tbuckley/cabot-search huggingface dataset:
Abstract 2906: Targeting FoxA1 in estrogen receptor-positive breast cancer: biological characterization of kinase regulators
Authors: Simon J. Johnston, Kelly A. Holmes, Jason S. Carroll
Journal: Cancer Research (2016)

Abstract Estrogen receptor (ER) is the driving and defining transcription factor in 75% of breast cancers and is directly inhibited by targeted therapies such as tamoxifen. DNA interactions and transcriptional potential of ER depend on the pioneer factor, FoxA1, which thereby plays an essential role in determining tumour growth and progression - even when resistance to existing drugs has developed. The aim of this study is to characterize kinase regulators of FoxA1 function in order to identify druggable targets for the indirect inhibition of ER. To identify kinase regulators in ER+ breast cancer, primary screening of multiple cell lines was performed using an siRNA library of the human kinome. After secondary screening of ER+ specific growth-regulatory kinases using a stable luciferase reporter of FoxA1 activation, 50 putative kinase regulators of FoxA1 were identified. These were cross-referenced with kinase inhibitors of FoxA1 activation discovered via a separate cell-based compound screen and competitive-binding kinase displacement assay. This two-pronged screening approach revealed 6 common putative FoxA1-regulatory kinase enzymes. These were characterized by chromatin immunoprecipitation (ChIP) of FoxA1 and ER with quantitative PCR of archetypal ER enhancers, 48 hours after siRNA knockdown of the kinase. This revealed 3 kinases whose inhibition prevented FoxA1 and ER from accessing the chromatin, and 1 kinase that had the opposite effect. Mass spectrometry-based proteomic analysis of endogenous FoxA1-protein interactors using ChIP is underway to assess the change in FoxA1 co-factors following inhibition of these 4 candidate kinases. We used a proteomic purification method called RIME which permits analysis of phosphorylation events on FoxA1. We are currently assessing whether silencing of specific kinases influences phosphorylation of the putative substrate, FoxA1. In summary, the identified kinases demonstrate promising FoxA1 specificity, and may provide druggable targets for the inhibition of ER via FoxA1. This study has potential clinical value for patients with tumours that have become resistant to existing ER-targeted therapies. Citation Format: Simon J. Johnston, Kelly A. Holmes, Jason S. Carroll. Targeting FoxA1 in estrogen receptor-positive breast cancer: biological characterization of kinase regulators. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2906.
Radiomodification with fluor-pyrimidines in radiation therapy of breast cancer
Authors: N. V. Malyshev, E. V. Kostrova, N. V. Bochkova, A. H. Dosakhanov, V. B. Sirota
Journal: Journal of Clinical Oncology (2007)

11073 Background: to assess the effectiveness of fluor-pyrimidines used in altered fractionated radiation therapy (RT) of breast cancer. Methods: 122 breast cancer patients (stage II) were included in this trial. Mean age - 51.3 years. All of them were randomly assigned to three groups. The first group - 41 patients treated by preoperative course of extra-beam radiation therapy, with double daily fractionation by 2 Gy (time between fractions - 4.5 hours, 4 Gy per day, 8 days), total dose - 32 Gy. The second group - 39 patients treated by the same regimen of radiation therapy, but with the concurrent application of the factory-made papers, sodden with 5-fluorouracil, on the irradiated breast. Papers covered the breast for 8 days, and were removing only during irradiation (2 times a day). The third group - 42 patients treated by the same regimen of radiation therapy, but with the concurrent radiomodification by capecitabine (1000mg/sq.m. per os twice daily before each irradiation, 8 days). In all three groups the radiation therapy was always followed by radical mastectomy in 1–2 days. The endpoints were: frequency of clinical effect and of level 3–4 pathological response. Results: positive clinical effect (complete response and partial response) and stabilization of disease were observed in the first group in 34.1% and 65.9% of patients, in the second group in 33.3% and 66.7% and in the third group in 42.9% and 57.1%. Progression was never observed. There were no signs of pathological response in 17% of patients of the first group, in 5.1% of patients of the second group and in 16.7% of patients of the third group. Level 1–2 and level 3–4 pathological response were observed in the first group in 63.4% and accordingly in 19.6% of patients, in the second group in 12.8% and 46.2% of patients and in the third group in 57.2% and 23.8% of patients. Conclusions: Therefore, using of papers with 5-fluorouracil in preoperational RT of breast cancer demonstrated more frequent level 3–4 pathological response. Using of capecitabine, on the contrary, demonstrated the highest clinical effect, but lower rate of level 3–4 pathological response. No significant financial relationships to disclose.
Spontaneous amelioration in early, DMARD naive patients with rheumatoid arthritis: Role of antibody profiles and carriage of the HLA shared epitope in predicting decrease of disease activity
Authors: B. Vander Cruyssen, A. M. M. Miltenburg, F. Van den Bosh, J. G. A. Houbiers, R. Wittoek, Annemieke Boots, F. De Keyser
Journal: Annals of the Rheumatic Diseases (2007)
Abstract LB-370: Fine mapping of 32 breast cancer risk loci in women of East Asian ancestry
Authors: Chenjie Zeng, Qiuyin Cai, Jirong Long, Ying Zheng, Yong-Bing Xiang, Jiajun Shi, Xiao-Ou Shu, Wei Zheng
Journal: Cancer Research (2016)

