bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 225: Chemoproteomic evaluation of target engagement in clinical samples
Authors: Nomanbhoy Tyzoon K. 
Published: July 2017

Abstract
One of the challenges during the clinical development of kinase inhibitors is understanding whether or not a compound is actually binding the kinase of interest, in the appropriate tissue, during the course of compound treatment. While compound concentration in blood can be determined from pharmacodynamics, there are very few approaches that directly measure whether or not the compound is binding the target kinase. Herein, we apply a chemoproteomics platform (KiNativ®) using a desthiobiotin ATP acyl phosphate probe (ATP probe), to monitor target engagement in clinical samples. As a proof of concept, we demonstrate that compound can be added to whole blood, after which peripheral blood mononuclear cells (PBMCs) are isolated, lysed, labeled with the ATP probe, and analyzed by mass spectrometry to determine whether or not compound treatment blocks the probe-labeling of the target. We successfully applied this approach in the analysis of both the reversible JNK inhibitor CC-930, as well as the covalent BTK inhibitor Ibrutinib (Imbruvica®). We then extended the study to monitor the inhibition of BTK by Ibrutinib in PBMCs isolated from patients undergoing drug treatment. Finally, we demonstrate that in addition to profiling kinases in PBMCs isolated from whole blood, this method can also be used to profile kinases in solid tumors. Thus, the chemoproteomics approach described here could be applied as a general method to monitor target engagement for inhibitors developed against a variety of different kinases in clinical samples.
Citation Format: Tyzoon K. Nomanbhoy. Chemoproteomic evaluation of target engagement in clinical samples [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 225. doi:10.1158/1538-7445.AM2017-225
Abstract 2255: SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal cancer
Authors: Ahmed Maqbool , Siraj Abdul K. , Masoodi Tariq , Bu Rong , Al-Dayel Fouad , Al-Kuraya Khawla S. 
Published: July 2017

Abstract
Background: Colorectal cancer (CRC) is major cause of morbidity and mortality in cancer patients worldwide and it ranks as the most common cancer in males and the third most common among females in Saudi Arabia. Alteration in TGF-β pathway has been reported in many cancers. So In search for new molecular targets we analyzed the role of SMAD4, critical TGF-β pathway mediator, in Saudi colorectal cancers
Methods: 426 CRC cases were analyzed for SMAD4 mutations by targeted capture sequencing and protein expression status by immunohistochemistry in a tissue microarray format. Results were analyzed for association with any clinico-pathological parameters and for prognostic significance.
Results: SMAD4 mutations were detected in 11.9 %( 50/418) cases of Saudi colorectal cancers. CRC with SMAD4 mutations were significantly associated with NRAS mutations (p=0.0481). SMAD4 complete loss of expression by immunohistochemistry was seen in 12.8% (52/404) cases and this loss was associated with young age (p=0.0236) and inversely with MSI-high tumors (p=0.0005). SMAD4 expression loss by immunohistochemistry and mutation were significantly associated with each other
(p=0.0028). In the multivariate analysis using the Cox proportional hazard model SMAD4 expression loss was an independent marker of poor prognosis (p=0.0119)
Conclusion: SMAD4 alteration was found to be associated with a poor overall survival in the Saudi colorectal cancer patients. With the advent of targeted anticancer therapy, this study confirms the findings of other investigators and highlights a potential target which can be exploited to improve the survival of CRC patients in the Kingdom of Saudi Arabia
Citation Format: Maqbool Ahmed, Abdul K. Siraj, Tariq Masoodi, Rong Bu, Fouad Al-Dayel, Khawla S. Al-Kuraya. SMAD4 loss is associated with poor prognosis in Middle Eastern colorectal 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 2255. doi:10.1158/1538-7445.AM2017-2255
Abstract 2260: Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors
Authors: Kobayashi Shinta , Silva Edaise da , Contractor Tanupriya , Tang Laura , Harris Chris R. 
Published: July 2017

Abstract
Neuroendocrine tumors are the most common tumors of the small intestine. Very little is known about genetic changes that cause SI-NETs, which have a very low frequency of mutations. SI-NETs are highly metastatic to the liver, and patients with liver metastases have a five year survival rate of less than 50%. Caucasian patients are more likely to develop metastasis than patients of other races. We have studied a 900 kB inversion at chromosome 17q21.31, which is common to Caucasians but rare in other races. Within a collection of 117 Caucasian patients with ileal carcinoids, patients with the inversion haplotype were significantly less likely to have liver metastasis. A second Caucasian-specific haplotype in this region, beta2, was also tested for potential association with metastasis of ileal carcinoids. Unlike the inversion haplotype, beta2 associates with increased metastasis of ileal carcinoids. We suspect that the fact that the metastasis-promoting beta2 haplotype is more common among Caucasians than the metastasis-suppressing inversion haplotype (44% incidence vs. 33% incidence) is probably why Caucasians wind up with a higher frequency of metastasis than races that carry neither beta2 nor the inversion.
Citation Format: Shinta Kobayashi, Edaise da Silva, Tanupriya Contractor, Laura Tang, Chris R. Harris. Haplotypes of chromosome 17q21.31 affect liver metastasis by small intestinal neuroendocrine tumors [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 2260. doi:10.1158/1538-7445.AM2017-2260
Abstract 2262: Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma
Authors: Hsu Cheng-Lung , Wang Hung-Ming , Lin Tung-Liang , Kuo Yung-Chia 
Published: July 2017

