bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 5248: Pioglitazone prevents hepatocellular carcinoma development in a rat model of cirrhosis
Authors: Li Shen , Ghoshal Sarani , Arora Gunisha , Erstad Derek J. , Lanuti Michael , Tanabe Kenneth K. , Fuchs Bryan C.
Published: July 2017

Introduction: Advanced hepatocellular carcinoma (HCC) is a leading cause of mortality worldwide with limited treatment options. There is a readily identifiable cohort of cirrhosis patients at risk and they are ideal candidates for chemoprevention. Anti-hyperglycemic agents have garnered interest for their potential anti-fibrotic as well as chemo-preventive effects. Pioglitazone, a selective PPAR-γ agonist, has been shown to reduce non-alcoholic steatohepatitis (NASH), but its role as an anti-fibrotic and chemopreventive agent has yet to be elucidated. The hypothesis of this study is that Pioglitazone reduces cirrhosis and subsequent HCC development in rats with diethylnitrosamine (DEN)-induced cirrhosis.

Methods: Male Wistar received DEN 50mg/kg by intraperitoneal injection. DEN injury reliably recapitulates histological and molecular features of human HCC development with induction of hepatic fibrosis at 8 weeks, cirrhosis at 12 weeks, and HCC by 18 weeks. DEN-injured rats were randomized to receive oral gavage of pioglitazone at 3mg/kg/day (n=9) or vehicle control (n=9). Initiation of pioglitazone coincided with the development of liver fibrosis at 8 weeks. All animals were sacrificed at 18 weeks.

Results: As expected, repeated injections of DEN in rats resulted in progressive fibrosis, cirrhosis, followed by HCC formation. Treatment with pioglitazone resulted in a 56% reduction of surface nodules relative to treatment with vehicle (7.4±4.9 vs. 17±7; p<0.005). Liver sections were stained by picrosirius red to assess fibrosis and pioglitazone significantly reduced collagen deposition in DEN-injured rats (collagen proportional area = 3.2±1.8% vs. 9.2±2%; p<0.035). This histologic observation was further confirmed by gene expression analysis with reductions in collagen-I, α-smooth muscle actin, and transforming growth factor beta in rats treated with pioglitazone. Finally, weekly injection of DEN also caused a significant decrease in overall body weight in comparison to untreated rats (398.1±60 vs. 598±46 grams; p<0.015), and pioglitazone treatment resulted in a trend for better protection of body weight relative to vehicle (398.1±60 vs. 427.5±56.3 grams).

Conclusion: Overall our data supports the hypothesis that the anti-diabetic agent pioglitazone may be repurposed as a drug to reduce fibrosis and prevent HCC. This could be beneficiary in patient management given the low cost as well as minimal side effects.

Citation Format: Shen Li, Sarani Ghoshal, Gunisha Arora, Derek J. Erstad, Michael Lanuti, Kenneth K. Tanabe, Bryan C. Fuchs. Pioglitazone prevents hepatocellular carcinoma development in a rat model of cirrhosis [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 5248. doi:10.1158/1538-7445.AM2017-5248
Abstract 5252: Quercetin inhibits prostate cancer by modulating ROS and key regulators of apoptosis and cell survival
Authors: Ward Ashley B. , Mir Hina , Kapur Neeraj , Sonpavde Guru , Singh Shailesh
Published: July 2017

Long latency and indolent nature of prostate cancer (PCa) provides a window of opportunity for preventive interventions using natural and synthetic agents. Hence, the focus of this study was to ascertain the chemopreventive role of Quercetin, a bioflavonoid, commonly used to treat prostatitis. Human PCa cells (LNCaP, DU145 and PC3) were treated with different concentrations of Quercetin and its effect on cell survival and apoptosis was determined by MTT assay. Human PCa cells treated with Quercetin showed significant reduction in cell viability and proliferation compared with untreated controls, which was dose and time dependent. In addition to this our FACS analysis showed higher percentage of apoptotic cells after Quercetin treatment compared to untreated cells. Quercetin induced apoptosis in PCa cells is a cumulative effect of modulation of key apoptotic proteins, changes in mitochondrial membrane potential and ROS production. Our results demonstrate that Quercetin is a potent chemopreventive agent, which may improve outcomes of PCa by inhibiting mechanisms involved in tumor progression.

Citation Format: Ashley B. Ward, Hina Mir, Neeraj Kapur, Guru Sonpavde, Shailesh Singh. Quercetin inhibits prostate cancer by modulating ROS and key regulators of apoptosis and cell survival [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 5252. doi:10.1158/1538-7445.AM2017-5252
Abstract 5266: The mechanisms of apoptosis induction by deubiquitylatinase inhibitor b-ap15 in esophageal squamous cell carcinoma cells
Authors: Li Pei , Chen Ping , Chen Xiao-Yu , Zhang Jing-Yang , Sha Bei-Bei , Hu Tao , Zhang Yi-Lin , Du Ying , Dong Zi-Ming
Published: July 2017

Deubiquitinases (DUBs) act on ubiquitinated substrates to catalyze the removal of ubiquitin moieties which can reverse the process of protein degradation, and further affect or regulate cell metabolism, proliferation and differentiation. As a novel small molecular inhibitor, b-AP15 can specifically inhibit the deubiquitinating activity of 19S regulatory subunit UCHL5(ubiquitin C-terminal hydrolase 5) and USP14(ubiquitin-specific peptidase 14) in cancer cells. In this study, we aimed to check whether b-AP15 have anti-tumor activity in esophageal cancer cells in vitro and try to explore the underling mechanisms.

