate 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 4241. doi:10.1158/1538-7445.AM2017-4241
Abstract 106: Traditional medicinal plants effect on five cancer cell lines
Authors: Elbert L. Myles
Journal: Cancer Research (2017)

Abstract Cancer refers to as a group of numerous diseases that can originate in various parts of the body. From the beginning of human history natural compounds have been used for medical purposes. Many of the most frequently used natural compounds have their origin from plants. Plants are very diverse and responsible for the synthesis of a number different secondary compounds. Scientist and non-scientist have taken advantage of these secondary compounds treatment of a variety of diseases. In the current study, we are investigating the viability of specific cancer cell lines after exposure to methanolic extracts from each of the following plants. The plants are Costus, Fenugreek, and Rhamnus. The cell lines used in this investigation are lung cancer (A549), colon cancer, (SW620 and Colo320), breast cancer (BT549), and cervical cancer (HeLa). The determination of cell viability found inhibition. The three test compounds were methanolic extracts from the plants Costus, Fenugreek, and Rhamnus. All showed different levels of viability and was dependent on the specific cell line. Citation Format: Elbert L. Myles. Traditional medicinal plants effect on five cancer cell lines [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 106. doi:10.1158/1538-7445.AM2017-106
Abstract 2749: Liquid biopsy testing allows highly-sensitive detection of plasma cfDNA mutations in 87 breast cancer-related genes
Authors: Maruja E. Lira, Tao Xie, Shibing Deng, Jennifer Kinong, Jingjin Gao, Zhou Zhu, Nathan Lee, Paul Rejto, Jadwiga Bienkowska, James Hardwick, Kai Wang, Stephen Huang
Journal: Cancer Research (2017)

Abstract Liquid biopsies have the potential to revolutionize the way physicians select personalized anti-cancer therapies, monitor patient responses to treatment, and characterize acquired resistance to cancer drugs. New tests that use a simple peripheral blood draw offer snapshots of a patient‘s total tumor DNA mutation profile and are attractive because of their minimally-invasive modality and because they integrate information from both primary and metastatic disease. Currently, most plasma cell-free DNA (cfDNA) mutation detection tests used in clinical research detect known hotspot mutations in a limited number of genes. Technologies that interrogate multi-gene panels in cfDNA are advancing, but commercially-available options suitable for clinical use are limited, come at a high cost, and are not customizable. We designed and developed a customized, next generation sequencing-based, liquid biopsy assay capable of detecting somatic mutations in 87 breast cancer genes involved in cell cycle and estrogen receptor signaling. Targeted regions (147 Kb) were enriched using hybrid capture resulting in an average capture specificity and uniformity of 65.93% and 96.38%, respectively. When tested on cfDNA from healthy donors (n=14), we demonstrated a level of specificity &amp;gt;99.99%. Analytical sensitivity of 0.1% was established on HapMap and reference mutant cell line DNA. Using a pool of HapMap genomic DNA (n=10), 96% (48/50) of SNPs with expected allele frequency of 0.1% were detected. In reference mutant cell line DNA with 1% or 0.1% mutant allele frequencies, we were able to reliably detect all mutations present at 1% and mutations at 0.1% in 50% of the cases. Assay validation on plasma cfDNA with matching tumor from ER+, HER2- breast cancer patients will be presented. In conclusion, we developed a highly sensitive and specific liquid biopsy assay to interrogate 87 breast cancer-related genes. The high level of specificity and sensitivity makes the test ideal not only for detecting known cancer gene hotspot mutations but also for detection of novel gene mutations that may arise during treatment as a result of acquired drug resistance. Citation Format: Maruja E. Lira, Tao Xie, Shibing Deng, Jennifer Kinong, Jingjin Gao, Zhou Zhu, Nathan Lee, Paul Rejto, Jadwiga Bienkowska, James Hardwick, Kai Wang, Stephen Huang. Liquid biopsy testing allows highly-sensitive detection of plasma cfDNA mutations in 87 breast cancer-related genes [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 2749. doi:10.1158/1538-7445.AM2017-2749
Outcome after a "perfect" Fontan operation.
Authors: F Fontan, J W Kirklin, G Fernandez, F Costa, D C Naftel, F Tritto, E H Blackstone
Journal: Circulation (1990)