Abstract Background: Genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for breast cancer risk. The majority of these loci, however, were identified in studies conducted in European descendants. A comprehensive evaluation of these risk loci using densely genotyped data in East Asians may help to identify independent association signals and risk variants that are more closely related to breast cancer risk in East Asian women than those reported initially. Methods: We performed a fine-scale mapping of 32 breast cancer susceptibility loci identified in previous GWAS in 5,703 breast cancer cases and 5,766 controls in studies conducted in Shanghai, China, Nearly 4,100 variants in these 32 loci were genotyped. We imputed genotypes using the 1000 Genomes Project (Phase 3) as the reference. Included in this analysis were 4,086 genotyped and more than 17,000 well-imputed common variants. At each locus, analyses using logistic regression models were conducted to identify variants that better capture the association with breast cancer risk and new risk variants that are not correlated with the risk variants reported from the initial studies (index SNPs). To identify additional independent risk variants, logistic regression conditional on the most significantly associated variant was performed. Results: We identified risk variants that better captured the association than the index SNPs at 3 loci (2q35, rs1478596, OR = 1.14, P = 5.6×10-6; 6q25.1, rs9322344, OR = 0.89, P = 3.1×10-5;11q24.3, rs11221769, OR = 1.12, P = 6.1 ×10-5), new risk variants at 2 loci (1p13.2, rs3789614, OR = 1.31, P = 0.002; 2q31.1, rs117055746, OR = 0.87, P = 0.004), and independent risk variants at two loci (6q14.1, rs200626240, OR = 0.89, P = 0.001; 6q25.1 rs2982684, OR = 0.87, P = 2.7×10-5, Chr6:152107810, OR = 0.91, P = 1.4×10-4). Conclusion: This study identified multiple risk variants that were more relevant to East Asians than the index SNPs. These risk variants combined explained a further 2% of the familial relative risk in this population. This study highlighted the need of fine-mapping studies in non-European ancestral populations to search for additional risk variants. Citation Format: Chenjie Zeng, Qiuyin Cai, Jirong Long, Ying Zheng, Yong-Bing Xiang, Jiajun Shi, Xiao-Ou Shu, Wei Zheng. Fine mapping of 32 breast cancer risk loci in women of East Asian ancestry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-370.
TAXYNERGY: Randomized trial of early switch from first-line docetaxel (D) to cabazitaxel (C) or vice versa with circulating tumor cell (CTC) biomarkers in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Scott T. Tagawa, Emmanuel S. Antonarakis, Fred Saad, Marie Vanhuyse, Guru Sonpavde, Scott A. North, Costantine Albany, Che-Kai Tsao, John Stewart, Atef Zaher, Ted P. Szatrowski, Wei Zhou, Giuseppe Galletti, Daniel Worroll, Mario A. Eisenberger, David M. Nanus, Paraskevi Giannakakou
Journal: Journal of Clinical Oncology (2016)