Results: CCK-8 assay, colony formation assay and morphological observation results indicate that b-AP15 can significantly inhibit the proliferation activity of EC1 and Kyse 450 esophageal cancer(EC) cell lines in a concentration-dependent manner in vitro studies. Flow cytometry results show cells were arrested in G2/M phase after being treated with b-AP15. Western blot results show that the expression of G2/M phase related proteins p21, p27 and pWee1 significantly increased while the expression of the G1/S phase marker proteins including cyclinA, cyclinD show no significant change after being treated with b-AP15. FITC annexin V Apoptosis detection kit with PI and Caspase 3 Assay kit results show that b-AP15 treatment can significantly induce apoptosis in two EC cell lines. The results from western blot show that the expression of apoptotic protein c-PARP and c-caspase 3 significantly increased and was dose-dependent. JC-1 flow cytometry analysis show that b-AP15 treatment can significantly decrease mitochondrial membrane potential. All these results suggest that b-AP15 can induce EC cells apoptosis and may play certain role in mitochondrial control of apoptosis signaling pathway.

Conclusion: b-AP15 shows a significantly anti-tumor activity in vitro models of ESCC and the results confirm that b-AP15 can inhibit proliferation of EC cell lines by inducing cell-cycle arrest and promoting cell apoptosis.

Key words: b-AP15;esophageal cancer;deubiquitylatinase(DUBs);apoptosis;

Citation Format: Pei Li, Ping Chen, Xiao-Yu Chen, Jing-Yang Zhang, Bei-Bei Sha, Tao Hu, Yi-Lin Zhang, Ying Du, Zi-Ming Dong. The mechanisms of apoptosis induction by deubiquitylatinase inhibitor b-ap15 in esophageal squamous cell carcinoma 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 5266. doi:10.1158/1538-7445.AM2017-5266
Abstract 5267: Chemoprevention of lung carcinogenesis by dietary nicotinamide and inhaled budesonide
Authors: Seabloom Donna , Wuertz Beverly , Galbraith Art , Antonides Jenny , Steele Vernon , Wattenberg Lee , Ondrey Frank G.
Published: July 2017

Nicotinamide, the amide form of vitamin B3, and budesonide, a synthetic glucocorticoid used in the treatment of asthma, were evaluated for efficacy of chemoprevention of lung adenoma formation in a benzo(a)pyrene murine carcinogenesis model. Female A/J mice were given three doses of 3 mg benzo[a]pyrene three days apart and started on experimental diets either 1 week (early stage intervention) or 8 weeks (late stage) after last carcinogen dose. Aerosol treatments were delivered 5 days per week starting 1 or 8 weeks post carcinogen. Nicotinamide, fed at a dietary concentration of 0.75% starting 1 week after last carcinogen administration, inhibited adenoma formation by 54%, and by 39% when begun 8 weeks post final carcinogen. Nicotinamide fed at 0.25% of the diet was not found to effect adenoma formation . Dietary nicotinamide under the same conditions with budesonide administered via aerosol administration at 25μg/kg, reduced lung adenoma formation by 90% at early stage intervention and 49% at late stage intervention. Budesonide alone administered at the same dose level gave 77% inhibition at early stage and 41% inhibition at late stage. Decreases in adenoma formation were statistically significant via ANOVA analysis at both early and late interventions. Combination therapy decreased adenoma formation significantly over either individual therapy at the early stage and significantly compared to nicotinamide alone at the late stage. However, administration of nicotinamide by aerosol inhalation at doses up to 15 mg/kg/day did not result in a statistically significant reduction in tumor multiplicity at 1 or 8 weeks post last carcinogen administration . There is a high level of clinical interest in minimal toxicity lung cancer chemoprevention strategies. We feel administration of a safe dietary agent such as nicotinamide when combined with direct epithelial delivery of a glucocorticoid such as budesonide, commonly used for asthma therapy, is a promising approach for aerodigestive chemoprevention.

Citation Format: Donna Seabloom, Beverly Wuertz, Art Galbraith, Jenny Antonides, Vernon Steele, Lee Wattenberg, Frank G. Ondrey. Chemoprevention of lung carcinogenesis by dietary nicotinamide and inhaled budesonide [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 5267. doi:10.1158/1538-7445.AM2017-5267
Abstract 5268: Nexrutine and palmatine mediated effects on the STAT3/EP4/IL-6 axis in pancreatic cancer
Authors: Munoz Amanda R. , Bedolla Roble G. , Rivas Paul , Chakravarthy Divya , Reddick Robert L. , Hanes Martha A. , Halff Glenn A. , Ghosh Rita , Kumar Addanki P.
Published: July 2017

