Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2587
A. Benmoussa, L. Levasseur, Shuxia Coté-Sergerie, V. Bélanger, E. Levy, C. Laverdière, A. Stintzi, D. Sinnett, V. Marcil
{"title":"Abstract 2587: Investigating the impact of chemotherapy on gut microbiota and microbiota-derived metabolites and their link to inflammation and cardiometabolic disorders in children with cancer","authors":"A. Benmoussa, L. Levasseur, Shuxia Coté-Sergerie, V. Bélanger, E. Levy, C. Laverdière, A. Stintzi, D. Sinnett, V. Marcil","doi":"10.1158/1538-7445.AM2021-2587","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2587","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90627887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-109
Jill P. Smith, H. Cao, B. Kallakury, T. Phillips, L. Sutton, A. Cato
{"title":"Abstract 109: Vaccination with Polyclonal Antibody Stimulator (PAS) prevents pancreatic carcinogenesis in the KRAS mouse model","authors":"Jill P. Smith, H. Cao, B. Kallakury, T. Phillips, L. Sutton, A. Cato","doi":"10.1158/1538-7445.AM2021-109","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-109","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88693535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-LB222
Louise Wang, H. Desai, A. Le, R. Hausler, S. Verma, A. Verma, R. Judy, A. Doucette, P. Gabriel, S. Damrauer, M. Ritchie, Daniel Rader, R. Kember, K. Maxwell
Background: Genome wide association studies (GWAS) have identified hundreds of common, low risk genetic variants significantly associated with a number of gastrointestinal cancers, but the predictive ability of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear especially among minorities. Specific Aims: To evaluate the discriminatory ability of PRS models to differentiate cancer cases vs. controls in patients of European (EUR) and African (AFR) ancestry in an academic biobank. Methods: We identified 445 cases of esophageal, colon, and pancreatic cancers and 12,565 cancer-free controls. Genome-wide significant variants were selected for each of the cancers, and Plink 1.9 was used to generate a PRS, an effect size weighted sum of specific cancer associated alleles for each population. To determine the discriminatory ability of PRS, we performed multivariate logistic regressions in R controlling for age, sex, and the first 10 principal components. Results: There were 285 cases of colon (48.4% AFR), 63 cases of esophageal (34.9% AFR), and 97 cases of pancreatic cancer (51.5% AFR) vs. 12,565 controls (48.5% AFR). Among the EUR individuals, the PRScolon was significantly associated with colon cancer [OR 1.25 (1.06-4.48, p=0.007)] (Table 1). The discriminatory ability of the model comprised of age, gender and principal components was 0.680-0.732 in the respective cancer cancers and the AUC minimally increased to 0.688-0.747 after inclusion of the PRS in the model. Among AFR individuals, the discriminatory ability was overall higher in the full model (AUC 0.755-0.812) but PRS increased the AUC less in AFR vs. EUR. Conclusion: Colon, esophageal, and pancreatic cancer PRS models have a moderate discriminatory ability to identify cases. However, the individual contribution of PRS to the model was small. Further studies are needed to determine additional genetic predictors of cancer risk and how best to incorporate PRS into gastrointestinal cancer risk prediction models. Citation Format: Louise Wang, Heena Desai, Anh Le, Ryan Hausler, Shefali Verma, Anurag Verma, Renae Judy, Abigail Doucette, Peter Gabriel, Scott Damrauer, Marylyn Ritchie, Daniel Rader, Rachel Kember, Kara Maxwell. Performance of polygenic risk scores for GI cancer prediction in an academic biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB222.