5007 Background: TAXYNERGY (NCT01718353), a randomized phase II trial, evaluated early taxane switch with CTC biomarkers to study mechanisms of sensitivity/resistance in men with chemo-naïve mCRPC. Methods: Pts were randomized 2:1 to first-line D or C. Pts not achieving ≥30% PSA decline by Cycle 4 (C4) switched to the other taxane. Pts remained on treatment until progression, unacceptable toxicity, investigator decision or study cut-off. CTCs were collected at multiple time points. Co-primary endpoints: achievement of confirmed ≥50% PSA response vs historical control (TAX327) and analysis of drug target engagement in post-treatment CTCs by androgen-receptor (AR) nuclear localization (ARNL). Results: 63 pts were randomized to D (n = 41) or C (n = 22). Median age was 71 yr; ECOG PS was ≤1 in 93.7%. Baseline characteristics in both arms were similar; 44.4% received prior potent AR-targeted therapy. 33 pts (52.4%; D 48.8%, C 59.1%) had ≥30% PSA decline by C4 and did not switch taxane. Of 30 pts (47.6%) not achieving ≥30% PSA decline by C4, 15 (23.8%; D 29.3%, C 13.6%) switched taxane and 15 discontinued. 8/15 (53.3%) pts who switched taxane achieved ≥50% PSA response. Overall, 35 pts (55.6%) had confirmed ≥50% PSA response; the pre-defined endpoint of lower limit of the 10% 1-sided CI of 47.5% exceeded the historical control rate of 45.4%. In pts with ≥50% PSA decline, mean %ARNL in CTCs decreased by 6.5%, while in pts without 50% PSA decline %ARNL increased by 6.1% (P = 0.029). Composite PFS was 9.1 mo (95% CI 4.9, 11.7); median OS was not reached after median follow up of 14 mo. Key toxicities in pts on D or C throughout or who switched, respectively, included diarrhea (48%; 63%; 60%), nausea (30%; 53%; 47%), neutropenia (19%; 32%; 13%) and febrile neutropenia (19%; 16%; 0%). Conclusions: TAXYNERGY, the first prospective trial to report ARNL in CTCs as a correlative taxane biomarker, met its co-primary clinical and biomarker endpoints, with an early switch in taxane resulting in a higher PSA response rate vs TAX327. Consistent with the proposed MOA, ARNL may indicate taxane sensitivity/resistance. Funding: Sanofi Clinical trial information: NCT01718353.
Abstract 1785: Sociodemographic correlates of knowledge and risk perception of HPV and HPV-associated oropharyngeal cancer
Authors: Betty Y. Chen, Nosayaba Osazuwa-Peters, Eric Adjei Boakeye, Jennifer Clancy, Jonathan Su, Patrice Vallot, Geoffrey Beck, Ronald J. Walker, Mark A. Varvares
Journal: Cancer Research (2016)