With a 5 year survival of less than 8%, the poor prognosis of pancreatic cancer (PanCA) underlines the importance of improving therapies for effective management of this disease. In previous studies, we identified the tumor cell growth inhibitory activities for Nexrutine® (Nx, a bark extract from Phellodendron amurense) and palmatine (PMT) which is a constituent of Nx. These studies revealed an important role for downregulation of KRAS downstream effectors including GLI, STAT3 and NF-κB in mediating growth inhibitory effects. Remarkably, both Nx and PMT exerted synergistic growth inhibitory effects in combination with the conventional chemotherapeutic agent, Gemcitabine (GEM). Despite such promising in vitro observations, the in vivo efficacy of Nx or PMT had not been established. In this investigation, we evaluated the ability of Nx and PMT to (i) prevent the development of pancreatic tumors; and (ii) inhibit the growth of patient derived pancreatic cancer tissue in short term ex vivo cultures. Studies were also conducted to investigate the underlying molecular mechanism using cell culture models. Our results show that both Nx and PMT are well tolerated in vivo as evidenced by a lack of significant changes in the body weights of athymic mice implanted with Capan-2 cells. Interestingly, both Nx and PMT showed a significant decrease in the circulating levels of inflammatory molecules including IL-6 and CXCL1. In this first proof-of-concept study, PMT treated animals demonstrated a trend towards decreased pancreatic tumor weight with associated histopathogical changes. Remarkably, both Nx and PMT inhibited the growth of patient derived pancreatic cancer cells. Mechanistic investigations identified downregulation of STAT3, TrkA, Src, and RPS6 activities as potential contributors to Nx or PMT-induced synergistic growth inhibitory effects with GEM. Further investigation of STAT3 signaling revealed the involvement of the prostaglandin receptor, EP4, in a potential feedback loop with STAT3 and in asserting STAT3-mediated inhibition of autophagy. Taken together these data support potential utility for Nx and/or PMT in the management of PanCA and suggest that these agents use multiple mechanisms to affect growth of pancreatic tumors. Supported by NCCIH (R01 AT007448; APK) and VA-MERIT Award (I01 BX 000766; APK).

Citation Format: Amanda R. Munoz, Roble G. Bedolla, Paul Rivas, Divya Chakravarthy, Robert L. Reddick, Martha A. Hanes, Glenn A. Halff, Rita Ghosh, Addanki P. Kumar. Nexrutine and palmatine mediated effects on the STAT3/EP4/IL-6 axis in pancreatic 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 5268. doi:10.1158/1538-7445.AM2017-5268
Abstract 5272: Chemopreventive activities of a polyphenol rich purified extract from olive oil processing on colon cancer cells
Authors: Bassani Barbara , Rossi Teresa , Stefano Daniela De , Pizzichini Daniele , Corradino Paola , Bruno Antonino , Noonan Douglas M. , Albini Adriana
Published: July 2017

Epidemiological studies showed that diet can play a relevant role in reducing the risk of developing colon cancer (CC) and lower rate of CC insurgence has been observed amongst populations living within the Mediterranean basin. Olive oil, a major component of the Mediterranean diet, is an abundant source of phenolic compounds. Olive oil production is associated with the generation of waste material, termed ‘olive mill wastewaters’ (OMWW), that have been reported to be enriched in polyphenols as well. Given the beneficial activity of polyphenols on human health, we investigated whether the use of different batches of purified extracts from OMWW, termed A009, might be effective in exerting chemopreventive activities in vitro and in vivo, on CC cell lines.

Cell proliferation and survival were evaluated on A009 treated cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while the induction of apoptosis was assessed by flow cytometry. Further, functional studies to investigate the ability of A009 to interfere with CC cell line adhesion, migration, sprouting and invasion were performed. Finally, the ability of A009 to interfere with CT-26 CRC tumour cell growth was assessed in vivo. Purified hydroxytyrosol, the major component in the A009 extracts, was used as a control.

A009 inhibited cell proliferation, migration, invasion, adhesion and sprouting of CC cells along with the release of pro-angiogenic and pro- inflammatory cytokines (VEGF, IL-8) similar to hydroxytyrosol alone. In vivo, A009 inhibited CT-26 tumour growth in a significant manner over that of hydroxytyrosol alone.

Our results show that A009 extracts exert promising chemopreventive properties, suggesting that different polyphenols act synergistically, improving their single component effects in CC cell lines. Finally, our results support the idea of repositioning a waste derived material for nutraceutical employment, with environmental and industrial cost management benefits.

Citation Format: Barbara Bassani, Teresa Rossi, Daniela De Stefano, Daniele Pizzichini, Paola Corradino, Antonino Bruno, Douglas M. Noonan, Adriana Albini. Chemopreventive activities of a polyphenol rich purified extract from olive oil processing on colon 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 5272. doi:10.1158/1538-7445.AM2017-5272
Abstract 5273: Detection of sessile serrated adenomas/polyps in African Americans
Authors: Atefi Nazli , Singh Sanmet , Shokrani Babak , Lee Edward , Afsari Ali , Nouraie Mehdi , Laiyemo Adeyinka , Mathews Joseph , Williams Carla , Brim Hassan , Ashktorab Hassan
Published: July 2017

Introduction: The majority of colorectal cancers (CRCs) develop through the adenoma-carcinoma sequence, while 15-20% develop via the serrated pathway. Sessile Serrated Adenoma/Polyps (SSA/P) are more difficult to detect during colonoscopy and generally require a shorter time follow-up than other lesions (3 vs. 5 years). These polyps lead to cancer faster than conventional adenomas. In order to better define patients at risk for these lesions, we performed a retrospective study to evaluate clinicopathological features of patients diagnosed with SSA/P.