背景:全基因组关联研究(GWAS)已经确定了数百种常见的低风险遗传变异与许多胃肠道癌症显著相关,但个体变异或多基因风险评分(PRS)的预测能力仍不清楚,特别是在少数民族中。具体目的:评估PRS模型在学术生物库中区分欧洲(EUR)和非洲(AFR)血统患者的癌症病例与对照组的区别能力。方法:我们确定了445例食管癌、结肠癌和胰腺癌以及12565例无癌对照。为每种癌症选择全基因组显著变异,并使用Plink 1.9生成PRS,即每个人群的特定癌症相关等位基因的效应大小加权总和。为了确定PRS的区分能力,我们对年龄、性别和前10个主成分进行了多变量logistic回归。结果:结肠癌285例(48.4%),食管癌63例(34.9%),胰腺癌97例(51.5%),对照组12565例(48.5%)。在EUR个体中,PRScolon与结肠癌显著相关[OR 1.25 (1.06-4.48, p=0.007)](表1)。由年龄、性别和主成分组成的模型在各自癌症中的区分能力为0.680-0.732,将PRS纳入模型后,AUC最低增加到0.688-0.747。在AFR个体中,在完整模型中,歧视能力总体上更高(AUC 0.755-0.812),但与欧元相比,PRS对AFR个体的AUC增加较少。结论:结肠癌、食管癌和胰腺癌PRS模型具有中等的鉴别能力。然而,PRS对模型的个人贡献很小。需要进一步的研究来确定癌症风险的其他遗传预测因子,以及如何最好地将PRS纳入胃肠道癌症风险预测模型。引文格式:Louise Wang, Heena Desai, Anh Le, Ryan Hausler, Shefali Verma, Anurag Verma, Renae Judy, Abigail Doucette, Peter Gabriel, Scott Damrauer, marilyn Ritchie, Daniel Rader, Rachel Kember, Kara Maxwell。多基因风险评分在学术生物库中预测胃肠道癌症的表现[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要nr LB222。
{"title":"Abstract LB222: Performance of polygenic risk scores for GI cancer prediction in an academic biobank","authors":"Louise Wang, H. Desai, A. Le, R. Hausler, S. Verma, A. Verma, R. Judy, A. Doucette, P. Gabriel, S. Damrauer, M. Ritchie, Daniel Rader, R. Kember, K. Maxwell","doi":"10.1158/1538-7445.AM2021-LB222","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-LB222","url":null,"abstract":"Background: Genome wide association studies (GWAS) have identified hundreds of common, low risk genetic variants significantly associated with a number of gastrointestinal cancers, but the predictive ability of individual variants or a polygenic risk score (PRS) derived from multiple variants is still unclear especially among minorities. Specific Aims: To evaluate the discriminatory ability of PRS models to differentiate cancer cases vs. controls in patients of European (EUR) and African (AFR) ancestry in an academic biobank. Methods: We identified 445 cases of esophageal, colon, and pancreatic cancers and 12,565 cancer-free controls. Genome-wide significant variants were selected for each of the cancers, and Plink 1.9 was used to generate a PRS, an effect size weighted sum of specific cancer associated alleles for each population. To determine the discriminatory ability of PRS, we performed multivariate logistic regressions in R controlling for age, sex, and the first 10 principal components. Results: There were 285 cases of colon (48.4% AFR), 63 cases of esophageal (34.9% AFR), and 97 cases of pancreatic cancer (51.5% AFR) vs. 12,565 controls (48.5% AFR). Among the EUR individuals, the PRScolon was significantly associated with colon cancer [OR 1.25 (1.06-4.48, p=0.007)] (Table 1). The discriminatory ability of the model comprised of age, gender and principal components was 0.680-0.732 in the respective cancer cancers and the AUC minimally increased to 0.688-0.747 after inclusion of the PRS in the model. Among AFR individuals, the discriminatory ability was overall higher in the full model (AUC 0.755-0.812) but PRS increased the AUC less in AFR vs. EUR. Conclusion: Colon, esophageal, and pancreatic cancer PRS models have a moderate discriminatory ability to identify cases. However, the individual contribution of PRS to the model was small. Further studies are needed to determine additional genetic predictors of cancer risk and how best to incorporate PRS into gastrointestinal cancer risk prediction models. Citation Format: Louise Wang, Heena Desai, Anh Le, Ryan Hausler, Shefali Verma, Anurag Verma, Renae Judy, Abigail Doucette, Peter Gabriel, Scott Damrauer, Marylyn Ritchie, Daniel Rader, Rachel Kember, Kara Maxwell. Performance of polygenic risk scores for GI cancer prediction in an academic biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB222.","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87140927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2550