Abstract Purpose To analyze how key sociodemographic variables correlate with risk perception and knowledge of HPV-associated oropharyngeal cancer in the community. Methods A cross-sectional study was conducted at a drag racing event on September 12-13, 2015 in Madison, Illinois. The independent variables were sociodemographic factors including age, gender, race, income level, education level, drinking history, smoking history, and number of sexual partners. The outcome variables were HPV risk perception and knowledge of HPV-associated oropharyngeal cancer, both derived from combining questionnaire items to form knowledge and perception scores. Multivariable linear regression analysis assessed the predictors of risk perception and knowledge of HPV-associated oropharyngeal cancer. Results Final sample population was 301. Mean risk perception score was 2.16 ± 1.37 out of 6, and mean knowledge score was 5.65 ± 4.63 out of 15. In multivariable linear regression, race and education were significant predictors of HPV risk perception. Compared to Caucasians, African Americans had a lower perceived risk of developing oropharyngeal cancer (β = -0.35; 95% CI: -0.69 - -0.02). Participants with ≤ high school diploma had a lower perceived risk of developing oropharyngeal cancer compared to those with ≥ college degree (β = -0.60; 95% CI: -1.05 - -0.15). Age, gender, race and education were significant predictors of HPV-associated oropharyngeal cancer knowledge in multivariable analysis. For every one year increase in age, HPV-associated oropharyngeal cancer knowledge decreased by 5%. Men had lower HPV-associated oropharyngeal cancer knowledge (β = -1.30; 95% CI: -2.35 - -0.26) as were African Americans compared to Caucasians (β = -1.30; 95% CI: -2.36 - -0.25). Participants with ≤ high school diploma had lower HPV-associated oropharyngeal cancer knowledge compared to those with ≥ college degree (β = -3.33; 95% CI: -4.75 - -1.91). Conclusions Age and gender were independent predictors of knowledge of HPV-associated oropharyngeal cancer, while race and education predict both knowledge and risk perception of HPV-associated oropharyngeal cancer. The sociodemographic correlates demonstrated in our study should inform future interventions targeted at increasing knowledge of HPV-associated oropharyngeal cancer in the community. Citation Format: Betty Y. Chen, Nosayaba Osazuwa-Peters, Eric Adjei Boakeye, Jennifer Clancy, Jonathan Su, Patrice Vallot, Geoffrey Beck, Ronald J. Walker, Mark A. Varvares. Sociodemographic correlates of knowledge and risk perception of HPV and HPV-associated oropharyngeal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1785.
Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, <i>K-RAS </i>wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Lillian L. Siu, Jeremy David Shapiro, Derek J. Jonker, Christos Stelios Karapetis, John Raymond Zalcberg, John Simes, Felix Couture, Malcolm J. Moore, Timothy Jay Price, Jehan Siddiqui, Louise M. Nott, Danielle Charpentier, Winston S. Liauw, Michael B. Sawyer, Michael Jefford, Nadine M Magoski, Andrew Mark Haydon, Ian B. Walters, Dongsheng Tu, Christopher J. O'Callaghan
Journal: Journal of Clinical Oncology (2012)

3504 Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with chemotherapy refractory, K-RAS WT mCRC. BRIV is a potent inhibitor of multiple receptor tyrosine kinases including both VEGFR and FGFR. The combination of CET and BRIV targets tumor growth and angiogenesis and demonstrated encouraging activity in an early phase clinical trial. Methods: Pts with mCRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m 2 IV loading dose followed by weekly maintenance of 250 mg/m 2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; &gt;3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Primary analysis was conducted per protocol after 536 deaths were observed, with median OS of 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p&lt;0.0001. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Planned subgroup analyses revealed no statistically difference in treatment effects on OS based on pre-specified factors of age, gender, ECOG and race. Likewise, no difference was detected based on exploratory subgroup analyses of LDH and prior anti-VEGF therapy. Conclusions: Despite positive effects on PFS, the combination of CET+BRIV did not significantly improve OS in pts with chemotherapy refractory, K-RAS WT mCRC. Final updated results based on 20-25% additional events for a total of nearly 700 deaths, as well as further exploratory subgroup analyses, will be presented.
Therapeutic translation in acute kidney injury: the epithelial/endothelial axis
Authors: Bruce A. Molitoris
Journal: Journal of Clinical Investigation (2014)

Acute kidney injury (AKI) remains a major clinical event with rising incidence, severity, and cost; it now has a morbidity and mortality exceeding acute myocardial infarction. There is also a documented conversion to and acceleration of chronic kidney disease to end-stage renal disease. The multifactorial nature of AKI etiologies and pathophysiology and the lack of diagnostic techniques have hindered translation of preclinical success. An evolving understanding of epithelial, endothelial, and inflammatory cell interactions and individualization of care will result in the eventual development of effective therapeutic strategies. This review focuses on epithelial and endothelial injury mediators, interactions, and targets for therapy.
Persantine and aspirin in coronary heart disease. The Persantine-Aspirin Reinfarction Study Research Group.
Journal: Circulation (1980)