Abstract
Differential overall survival of different organ site metastases in nasopharyngeal carcinoma (NPC) had been reported but the underlying mechanism was unclear. We try to find out the possible mechanism from plasma and tumor tissue markers. Total 178 patients of metastatic NPC were enrolled. Their pre-treatment plasma EBV DNA concentrations and cytokines and tissue macrophage, proliferation and apoptosis markers were determined. The overall patient response rate after treatment was 51.7% and median overall survival (OS) was 19 months. Single organ site metastasis had better outcome than multiple organs involved (median OS: 26 months vs. 16 months) with statistical significance. Among single organ site involved, pure lung metastasis had longer survival than bone or liver involved (median OS: 50 months vs. 21 months vs. 18 months) with P&lt;0.001. Pretreatment plasma EBV DNA concentrations were lower in patients with lung metastasis than bone or liver metastasis in single organ involved group. Plasma IP-10 and MCP-1 expression level correlated with the differential single organ site metastasis OS and EBV DNA load. Liver metastatic tissue had higher macrophage infiltration density and higher proliferation index than lung metastatic group. In single organ site metastasis of NPC, lung involved patients had better outcome than bone or liver metastasis. Low pretreatment plasma EBV DNA load, cytokines expression such as IP-10 and MCP-1, tissue macrophage infiltration, and proliferation index may contribute these results.
Citation Format: Cheng-Lung Hsu, Hung-Ming Wang, Tung-Liang Lin, Yung-Chia Kuo. Correlation between number and sites of metastases and differential pretreated EBV DNA load profiles and their effects on outcomes in patients with metastatic nasopharyngeal carcinoma [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 2262. doi:10.1158/1538-7445.AM2017-2262
Abstract 2263: Neonatal hormone levels and risk of testicular germ cell tumors (TGCT)
Authors: Morimoto Libby , Zava David , McGlynn Katherine , Stanczyk Frank , Wiemels Joseph , Ma Xiaomei , Metayer Catherine 
Published: July 2017

Abstract
Testicular germ cell tumors (TGCT) are the most commonly occurring cancers in adolescent and young adult males in the U.S. Steroid sex hormones play a central role in the development of the testis. As proposed by the testicular dysgenesis syndrome hypothesis, the origins of TGCT are likely to be in utero or early in life, and to be a manifestation of disturbed prenatal testis development. However, no studies have provided direct, empirical evidence to date. Using an innovative linkage between the California birth records and cancer registry data, we conducted a population-based case-control study of neonatal hormones levels and risk of TGCT diagnosed at 0-19 year of age. We obtained archived neonatal dried blood spot (DBS) specimens from 370 TGCT cases (276 adolescent and young adults [AYA] aged 15-19 yrs at diagnosis; 94 0-4 yrs at diagnosis), and 344 age- and race/ethnicity-matched controls, born between 1982 and 2009. Liquid chromatography with tandem mass spectrometry was used to measure a panel of 17 sex steroids, glucocorticoids, and mineralcorticoids; 12 were present at detectable levels in the newborn DBS samples, including estrone (E1), estradiol (E2), estriol (E3), testosterone (T), dehydroepiandrosterone (DHEA), and androstenedione (A4). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), adjusting for matching factors and age (in hours) of child at blood spot collection. A4, a precursor for T and E1, was positively associated with TGCT (OR: 1.71, 95% CI: 1.09-2.69). Analyses stratified by age group showed that this association was limited to AYA, and was of stronger magnitude in this group (OR: 2.33, 95% CI: 1.37-3.97). A similar, though weaker, trend was observed for T (ORoverall: 1.37, 95% CI: 0.86-2.19; ORAYA: 1.73. 95% CI: 1.00-3.00). There was no significant association of the other measured hormones with risk. In the first case-control study of TGCT with direct measures of neonatal hormone levels, we found that higher levels of T and A4 were associated with increased risk of TCGT, particularly among males diagnosed at 15-19 years of age. These results oppose the dominant theory in TGCT etiology, that TGCT is related to androgen insufficiency in utero, and provides an important link in the etiologic pathway of this increasingly common cancer.
Citation Format: Libby Morimoto, David Zava, Katherine McGlynn, Frank Stanczyk, Joseph Wiemels, Xiaomei Ma, Catherine Metayer. Neonatal hormone levels and risk of testicular germ cell tumors (TGCT) [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 2263. doi:10.1158/1538-7445.AM2017-2263
Abstract 2276: Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort
Authors: Jang Jieun , Hwang Yunji , Ahn Choonghyun , Ko Kwang-Pil , Shin Aesun , Yoo Keun-Young , Park Sue K. 
Published: July 2017