A study was undertaken to determine the early and long-term outcomes dictated by the Fontan state per se (a state in which the force driving pulmonary blood flow is solely or largely a residue, in the systemic venous pressure, of the main ventricular chamber's contractile force) and the transition (by surgery) to it from the state of congenital heart disease under optimal conditions (after a "perfect" Fontan operation). The primary study design used a solution of a multivariate risk factor equation for death, by which survival rate under optimal conditions was predicted to be 92%, 89%, 88%, 86%, 81%, and 73% at 1 month, 6 months, and 1, 5, 10, and 15 years, respectively, after the Fontan operation. The hazard function (instantaneous risk of death at each moment in time after the operation) had an early rapidly declining phase of hazard that at about 6 months began to give way to a late hazard phase, which was rising by about 6 years after surgery. A secondary study design, using the theory of competing risks, yielded survival and hazard function information very similar to that of the primary study design. The functional capacity of the patients as expressed by New York Heart Association class was less, the longer the period of follow-up. No risk factors (other than older age at time of surgery) were found for the late decline in survival or the decline in functional status. The inference is that the premature decline in survival and functional status and the late rise in hazard function are from the Fontan state per se and that the Fontan operation is, therefore, palliative but not curative.
Impact of genetic variations in the MAPK signaling pathway on outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI and bevacizumab: data from FIRE-3 and TRIBE trials
Authors: M.D. Berger, S. Stintzing, V. Heinemann, D. Yang, S. Cao, Y. Sunakawa, Y. Ning, S. Matsusaka, S. Okazaki, Y. Miyamoto, M. Suenaga, M. Schirripa, S. Soni, W. Zhang, A. Falcone, F. Loupakis, H.-J. Lenz
Journal: Annals of Oncology (2017)
Abstract 4462: ACTN4 stabilises RIPK1 to function as an oncogenic driver in melanoma
Authors: Lei Jin, Hessam Tabatabaeehatambakhsh, Chen Chen Jiang, Xu Guang Yan, Jia Yu Wang, Yuan Yuan Zhang, Hamed Yari, Chun Yan Wang, Ting La, Fu Xi Lei, Yu Chen Feng, Su Tang Guo, Xu Dong Zhang
Journal: Cancer Research (2017)

Abstract We have recently reported that receptor-interacting protein kinase 1 (RIPK1) is commonly up-regulated through cellular inhibitor apoptosis protein (cIAP)-mediated stabilization and functions as an oncogenic driver via activation of NF-κB in melanoma cells. Here we show that α-actinin-4 (ACTN4), an isoform of α-actinins of spectrin superfamily proteins that is emerging as an oncogenic regulator, is required for cIAP-mediated stabilization of RIPK1 and plays a pro-oncogenic role in melanoma. Similar to RIPK1, ACTN4 was found to be commonly increased in melanoma cells. While knockdown of ACTN4 inhibited melanoma cell proliferation that was associated with down-regulation of RIPK1 and reduction in the basal levels of NF-κB activation, overexpression of ACTN4 resulted in enhanced proliferation of melanocytes that was associated with elevation in RIPK1 expression and increased NF-κB activation. The inhibitory effect of ACTN4 knockdown on melanoma cell proliferation and activation of NF-κB was due to decreased expression of RIPK1, as it was abolished by overexpression of RIPK1. On the other hand, knockdown of RIPK1 diminished ACTN4 overexpression-triggered enhancement in proliferation in melanocytes. Strikingly, knockdown of ACTN4 attenuated the association between cIAPs and RIPK1 and reduced K63-linked ubiquitination of the protein, leading to RIPK1 protein degradation. Mechanistic studies showed that ACTN4 bound to RIPK1 through its N-terminus, whereas it was associated with cIAPs via its C-terminus, and that dimerization of ACTN4 in an anti-parallel manner is required for the interaction between cIAPs and RIPK1. Collectively, ACTN4 is necessary for stabilization of RIPK1 by cIAPs and functions as an oncogenic driver in melanoma. Citation Format: Lei Jin, Hessam Tabatabaeehatambakhsh, Chen Chen Jiang, Xu Guang Yan, Jia Yu Wang, Yuan Yuan Zhang, Hamed Yari, Chun Yan Wang, Ting La, Fu Xi Lei, Yu Chen Feng, Su Tang Guo, Xu Dong Zhang. ACTN4 stabilises RIPK1 to function as an oncogenic driver in melanoma [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 4462. doi:10.1158/1538-7445.AM2017-4462