Ghadeer Albashir, S. J. Sojourner, Marlo M. Vernon, J. Moore, S. Looney, M. Tingen
{"title":"Abstract 2550: Participant's satisfaction with the cancer community awareness access research and education (C-CARE) project at urban and rural sites","authors":"Ghadeer Albashir, S. J. Sojourner, Marlo M. Vernon, J. Moore, S. Looney, M. Tingen","doi":"10.1158/1538-7445.AM2021-2550","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2550","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"689 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85719296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2522
Xiu Liu, Xuan Zhang, K. Ou, Chelong Lu, Dong-Huan Zheng, Jun Liu, Qiang Xu, Lin Yang
{"title":"Abstract 2522: Exploring the prognostic and predictive value of circulating tumor DNA in patients with advanced colorectal cancer and chemotherapy","authors":"Xiu Liu, Xuan Zhang, K. Ou, Chelong Lu, Dong-Huan Zheng, Jun Liu, Qiang Xu, Lin Yang","doi":"10.1158/1538-7445.AM2021-2522","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2522","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83204896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-108
Yongtao Wang, M. Sojoodi, G. Qiao, Zenan Lin, S. Barrett, L. Zukerberg, M. Lanuti, M. Qadan, K. Tanabe
{"title":"Abstract 108: Inhibiting methionine aminopeptidase 2 prevents liver fibrosis and hepatocellular carcinoma","authors":"Yongtao Wang, M. Sojoodi, G. Qiao, Zenan Lin, S. Barrett, L. Zukerberg, M. Lanuti, M. Qadan, K. Tanabe","doi":"10.1158/1538-7445.AM2021-108","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-108","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74550079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2588
D. Upreti, Susumu Ishiguro, Mayme Loyd, Nicole Robben, P. Cote, Morgan Phillips, Ayaka Nakashima, Kengo Suzuki, J. Comer, M. Tamura
Euglena gracilis, a single-celled alga, is rich in nutrients and thus, used as a nutritional dietary supplement. This alga can be found in both fresh and saltwater and possesses characteristics of both plants and animals. Euglena gracilis extracts have a wide range of medicinal properties including stimulation of anticancer immunity against multiple types of cancers; however, the anticancer mechanism has not yet been fully elucidated. Therefore, a water extract from Euglena gracilis devoid of water-insoluble mature paramylons was evaluated as an anticancer agent against lung carcinoma. Two different extracts were prepared using dried powder from whole Euglena gracilis. First, partially purified water extract (EWE) was prepared by suspending dry powder in PBS and centrifugation at 10,000g for 20 min followed by a filtration using a 0.22µm pore size membrane. Second, boiled EWE (bEWE) was prepared by immersing unfiltered EWE in boiling water for 12 min followed by centrifugation at 10,000g for 10 min and filtration using 0.22µm pore size membrane. Both EWE and bEWE treatments inhibited the growth of lung carcinoma cells in vitro in a dose- and time-dependent manner. Furthermore, both extracts significantly inhibited the three-dimensional growth of Lewis Lung Carcinoma (LLC) cells. Flow cytometry analysis showed that the EWE treatment attenuates granulocytic myeloid-derived suppressor cells (MDSCs) in bone marrow cell cultures. The in vivo study was conducted using a mouse LLC orthotopic allograft model. Oral administration of EWE and bEWE (100-200 mg/kg/day) three weeks prior to LLC cell inoculation attenuated the tumor growth in the lungs of immunocompetent mice while decreasing the peripheral granulocytes. However, this attenuation was not seen for the extract treatment initiated after LLC cell inoculation. The tumor growth