Methods: We reviewed pathology reports of patients at Howard University Hospital from 2010-2015. We identified 5,900 patients with colorectal lesions, of whom 312 (5.3%) were diagnosed with SSA/P. We analyzed the specific clinical, pathological and demographic features of patients with SSA/P lesions.

Results: We identified 312 cases with SSA/P. The incidence of SSA/P over the 5 years period was 5.3%: 198/312 (63.4%) patients had 2 or more polyps, 54.5% of the SSA/P patients were females, 70.5% of patients were 50-64 years of age and 18% were older than 65. SSA/P lesions’ locations were as follows: rectal: 32.1%; rectosigmoid: 18.6%; sigmoid: 16.8%; Ascending Colon: 13.2 % and Descending Colon: 7.1%. Reasons for colonoscopy were as follows: Screening: 43.6 %; GI bleeding: 15.1%; Abdominal Pain: 13.1%and Change in Bowel Habits: 10.2%.

Conclusion: Our results show that there is a slightly increased predominance of SSA/P occurrence in females. Most SSA/P occurred in patients 50 to 64 years old. This age range is younger in comparison to patients with conventional adenomas. SSA/Ps were predominantly distal (rectal, rectosigmoid, sigmoid) whereas previous literature reports a proximal location. Most patients in our study were diagnosed in screening colonoscopies; however, other patients presented with symptoms such as GI bleeding, abdominal pain, or change in bowel habits.

Citation Format: Nazli Atefi, Sanmet Singh, Babak Shokrani, Edward Lee, Ali Afsari, Mehdi Nouraie, Adeyinka Laiyemo, Joseph Mathews, Carla Williams, Hassan Brim, Hassan Ashktorab. Detection of sessile serrated adenomas/polyps in African Americans [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 5273. doi:10.1158/1538-7445.AM2017-5273
Abstract 5279: Association of Vitamin D deficiency with breast cancer in African-American and Hispanic women in south Los Angeles
Authors: Wu Yanyuan , Sarkissyan Marianna , Clayton Sheilah , Vadgama Jay
Published: July 2017

Background: Experimental evidence supports a protective role of Vitamin D level in breast carcinogenesis, but epidemiologic evidence is inconsistent. African Americans have high prevalence of Vitamin D deficiency and the African American women with breast cancer have the highest mortality rate. The aim of this study is to investigate the association of Vitamin D levels with breast cancer risk and disease progression in African American and Hispanic women.

Methods: This is a cases-control study of 660 African American and Hispanic women with and without breast cancer in South Los Angeles. Blood samples were collected prior cancer treatment and the serum 25-hydroxyvitamin D (25(OH) D was measured by Quest Diagnostics. Information regarding BMI and clinical factors were obtained by medical record abstraction. Logistic Regression with multivariate analysis was used for determining the association of Vitamin D deficiency (<20ng/ml) with breast cancer. Kaplan-Meier survival analysis and Cox Regression with multivariate analysis were used to assess disease-free survival and the relative risk of disease progression.

Results: Our data shows that 69.2% of African American women and 37.8% of Hispanic women suffer from Vitamin D deficiency in our cohort. African American women had significant lower level of Vitamin D3 compared with Hispanic women in all age groups. The lower Vitamin D3 level was observed among age groups of 31 to 50 in African Americans. The deficiency in Vitamin D levels was significantly associated with breast cancer in both African Americans (OR=2.5, p=0.007) and Hispanics (OR=1.9, p=0.009). Interestingly, we found that a significant association of Vitamin D deficiency with trip negative breast cancer (TNBC) in African Americans (OR=3.2, p=0.04), but not in Hispanics. The lowest Vitamin D3 level was observed in African American women with TNBC. There was no significant association of Vitamin D deficiency with tumor size, lymph node involvement and tumor stage. The deficiency of Vitamin D3 level was not associated with disease progression in this cohort of women.

Conclusion: Our data suggests that a significant association of Vitamin D deficiency with breast cancer in both African Americans and Hispanics, especially more associated with type of TNBC in African American women in our cohort.

Citation Format: Yanyuan Wu, Marianna Sarkissyan, Sheilah Clayton, Jay Vadgama. Association of Vitamin D deficiency with breast cancer in African-American and Hispanic women in south Los Angeles [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 5279. doi:10.1158/1538-7445.AM2017-5279
Abstract 5284: Gastric cancer in Alaska Native people: A cancer health disparity
Authors: Martinson Holly , Alberts Steven , Olnes Matthew
Published: July 2017

Gastric cancer in the Alaska Native (AN) people occurs at a 3-fold higher incidence and 4-fold higher mortality rate compared to Non-Hispanic Whites (NHW), representing one of the largest cancer disparities in the AN population. We aimed to review the AN gastric cancer burden and identify clinicopathological factors that are associated with cancer outcomes. Patient information was collected from 132 AN gastric cancer patients diagnosed between 2006-2015 at the Alaska Native Medical Center. The Surveillance, Epidemiology and End Result database 18 was used to collect comparison United States NHW gastric cancer patient data. Compared to NHW patients, AN gastric cancer patients have a higher incidence rate, are significantly younger, 60 versus 69 years, and have a poorer 5-year overall survival rate of 10% compared to 22%. AN patients differ from NHW patients in gastric cancer anatomic location, subtype, and higher presence of signet ring cell carcinomas. Forty-one percent of AN patients were positive at the time of diagnosis for Helicobacter pylori, 77% had chronic gastritis, 30% had a family history of a first-degree relative with gastrointestinal cancers, and 82% were current or former tobacco users. Using univariate analysis, diminished overall survival was observed with anatomic site, increasing stage, no treatment, the number of lymph nodes examined during resection, blood type, and chronic gastritis. Multivariable analysis revealed stage and treatment type were independently associated with improved overall survival. AN gastric cancer cases vary in their clinical and epidemiologic features, relative to NHW.