Abstract
Backgrounds: Attenuation by genistein, an isoflavone abundant in soybean, of gastric carcinogenesis induced by sodium chloride was reported in an animal study. Up to date, role of isoflavone as an effect modifier on the association between salt intake and gastric cancer risk is not clearly established.
Methods: We randomly selected 640 subcohort subjects without cancer history at enrollment from the Korean multi-center cancer cohort participants. Ninety-nine gastric cancer cases were identified from the inside (N=8) and the outside (N=91) of the subcohort after the 12.2 years of median follow-up time. To estimate individual’s salt intake, we measured 24-hour urinary sodium excretion from spot urine using the Tanaka’s equation. Three isoflavone plasma concentrations (Genistein, daidzein, and equol) of 167 subjects among case-cohort subjects had been measured using time-resolved fluoroimmunoassay. Cubic spline curve for gastric cancer risk according to urinary sodium level was used to define optimal cut-off points of urinary sodium excretion concentration. Weighted Cox proportional hazard regression was used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs). Stratified analysis by isoflavone level was conducted to assess effect modification by isoflavone on the association between salt intake and gastric cancer.
Results: Gastric cancer risk in the high salt intake group (urinary sodium excretion ≥6,000mg/day) was significantly increased (HR, 1.69; 95% CI, 0.99-2.90) compared to the reference group (urinary sodium excretion 4500-5,999mg/day). Magnitudes of gastric cancer risk by high salt intake were more strengthened in the group with low plasma isoflavone concentrations (One or no genistein, diadzein or equol levels over the median concentrations) (HR, 6.92; 95% CI, 1.80-26.56). Contrary to the low isoflavone group, no significant differences in gastric cancer risk according to salt intake levels were found in the group with high isoflavone concentration.
Conclusions: High salt intake is associated with gastric cancer risk, but this association can be attenuated by high concentration of isoflavones. We suggest that sufficient intake of soybean products, the rich sources of isoflavone, may give protection against gastric cancer in the population with high salt intake.
Citation Format: Jieun Jang, Yunji Hwang, Choonghyun Ahn, Kwang-Pil Ko, Aesun Shin, Keun-Young Yoo, Sue K. Park. Effect modification by isoflavones on the association between salt intake and gastric cancer risk: A case-cohort study within the Korean multi-center cancer cohort [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 2276. doi:10.1158/1538-7445.AM2017-2276
Abstract 2284: Effects of smoking on breast tumor pathology
Authors: Costantino Nicholas , Shriver Craig D. , Ellsworth Rachel E. 
Published: July 2017

Abstract
Background Although smoking is not a well-established breast cancer risk factor, proximity of lungs to the breasts and findings that tobacco smoke constituents serve as mammary carcinogens in animal models suggests that smoking may alter the breast microenvironment and affect breast tumorigenesis. To determine how smoking influences tumor pathogenesis, the relationships between smoking and pathological characteristics and outcome were evaluated in 1,707 women with invasive breast cancer.
Methods Patients enrolled in the Clinical Breast Care Project 2001-2013 filled out a questionnaire that included answers to current smoking status, current and previous pack use/day, number of years smoked, and length since last smoked. Patients were classified as never, former or current smokers. Pack years was calculated as years smoked x pack use/day. Logistic regression was performed to determine whether smoking was associated with any characteristics. Significance was defined as P&lt;0.05
Results 55.7% of women never smoked, 31.5% were former smokers and 12.8% were current smokers. The average number or pack years was 14.5 in former smokers and 25.5 in current smokers. Current smoking status was associated with lymph node metastasis (OR 1.44; 95% CI 1.03-2.01), positive HER2 status (OR 1.54, 95% CI 1.04-2.25), larger tumor size (OR 1.55; 95% CI 1.14-2.11) and higher tumor stage (OR 1.54, 95% CI 1.16-2.04) when compared to never smokers. Former smokers were less likely to be diagnosed with later stage tumors (OR 0.77, 95% CI 0.62-0.96) compared to never smokers. No significant associations were detected when pack years were considered as a continuous variable; when categorized as 0, &lt;20, 20-34 or &gt;35 pack years, &gt;35 pack years was associated with positive HER2 status (OR 1.80, 95% CI 1.06-3.03) and tumors of the ER+HER2+ subtype (OR 1.99, 95% CI 1.07-3.7). Overall survival was significantly lower for former and current smokers compared to never smokers (P=0.014); however, breast cancer specific survival did not differ significantly between groups (P=0.226).
Conclusions Current smokers are at increased risk for having larger and later stage tumors with positive lymph node and HER2 status. Tumor size, stage and lymph node status are temporal factors, thus suggest that current smokers may have delayed diagnosis compared to never and former smokers. In contrast, HER2 status reflects a biological phenomenon and the risk of HER2 positivity increases with pack years, suggesting that carcinogens found in tobacco smoke may promote overexpression of HER2.
Citation Format: Nicholas Costantino, Craig D. Shriver, Rachel E. Ellsworth. Effects of smoking on breast tumor pathology [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 2284. doi:10.1158/1538-7445.AM2017-2284
Abstract 2306: Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II
Authors: Gapstur Susan M. , Stevens Victoria L. , Carter Brian D. , Wang Ying , Jacobs Eric J. 
Published: July 2017