In the Persantine-Aspirin Reinfarction Study (PARIS) trial, 2026 persons who had recovered from myocardial infarction (MI) were randomized into three groups: Persantine plus aspirin (PR/A) (n = 810); aspirin alone (ASA) (n = 810); placebo (PLBO) (n = 406). The average length of follow-up study was 41 months. Results for the three specified primary end points were: total mortality 16% lower in PR/A and 18% lower in ASA compared with PLBO; coronary mortality 24% and 21% lower; incidence of nonfatal MI plus fatal coronary disease 25% and 24% lower. These differences were not satistically significant by the study criterion (Z greater than or equal to 2.6). By life-table analysis, the rates of coronary mortality and coronary incidence were about 50% lower in the PR/A group than in the PLBO group from 8-24 months, and for coronary incidence all Z values were greater than or equal to 2.6; ASA rates were about 30% lower than PLBO rates, and for coronary incidence, Z values were greater than or equal to 2.6 at two points. For these end points, from 8-20 months, PR/A rates were about 30% lower than ASA rates, but all Z values were less than 2.0 PR/A and ASA patients entering within 6 months of last MI showed the largest percentage reductions in mortality; only the difference between PR/A and PLBO groups for 3-year coronary mortality yielded a Z value of 2.6.
Inhibition of MALT1 paracaspase by mepazine to decrease proliferation and enhance apoptosis in pancreatic cancer.
Authors: Alexander T. El Gammal, Leonie Konczalla, Nadine Scholz, Cenap Guengoer, Gerrit Wolters-Eisfeld, Bianca T. Hofmann, Maximilian Bockhorn, Yogesh Kumar Vashist, Alexander Stein, Jakob R. Izbicki, Daniel R. Perez
Journal: Journal of Clinical Oncology (2015)

e15223 Background: Mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a key mediator of upstream NF-kB signaling. Mepazine, a phenothiazine derivate, was previously described as potent inhibitor of MALT1 in lymphocytes.The present study reports the role of MALT1 in human pancreatic ductal adenocarcinoma (PDAC) and investigates potential implications with tumor biology. Methods: Expression of MALT1 was analyzed by IHC in 310 patients with PDAC. Protein and mRNA expression of MALT1 were analyzed by Western blots and qRT-PCR in PDAC cells and in a non-malignant human pancreatic ductal epithelial cell line (HPDE). Five different human PDAC cell lines and the HPDE reference cell line were treated with Mepazine. Proliferation, apoptosis and MALT1 activity were assessed by MTT assays, by cleaved caspase 3 assays, and by paracaspase activity assays. The treatment response to Mepazine is currently under investigation in an in vivo Panc-1 PDAC cell xenograft mouse model. Results: MALT1 is present in 75% (133/177) of primary PDACs and is highly expressed in 27% (49/177), moderately in 23% (40/177) and weakly in 25% (44/177) of primary tumor samples. MALT1 expression is associated with pathological tumor grading (p < 0.001) and survival (p = 0.027). MALT1 is highly active in PDAC cells but can be effectively inhibited by the application of Mepazine. The treatment with Mepazine reduces proliferation and induces cell apoptosis in cancer cells. In contrast, HPDE proliferation or apoptosis are not affected by Mepazine treatment. Preliminary in vivo data indicates a trend for smaller tumors in the treatment group (130 ± 64 mm³; n = 7) compared to the control group (1008 ± 593 mm³; n = 8; p = 0.054). Conclusions: We provide evidence for MALT1 expression and enzyme activity in human PDAC. Inhibition of MALT1 by Mepazine results in decreased proliferation and increased apoptosis. The response to Mepazine treatment in vivo seems promising and warrants further investigation.
Ex Vivo Model of Human Penile Transplantation and Rejection: Implications for Erectile Tissue Physiology
Authors: Nikolai A. Sopko, Hotaka Matsui, Denver M. Lough, Devin Miller, Kelly Harris, Max Kates, Xiaopu Liu, Kevin Billups, Richard Redett, Arthur L. Burnett, Gerald Brandacher, Trinity J. Bivalacqua
Journal: European Urology (2016)