Citation Format: Holly Martinson, Steven Alberts, Matthew Olnes. Gastric cancer in Alaska Native people: A cancer health disparity [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 5284. doi:10.1158/1538-7445.AM2017-5284
Abstract 5288: Perception of barriers and facilitators to hepatitis B virus screening, vaccination, and treatment care among Asian American physicians
Authors: Estrella Patricia , Yeh Ming Chin , Tan Yin , Fang Carolyn Y. , Golub Sarit A. , Ma Grace X.
Published: July 2017

Objective: To examine practices and factors affecting Hepatitis B Virus (HBV) screening, vaccination, and treatment among Asian-American physicians in New York City.

Methods: Members of the Chinese American Independent Practice Association (CAIPA) will be recruited to participate in a comprehensive survey, developed based on prior research, to assess physicians’ practice in HBV screening, vaccination and treatment. This study will also examinebarriers/facilitators toward HBV prevention and treatment in knowledge, familiarity or awareness of guidelines, perception, attitude/behaviors, self-efficacy, motivation, patient factors, cultural, and environmental factors. A bivariate analysis and multivariate regressions will be conducted to evaluate factors that predict study outcomes.

Results: We hypothesize that Asian American physicians are more likely to screen for HBV, but are experiencing many barriers unique to the Asian American physicians that are leading them improperly perceive certain patients not at risk for HBV infection. Furthermore, we anticipate finding significant key barriers and facilitators among Asian American physicians for HBV screening and vaccination and treatment towards Asian patients. Preliminary findings will be presented at the conference.

Conclusions & Implications: Asian/Pacific Islanders (APIs) are disproportionally affected by chronic hepatitis B. Therefore, identifying chronically infected persons and linking them to care is crucial. As a result of the reverence of the doctors, a cultural norm prevalence within the Asian community, physicians are uniquely positioned to improve HBV screening and vaccination rates and if necessary, recommend linkage to care. This study will fill in an important gap in creating a culturally-relevant, physician-focused intervention to improve HBV care and reduce the burden of HBV infection within the Asian community.

Citation Format: Patricia Estrella, Ming Chin Yeh, Yin Tan, Carolyn Y. Fang, Sarit A. Golub, Grace X. Ma. Perception of barriers and facilitators to hepatitis B virus screening, vaccination, and treatment care among Asian American physicians [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 5288. doi:10.1158/1538-7445.AM2017-5288
Abstract 5289: Assessment of environmental influences, behavioral risk factors and genetic differences among a cohort of 819 African American community members
Authors: Bucci Jacquelyn , Yeh Ming Chin , Navder Khursheed , Erblich Joel , Blackman Elizabeth , Ma Grace X. , Ragin Camille
Published: July 2017

Objectives: This study was designed to address genetic, environmental and lifestyle risk factors for cancer in populations of African Ancestry. We have established a non-cancer control registry which involves the collection of epidemiological, lifestyle, culture and cancer prevention behaviors (such as cancer screening and diet, etc).

Methods: Data was coded and analyzed using Stata from initial study surveys.

Results: At analysis, the cohort consisted of 819 participants. The cohort was 65.9% female, ages 18-89 (23.5% within 50-59 age group), 35.9% college graduates, and 17.4% with income level $20,000-$25,000. Two-thirds of the cohort had BMI greater than 25, indicating overweight or obese. When stratified by country of birth, participants born in the US & Territories were more likely to be current smokers (23.3%) and have higher rates of environmental exposure to smoking than any other region of birth analyzed. Participants from US & Territories had the highest access to health care (85.9%). Pap smears were the only screening test with statistically significant difference between the regions, with US & Territories having the highest rates of screening (p < 0.001).

Conclusions & Implications: Overall, the cohort and its data provide researchers with a resource to further investigate health disparities in cancer as well as other chronic diseases and tailor culturally relevant education materials to help decrease the rates of cancer in this vulnerable population.

Citation Format: Jacquelyn Bucci, Ming Chin Yeh, Khursheed Navder, Joel Erblich, Elizabeth Blackman, Grace X. Ma, Camille Ragin. Assessment of environmental influences, behavioral risk factors and genetic differences among a cohort of 819 African American community members [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 5289. doi:10.1158/1538-7445.AM2017-5289
Abstract 530: The role of EGFR in c-fos-dependent osteosarcoma formation
Authors: Linder Markus , Glitzner Elisabeth , Srivatsa Sriram , Shahrouzi Parastoo , Bakiri Latifa , Dumanic Monika , Mitterhauser Markus , Wagner Erwin F. , Sibilia Maria
Published: July 2017