Abstract
There is growing evidence that factors associated with circadian rhythm disruption may be associated with prostate cancer risk. In a previous analysis focusing on shift-work in the Cancer Prevention Study (CPS)-II that included only employed men, we observed an association between short sleep duration and higher risk of prostate cancer death that was limited to the first eight years of follow-up of the cohort. To corroborate and expand on these results, we examined the association between sleep duration and death from prostate cancer in a combined analysis of men in CPS-II and men enrolled in an earlier cohort study, CPS-I, regardless of employment status. After excluding men with uninterpretable sleep information, prevalent cancer and prevalent prostate disease at baseline, the analysis included 407,649 men from CPS-I followed from 1950 through 1972, and 416,040 men from CPS-II followed from 1982 through 2012. During follow-up, 1,546 men in CPS-I and 8,704 men in CPS-II died of prostate cancer. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) and estimates were meta-analyzed using a fixed-effects model because the design and population of CPS-I and CPS-II were similar. Among men aged 65 years and younger, short sleep duration was associated with higher risk of death from prostate cancer during the first eight years of follow-up; compared to 7 hours/night, the RRs (95% CIs) for 3-5, and 6 hours/night were 1.61 (1.10-2.37), and 1.25 (0.99-1.58), respectively. Among men older than age 65 years, the corresponding RRs (95% CIs) were 0.97 (0.68, 1.38), and 1.02 (0.82, 1.27), respectively. There was no association between sleep duration and fatal prostate cancer during later follow-up. These findings support evidence that factors related to circadian rhythms may increase fatal prostate cancer risk. The observed association between short sleep duration and higher risk of fatal prostate cancer only during the first 8-years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis. Reasons for lack of an association in older men are unclear but may include the marked decline in nocturnal melatonin levels with age, which could reduce the relative biologic impact of melatonin inhibition by sleep-deprivation.
Citation Format: Susan M. Gapstur, Victoria L. Stevens, Brian D. Carter, Ying Wang, Eric J. Jacobs. Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II [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 2306. doi:10.1158/1538-7445.AM2017-2306
Abstract 2307: The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins
Authors: Kim Eun Mi , Um Hong-Duck 
Published: July 2017

Abstract
Although well known as a transcription factor, the p53 tumor suppressor also exists in the cytoplasm (including the mitochondria) of normal and cancer cells. Moreover, nuclear p53 is translocated to the mitochondria upon apoptotic stimulation of cells. The cytoplasmic/mitochondrial p53 can bind pro-survival Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Bcl-w), liberating Bax therefrom. Bax then exerts its pro-apoptotic or anti-invasive function depending on experimental conditions. Given the ability of p53 to interact with p21, we investigated the possible involvement of p21 in these functions. Here, we show that whereas p53 can bind to Bcl-w alone, it requires p21 to liberate Bax from Bcl-w and suppress/promote cell invasion/death, respectively. p21 consistently binds Bcl-w, forming a p53/p21/Bcl-w complex. Only this trifold complex, but not any of the pairings, facilitates the release of Bax from Bcl-w. Accordingly, a p53 derivative incapable of binding p21 fails to mediate radiotherapy-induced tumor retardation and cell death in mice. We further show that Bcl-2 and Bcl-XL also serves as a target of p53/p21 cooperative action. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple types of cellular components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21.
Citation Format: Eun Mi Kim, Hong-Duck Um. The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins [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 2307. doi:10.1158/1538-7445.AM2017-2307