attenuation was more efficient with the bEWE treatment than with EWE treatment. The fecal microbiomes of the mice were analyzed by 16s rRNA gene amplicon sequencing which revealed that alpha diversity in three groups (EWE, bEWE, and PBS control) was similar, however, the microbial compositions of the EWE- and bEWE-treated mouse groups were more diversified than in the PBS group. Specifically, an increase in the ratio of Bacteroidetes to Firmicutes was observed, and a significant increase in Akkermansia and Muribaculum was detected in EWE- and bEWE- treated mice compared to PBS treated mice. These studies suggest that oral administration of partially purified water extracts from Euglena gracilis altered the intestinal microbiome and the alteration may attenuate host MDSCs, thereby preventing lung carcinoma growth. This study was supported by 2016EUGLENA-RC1 (MT), 2017EUGLENA-RC2 (MT and JC), Kansas State University College of Veterinary Medicine SMILE award (MT and JC), and NIH grant P20 RR017686 (MT). Citation Format: Deepa Upreti, Susumu Ishiguro, Mayme Loyd, Nicole Robben, Paige Cote, Morgan Phillips, Ayaka Nakashima, Kengo
{"title":"Abstract 2588: Oral administration of water extract fromEuglena gracilisprevents lung carcinoma growth in mice by alteration of intestinal microbiota","authors":"D. Upreti, Susumu Ishiguro, Mayme Loyd, Nicole Robben, P. Cote, Morgan Phillips, Ayaka Nakashima, Kengo Suzuki, J. Comer, M. Tamura","doi":"10.1158/1538-7445.AM2021-2588","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2588","url":null,"abstract":"Euglena gracilis, a single-celled alga, is rich in nutrients and thus, used as a nutritional dietary supplement. This alga can be found in both fresh and saltwater and possesses characteristics of both plants and animals. Euglena gracilis extracts have a wide range of medicinal properties including stimulation of anticancer immunity against multiple types of cancers; however, the anticancer mechanism has not yet been fully elucidated. Therefore, a water extract from Euglena gracilis devoid of water-insoluble mature paramylons was evaluated as an anticancer agent against lung carcinoma. Two different extracts were prepared using dried powder from whole Euglena gracilis. First, partially purified water extract (EWE) was prepared by suspending dry powder in PBS and centrifugation at 10,000g for 20 min followed by a filtration using a 0.22µm pore size membrane. Second, boiled EWE (bEWE) was prepared by immersing unfiltered EWE in boiling water for 12 min followed by centrifugation at 10,000g for 10 min and filtration using 0.22µm pore size membrane. Both EWE and bEWE treatments inhibited the growth of lung carcinoma cells in vitro in a dose- and time-dependent manner. Furthermore, both extracts significantly inhibited the three-dimensional growth of Lewis Lung Carcinoma (LLC) cells. Flow cytometry analysis showed that the EWE treatment attenuates granulocytic myeloid-derived suppressor cells (MDSCs) in bone marrow cell cultures. The in vivo study was conducted using a mouse LLC orthotopic allograft model. Oral administration of EWE and bEWE (100-200 mg/kg/day) three weeks prior to LLC cell inoculation attenuated the tumor growth in the lungs of immunocompetent mice while decreasing the peripheral granulocytes. However, this attenuation was not seen for the extract treatment initiated after LLC cell inoculation. The tumor growth attenuation was more efficient with the bEWE treatment than with EWE treatment. The fecal microbiomes of the mice were analyzed by 16s rRNA gene amplicon sequencing which revealed that alpha diversity in three groups (EWE, bEWE, and PBS control) was similar, however, the microbial compositions of the EWE- and bEWE-treated mouse groups were more diversified than