The Epidermal Growth Factor Receptor (EGFR) is overexpressed or mutated in human carcinomas and glioblastomas, which are tumors of epithelial and glial origin, respectively. Some publications indicated that EGFR overexpression could occur in human osteosarcomas (OS). Using EGFR knockout mice (Egfr-/-), we have recently shown that EGFR plays a role in bone development and osteoblast function, raising the possibility that EGFR is also involved in OS formation. Here we show that Egfrf/f Runx2-Cre mice (EgfrΔOb), lacking the EGFR in osteo-chondroprogenitor cells, develop an increased zone of hypertrophic chondrocytes in long bones and decreased bone formation. When bred to c-fos transgenic mice (H2-c-fosLTR) that develop osteosarcomas with 100% penetrance, EgfrΔOb mice show reduced tumor incidence and burden. At the molecular level, tumors from EgfrΔOb mice exhibit decreased expression levels of c-Fos and Cyclin D1. In vitro experiments in primary bone tumor cells further show that EGFR inhibition leads to reduced proliferation and increased apoptosis. Importantly, Egfr and c-Fos also play an important role in human OS, as co-expression of both proteins in tumor sections correlated with significantly reduced survival in patients suffering from primary OS. Taken together our data suggest an essential role of EGFR signaling during both development and progression of c-Fos-dependent OS and newly identified molecular targets currently under investigation will be presented.

Citation Format: Markus Linder, Elisabeth Glitzner, Sriram Srivatsa, Parastoo Shahrouzi, Latifa Bakiri, Monika Dumanic, Markus Mitterhauser, Erwin F. Wagner, Maria Sibilia. The role of EGFR in c-fos-dependent osteosarcoma formation [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 530. doi:10.1158/1538-7445.AM2017-530
Abstract 5301: Cancer causation: rethinking the role of analogy
Authors: Weed Douglas L.
Published: July 2017

Introduction. Fifty years has passed since the publication of Austin Bradford Hill’s classic paper on causal inference. Much has changed in the biomedical and public health sciences regarding cancer causation during that half century, but Hill’s considerations (often called “criteria”) remain durable. That said, there is a curious phenomenon involving Hill’s seminal work that has escaped the attention of the scientific community. His consideration of analogy—the last on his list just after experimentation—has all but disappeared. The purpose of this paper is to rethink and resurrect analogy as an important consideration in causal inference in environmental epidemiology.

Methods. Given that this is a conceptual—non-quantitative—project, the methods used are the informal logic of scientific thinking, methods of systematic reviews, and judgment.

Results. In contemporary epidemiology, analogy is either completely ignored (e.g. in many textbooks), equated with biologic plausibility or coherence, or aligned with the scientist’s imagination. None of these examples, however, capture Hill’s description of analogy which emphasizes the contrast of two bodies of evidence. Coupled with developments in the methods of systematic assessments of evidence—including but not limited to meta-analysis—analogy can be restructured as a key component of causal inference. For theoretical support see similar methods in biomedical ethics and artificial intelligence. Practical examples will be discussed.

Conclusions. Analogical reasoning—an updated version of analogy—can emerge assuming the following developments: (1) a collection—a library—of known cases of causal inference (i.e. bodies of evidence involving established causal relationships), including, for example, the assessments of the International Agency for Research on Cancer (IARC) and the National Toxicology Program (NTP), (2) a systematic process for describing the key features of a causal relationship creating paradigm cases, and (3) an objective comparison of a “new” body of evidence for a putative causal relationship with a relevant paradigm case.

Citation Format: Douglas L. Weed. Cancer causation: rethinking the role of analogy [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 5301. doi:10.1158/1538-7445.AM2017-5301
Abstract 5306: p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status
Authors: Lubpairee Tarinee , Prigge Elena , Doeberitz Magnus von Knebel , Reuschenbach Miriam , Zhang Lewei , Rosin Miriam P.
Published: July 2017

Objectives: p16INK4a is a key gatekeeper for multiple biological processes that are associated with protection from cancer, including cell cycle control and senescence. Elevated expression of this gene is strongly correlated with biological activity of HPV infection and cancer development in uterine cervix and tonsil. Although HPV DNA has been found in a small portion of oral cavity cancers and dysplasia, the relevance of its presence to cancer development at this site is unclear, as is the significance of an expression change in p16INK4a as a predictor of HPV status, tissue behavior and outcome.

Methods: Formalin-fixed, paraffin-embedded biopsies from 164 patients with mild, moderate and severe oral dysplasia in the “Oral Cancer Prediction Longitudinal study” (OCPL), British Columbia, Canada, were analyzed for HPV DNA using a semi-quantitative viral load Luminex technology. Expression of p16INK4a was assessed and categorized into 3 staining patterns (diffuse, focal, and negative).

Results: HPV DNA was found in 13 (8%) lesions, 7 had HPV-16 infection and 1 HPV-18. Of the 164 samples, diffuse p16INK4a expression was present in 18%, focal in 56% and no p16 staining in 23% of samples. There was no significant correlation between HPV DNA-positivity and p16INK4a staining. Different p16 staining patterns showed significantly different progression rates (P < 0.0001): progression occurred in 1/92 (1.1%) focally stained, 1/29 (3.5%) diffusely stained and 10/43 (23.3%) with no staining.

Conclusion: HPV DNA-positivity occurs in a small proportion of oral dysplasia but is poorly associated with p16INK4a expression. Future assessment of these samples for HR-HPV oncogene transcripts will provide information on its biological activity. The low likelihood of progression of p16INK4a focally stained lesions suggests a value of this marker in identification of low-risk cases.