in the PBS group. Specifically, an increase in the ratio of Bacteroidetes to Firmicutes was observed, and a significant increase in Akkermansia and Muribaculum was detected in EWE- and bEWE- treated mice compared to PBS treated mice. These studies suggest that oral administration of partially purified water extracts from Euglena gracilis altered the intestinal microbiome and the alteration may attenuate host MDSCs, thereby preventing lung carcinoma growth. This study was supported by 2016EUGLENA-RC1 (MT), 2017EUGLENA-RC2 (MT and JC), Kansas State University College of Veterinary Medicine SMILE award (MT and JC), and NIH grant P20 RR017686 (MT). Citation Format: Deepa Upreti, Susumu Ishiguro, Mayme Loyd, Nicole Robben, Paige Cote, Morgan Phillips, Ayaka Nakashima, Kengo ","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90468705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2553
Marlo M. Vernon, Ghadeer Albashir, S. J. Sojourner, J. Moore, S. Looney, M. Tingen
{"title":"Abstract 2553: Using a “train-the-trainer” approach with urban and rural minority community health workers to implement the cancer-Community Awareness Access Research and Education (c-CARE) Project","authors":"Marlo M. Vernon, Ghadeer Albashir, S. J. Sojourner, J. Moore, S. Looney, M. Tingen","doi":"10.1158/1538-7445.AM2021-2553","DOIUrl":"https://doi.org/10.1158/1538-7445.AM2021-2553","url":null,"abstract":"","PeriodicalId":20290,"journal":{"name":"Prevention Research","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85850290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2584
John W R Kincaid, Annie E. Hill-Baskin, N. Berger
Human leukemias have been reported to show sexual dimorphism in both incidence and behavior. However, few studies of this observation have been conducted in animal models. We used the C57BL/6J mouse, genetically engineered to contain the PML-RARA fusion gene at the mouse cathepsin G (mCG) locus, as a model (B6.mCG-PML-RARα) of acute promyelocytic leukemia (APL) to interrogate the impact of sex and diet variation on disease latency as measured by leukemia-free survival. At 30 days of age, control (WT) and mutant (mCG+/PR) mice were separated by sex and provided with high fat (HF) [57% coconut oil fat] or low fat (LF) [10% coconut oil fat] diets. Mice were followed with serial blood collections and sacrificed when peripheral blood revealed signs of leukemia development including elevated granulocytes (WBC >20 K/μL), anemia (Hb 425 days was observed. In contrast, male mCG+/PR mice fed LF diets showed a reduced MLFS of 360 days of age, indicating a difference in latency of 65 days, thereby demonstrating sexual dimorphism in the appearance of APL. HF diet accelerated the appearance of APL in both female (MLFS = 277 days of age) and male mCG+/PR mice (MLFS = 277 days of age), which also displayed a difference in latency of 65 days. Thus, HF diet accelerated appearance of APL by 148 days in male and 148 days in female mCG+/PR mice. There were no signs of leukemia development in WT mice on either HF or LF diets. There was no splenomegaly observed in WT mice on either HF or LF diets. Thus, although HF diet and obesity accelerate the onset of APL in B6.mCG-PML-RARα mice, sexual dimorphism remains, with females showing extended latency compared to males under conditions of both HF and LF diets. Overall, our studies provide a robust mouse model to study the mechanisms by which sex impacts leukemia latency, as well as demonstrate that obesity accelerates leukemia development without affecting sexual dimorphism. Citation Format: John W. Kincaid, Annie E. Hill-Baskin, Nathan A. Berger. Leukemia latency in the mCG-PML-RARα mouse model is impacted by sex and obesity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2584.