Acknowledgements: Supported by Else Kröner-Fresenius-Stiftung Foundation, Germany

Citation Format: Tarinee Lubpairee, Elena Prigge, Magnus von Knebel Doeberitz, Miriam Reuschenbach, Lewei Zhang, Miriam P. Rosin. p16INH4a status helps predict clinical outcome of dysplasia in the oral cavity irrespective of HPV status [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 5306. doi:10.1158/1538-7445.AM2017-5306
Abstract 5307: Analysis of volatile organic compounds for the diagnosis of lung cancer
Authors: Inoue Takuya , Takagi Hironori , Owada Yuki , Watanabe Yuzuru , Fukuhara Mitsuro , Yamaura Takumi , Muto Satoshi , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Manami Takeda , Sato Atsushi , Suzuki Hiroyuki
Published: July 2017

Background: Lung cancer is the leading cause of cancer-related deaths in the world. The prognosis of lung cancer depends on disease detection at an early stage. Recently, effectiveness of lung cancer screening by using low dose computed tomography scanning have been showing. However, it still has problems such as cost of screening and radiation exposure. Thus, less invasive and cost beneficial lung cancer screening procedure would be needed. In this context, several study to understand the efficacy of molecules from expiration of patients as a lung cancer screening were showing, but it was still controversial. In this study, we investigated to determine whether volatile organic compounds (VOC) from patients could be used for the detection for lung cancer by using novel small and unique absorbent material named MonoTrap .

Method: The subjects’ gas was collected from skin and exhaled breath in a MonoTrap (GL sciences), and the VOCs were analyzed by gas chromatography/ mass spectrometry (GC/MS). First of all, we preliminary analyzed for both sample from skin and exhaled breath for 12 patients and 11 healthy volunteers to clarify which samples were more sensitive to diagnose lung cancer. Subsequently, each VOC was determined in detail for 7 healthy individuals and 4 lung cancer patients and these values were statistically analyzed.

Results: By preliminary study, characteristics of VOC derived from skin were significantly correlated with cancer condition as compared with healthy volunteer by using comprehensive multivariate analysis. Therefore, we performed further quantitative analysis by targeting unique individual molecules derived from skin. In VOCs from skin, Mann-Whitney U test showed that 4-hydroxy-4-methyl-2-pentanone, hexadecane, and acetamide were significantly higher in lung cancer patients (p=0.036, p=0.006, p=0.036, respectively).

Conclusion: In this study, we found that 3 kinds of VOCs could be a potential diagnostic biomarkers of lung cancer. Further prospective study is now planning to validate these data using large number samples.

Citation Format: Takuya Inoue, Hironori Takagi, Yuki Owada, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Satoshi Muto, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Takeda Manami, Atsushi Sato, Hiroyuki Suzuki. Analysis of volatile organic compounds for the diagnosis of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5307. doi:10.1158/1538-7445.AM2017-5307
Abstract 5314: Long-term folate intake and prostate cancer risk in the health professionals follow-up study
Authors: Hamieh Nadine M. , Batista Julie L. , Markt Sarah C. , Downer Mary K. , Mucci Lorelei A. , Stampfer Meir J. , Giovannucci Edward L. , Wilson Kathryn M.
Published: July 2017

Background: Randomized trials of supplemental folate and observational studies of circulating folate support a positive association with prostate cancer risk. However, epidemiological studies of dietary and synthetic folate intake are conflicting. Given mandatory folic acid fortification of grains in the US beginning in 1998, evaluation of long-term folate intake from natural and synthetic sources in relation to prostate cancer risk is warranted.

Methods: We examined the association between folate intake and prostate cancer risk among 47,884 men in the Health Professionals Follow-up Study who were free from diagnosed cancer at baseline in 1986. Total, natural (from food sources), and synthetic (from supplements/fortification) folate intake was assessed every 4 years using a validated food frequency questionnaire, and categorized as the cumulative average and lagged (0-4, 4-8, 8-12, and 12-16 years in the past) intakes. Cox proportional hazards regression was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (CI).

Results: We identified 6,186 incident prostate cancer cases from 1986-2012, including 1,078 with lethal disease (distant metastasis or death). Mean total folate intake was 481 µg/day in 1986 and increased to 671 µg/day by 2010. The proportion of men meeting the recommended intake of 400 µg/day increased from 47% in 1986 to 74% after fortification began in 1998. Folate intake was positively correlated with physical activity, multivitamin use, and PSA testing, and inversely correlated with smoking. Total folate intake averaged over time was not significantly associated with total prostate cancer risk: HR≥800 vs. 400-599=1.03 (95% CI: 0.95-1.13, p-trend=0.76). Neither natural nor synthetic folate intake was associated with risk of total prostate cancer. No associations were observed between total, natural, or synthetic folate intake and risk of lethal, advanced stage, or high-grade disease.

Conclusions: Our findings do not support strong associations between intakes of total, natural, or synthetic folate and prostate cancer risk. We found no indication that folate intake of ≥800 µg/day (twice the recommended level) increases prostate cancer risk.

Citation Format: Nadine M. Hamieh, Julie L. Batista, Sarah C. Markt, Mary K. Downer, Lorelei A. Mucci, Meir J. Stampfer, Edward L. Giovannucci, Kathryn M. Wilson. Long-term folate intake and prostate cancer risk in the health professionals follow-up study [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 5314. doi:10.1158/1538-7445.AM2017-5314
Abstract 5320: Folate and other nutrients related to one-carbon metabolism and risk of melanoma
Authors: Dhana Ashar , Yen Hsi , Li Tricia , Holmes Michelle , Qureshi Abrar , Cho Eunyoung
Published: July 2017

Background: Nutrients involved in one-carbon metabolism - folate, vitamins B6 and B12, methionine, choline, and betaine - have been associated with multiple cancer sites. However, no study has assessed the association between these nutrients and risk of melanoma. Thus, the aim of this study was to evaluate the association between intake of these nutrients and melanoma risk within two prospective cohorts: the Nurses’ Health Study (NHS) and Health Professionals Follow-up Study (HPFS).

Methods: The cohorts included a total of 81,685 women in the NHS (1984 to 2010) and 49,617 men in the HPFS (1986 to 2010). We assessed nutrient intakes using a semi-quantitative food frequency questionnaire every 2 to 4 years. Total nutrient intake included both dietary and supplemental intake. Dietary intake included intake from food only. Study physicians reviewed medical and pathological records to confirm self-reported cases of invasive melanoma. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and then pooled the HRs for both cohorts using a random effects model.

Results: Over 24 to 26 years of follow-up, we documented 1,321 cases (641 men and 680 women) of invasive melanoma. Higher intake of folate from food only, but not total folate, was associated with increased risk of melanoma. The pooled multivariable HRs for the top versus bottom quintiles were 1.17 (95 % CI: 0.98-1.41; P for trend = 0.17) for total folate and 1.37 (95 % CI: 1.13-1.65; P for trend = 0.001) for folate from food only. The association was statistically significant in men, but not in women. Higher intake of vitamins B6 and B12, choline, betaine, and methionine was not associated with risk of melanoma.

Conclusion: We found some evidence that folate from food only, but not total folate, was associated with a modest increased risk of melanoma - a finding that warrants further investigation. Conversely, our findings suggest that other nutrients involved in one-carbon metabolism do not play an important role in the etiology of melanoma.

Citation Format: Ashar Dhana, Hsi Yen, Tricia Li, Michelle Holmes, Abrar Qureshi, Eunyoung Cho. Folate and other nutrients related to one-carbon metabolism and risk of 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 5320. doi:10.1158/1538-7445.AM2017-5320
Abstract 5328: RNF12 inhibits the proliferation of hepatocellular carcinoma through c-Myc and p21
Authors: Nie Meng , Huang Yongsheng , Wang Lin
Published: July 2017

Purpose: RNF12/RLIM, a RING E3 ubiquitin ligase, plays an important role in the epigenetic regulation of sex-specific nurturing tissues in female mice. Recently, a few studies demonstrated a correlation between RNF12 and the proliferation of multiple cancers. The role of RNF12 in hepatocellular carcinoma is incompletely understood. The purpose of this study is to investigate the effect of RNF12 on the proliferation of human hepatocellular carcinoma cells. RNF12 is also known to interact with a number of nuclear proteins, including CLIM, HDAC2, and Smad4. We also explored whether c-Myc and p21, an oncogene and tumor suppressor essential to liver tumorigenesis, were affected by RNF12.

Methods: Immunohistochemistry of RNF12 and c-Myc was performed on surgically dissected human hepatocellular carcinoma tissues. The soft-agar cloning, flow cytometry and Transwell invasion assays were carried out to investigate the role of RNF12 in SK-Hep1 cell proliferation, cell cycle and invasiveness. Real-time quantitative PCR and Western blotting were used to examine the mRNA and protein levels of RNF12 and related proteins in SK-Hep1 cells.

Results: We found that the level of RNF12 was lower in hepatocellular carcinoma, compared with the surrounding non-cancerous tissues, while the c-Myc expression was higher. Using a SK-Hep1 cell line stably expressing RNF12, we showed that RNF12 over-expression inhibited cell proliferation and induced cell cycle arrest at G1 phase. Furthermore, we showed that RNF12 over-expression decreased the level of oncoprotein c-Myc, while not much affecting its mRNA level. Co-immunoprecipitation demonstrated that RNF12 and c-Myc associated with each other, suggesting a direct protein-protein interaction. RNF12 over-expression also markedly increased the mRNA and protein levels of p21, a tumor suppressor and the downstream target of p53, c-Myc and many other cancer-related regulators. Consistently, silencing of RNF12 reduced p21 mRNA and protein levels and increased c-Myc protein.

Conclusion: Our study demonstrated reduced expression of RNF12 in hepatocellular carcinoma, and RNF12 over-expression inhibited the proliferation and cell cycle progression of SK-Hep1 cells. Mechanistically, RNF12 may directly regulate the level of c-Myc, similarly as other transcription factors such as CLIM and Smad4. The mechanisms underlying the increased expression of p21 is being investigated. Taken together, RNF12 may serve as a tumor suppressor in hepatocellular carcinoma, partly through oncoprotein c-Myc and tumor suppressor p21.

Note: This abstract was not presented at the meeting.

Citation Format: Meng Nie, Yongsheng Huang, Lin Wang. RNF12 inhibits the proliferation of hepatocellular carcinoma through c-Myc and p21 [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 5328. doi:10.1158/1538-7445.AM2017-5328