据报道,人类白血病在发病率和行为上都表现出性别二态性。然而,很少在动物模型中进行这一观察的研究。我们使用C57BL/6J小鼠,通过基因工程在小鼠组织蛋白酶G (mCG)位点含有PML-RARA融合基因,作为急性早幼粒细胞白血病(APL)的模型(b6 .mCG- PML-RARA α),研究性别和饮食变化对疾病潜伏期的影响。30日龄时,对照(WT)和突变(mCG+/PR)小鼠按性别分开,分别饲喂高脂(HF)[57%椰子油脂肪]或低脂(LF)[10%椰子油脂肪]日粮。小鼠连续采血,当外周血出现粒细胞升高(WBC >20 K/μL)、贫血(Hb 425 d)等白血病发展迹象时处死。相比之下,饲喂LF的雄性mCG+/PR小鼠在360日龄时MLFS减少,潜伏期差异为65天,从而显示APL外观的性别二态性。HF饮食加速了雌性(MLFS = 277日龄)和雄性mCG+/PR小鼠(MLFS = 277日龄)APL的出现,其潜伏期也有65天的差异。由此可见,HF饮食使mCG+/PR小鼠APL的出现在雄性小鼠和雌性小鼠中分别提前了148天和148天。无论是HF还是LF饮食,WT小鼠都没有白血病发展的迹象。无论是HF还是LF饮食,WT小鼠均未观察到脾肿大。因此,尽管HF饮食和肥胖加速了B6患者APL的发病。mCG-PML-RARα小鼠的性别二态性仍然存在,在HF和LF饮食条件下,雌性小鼠比雄性小鼠表现出更长的潜伏期。总之,我们的研究提供了一个强大的小鼠模型来研究性别影响白血病潜伏期的机制,并证明肥胖在不影响性别二态性的情况下加速了白血病的发展。引文格式:John W. Kincaid, Annie E. Hill-Baskin, Nathan A. Berger。mCG-PML-RARα小鼠模型的白血病潜伏期受性别和肥胖的影响[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):2584。
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Pub Date : 2021-07-01DOI: 10.1158/1538-7445.AM2021-2571
Shizhao Li, Huixin Wu, T. Tollefsbol
Breast cancer is one of the leading causes of cancer-related death among women in the United States. It is widely appreciated that abnormal epigenetic alterations act as one of the primary contributors to breast cancer initiation and progression. Parental, including maternal and paternal, nutritional interventions have shown considerable impact on fetal development leading to different susceptibility of offspring to various chronic diseases. Moreover, combinatorial dietary administration to parents could be more efficacious in ameliorating epigenetic aberrations and changing cancer risk in an individual9s later life. The bioactive dietary broccoli sprouts (BSp) and green tea polyphenol (GTP) are important epigenetic modulators that can prevent various cancers. Our study focusses on investigating the effect of paternal dietary BSp and GTP administration on mammary cancer prevention of their offspring. Two spontaneous breast cancer transgenic mouse models, C3(1)/SV40 and Her2/neu, were employed in this study. Male C3(1)/SV40 or Her2/neu transgenic mice were randomly assigned into four groups and treated with: control AIN-93G diet, 26% BSp (w/w) in food pellets, 0.5% GTPs (w/v) in drinking water or combined BSp and GTPs from 3 wks of age until 10 wks of age. Treated male mice of different groups were then mated with non-treated female mice. Female pups were selected after their weaning and tumor growth was monitored weekly until the termination of the experiment. Tumor- and epigenetic-related protein expression and histone modifications (methylation and acetylation) were measured. Our study indicated that paternal BSp or/and GTPs administration suppressed tumor growth, decreased tumor incidence, and delayed tumor latency compared with the control in both mouse models. Overall, paternal dietary intervention displayed more efficacy for mammary tumor prevention in C3(1)/SV40 mice and the combination group in this model also showed synergistically effects. Subsequent analysis with the C3(1)/SV40 mouse tumors demonstrated that paternal BSp or/and GTPs treatments upregulated the expression of tumor suppressor proteins, such as P16 and P53, and down-regulated tumor promoting proteins, such as MYC and BMI1. Moreover, altered DNA methylation, histone methylation and acetylation levels were also observed. These results suggested that paternal exposure to BSp and GTPs may contribute to ER-negative mammary tumor prevention in their offspring through epigenetic regulations and the combined addition of bioactive botanicals could be a more promising approach for coping with breast cancer initiation and progression in humans. Citation Format: Shizhao Li, Huixin Wu, Trygve Tollefsbol. Paternal epigenetic regulation contributes to the prevention of estrogen receptor-negative mammary cancer with combined broccoli sprouts and green tea polyphenols consumption in transgenic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2
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