bluuebunny/crossref_metadata_2025_split huggingface dataset:
YTHDF1 Promotes Gastric Carcinogenesis by Controlling Translation of FZD7
Authors: Pi Jingnan , Wang Wen , Ji Ming , Wang Xiaoshuang , Wei Xueju , Jin Jing , Liu Tao , Qiang Jiaqi , Qi Zhihong , Li Feng , Liu Yue , Ma Yanni , Si Yanmin , Huo Yue , Gao Yufeng , Chen Yiying , Dong Lei , Su Rui , Chen Jianjun , Rao Shuan , Yi Ping , Yu Shuyang , Wang Fang , Yu Jia 
Published: August 2020

Abstract

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in mammals that regulates homeostasis and function of modified RNA transcripts. Here, we aimed to investigate the role of YTH m6A RNA-binding protein 1 (YTHDF1), a key regulator of m6A methylation in gastric cancer tumorigenesis. Multiple bioinformatic analyses of different human cancer databases identified key m6A-associated genetic mutations that regulated gastric tumorigenesis. YTHDF1 was mutated in about 7% of patients with gastric cancer, and high expression of YTHDF1 was associated with more aggressive tumor progression and poor overall survival. Inhibition of YTHDF1 attenuated gastric cancer cell proliferation and tumorigenesis in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of a key Wnt receptor frizzled7 (FZD7) in an m6A-dependent manner, and mutated YTHDF1 enhanced expression of FZD7, leading to hyperactivation of the Wnt/β-catenin pathway and promotion of gastric carcinogenesis. Our results demonstrate the oncogenic role of YTHDF1 and its m6A-mediated regulation of Wnt/β-catenin signaling in gastric cancer, providing a novel approach of targeting such epigenetic regulators in this disease.

Significance:
This study provides a rationale for controlling translation of key oncogenic drivers in cancer by manipulating epigenetic regulators, representing a novel and efficient strategy for anticancer treatment.
Stochastic Epigenetic Mutations Are Associated with Risk of Breast Cancer, Lung Cancer, and Mature B-cell Neoplasms
Authors: Gagliardi Amedeo , Dugué Pierre-Antoine , Nøst Therese H. , Southey Melissa C. , Buchanan Daniel D. , Schmidt Daniel F. , Makalic Enes , Hodge Allison M. , English Dallas R. , Doo Nicole W. , Hopper John L. , Severi Gianluca , Baglietto Laura , Naccarati Alessio , Tarallo Sonia , Pace Luigia , Krogh Vittorio , Palli Domenico , Panico Salvatore , Sacerdote Carlotta , Tumino Rosario , Lund Eiliv , Giles Graham G. , Pardini Barbara , Sandanger Torkjel M. , Milne Roger L. , Vineis Paolo , Polidoro Silvia , Fiorito Giovanni 
Published: August 2020

Abstract

Background:
Age-related epigenetic dysregulations are associated with several diseases, including cancer. The number of stochastic epigenetic mutations (SEM) has been suggested as a biomarker of life-course accumulation of exposure-related DNA damage; however, the predictive role of SEMs in cancer has seldom been investigated.

Methods:
A SEM, at a given CpG site, was defined as an extreme outlier of DNA methylation value distribution across individuals. We investigated the association of the total number of SEMs with the risk of eight cancers in 4,497 case–control pairs nested in three prospective cohorts. Furthermore, we investigated whether SEMs were randomly distributed across the genome or enriched in functional genomic regions.

Results:
In the three-study meta-analysis, the estimated ORs per one-unit increase in log(SEM) from logistic regression models adjusted for age and cancer risk factors were 1.25; 95% confidence interval (CI), 1.11–1.41 for breast cancer, and 1.23; 95% CI, 1.07–1.42 for lung cancer. In the Melbourne Collaborative Cohort Study, the OR for mature B-cell neoplasm was 1.46; 95% CI, 1.25–1.71. Enrichment analyses indicated that SEMs frequently occur in silenced genomic regions and in transcription factor binding sites regulated by EZH2 and SUZ12 (P &lt; 0.0001 and P = 0.0005, respectively): two components of the polycomb repressive complex 2 (PCR2). Finally, we showed that PCR2-specific SEMs are generally more stable over time compared with SEMs occurring in the whole genome.

Conclusions:
The number of SEMs is associated with a higher risk of different cancers in prediagnostic blood samples.

Impact:
We identified a candidate biomarker for cancer early detection, and we described a carcinogenesis mechanism involving PCR2 complex proteins worthy of further investigations.
Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas
Authors: Wildes Tyler J. , Dyson Kyle A. , Francis Connor , Wummer Brandon , Yang Changlin , Yegorov Oleg , Shin David , Grippin Adam , Dean Bayli DiVita , Abraham Rebecca , Pham Christina , Moore Ginger , Kuizon Carmelle , Mitchell Duane A. , Flores Catherine T. 
Published: August 2020

Abstract

Purpose:
Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape.

Experimental Design:
We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT.

Results:
Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells.

Conclusions:
These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.
Preclinical Antitumor Activity and Biodistribution of a Novel Anti-GCC Antibody–Drug Conjugate in Patient-derived Xenografts
Authors: Abu-Yousif Adnan O. , Cvet Donna , Gallery Melissa , Bannerman Bret M. , Ganno Michelle L. , Smith Michael D. , Lai Katharine C. , Keating Thomas A. , Stringer Bradley , Kamali Afrand , Eng Kurt , Koseoglu Secil , Zhu Andy , Xia Cindy Q. , Landen Melissa Saylor , Borland Maria , Robertson Robbie , Bolleddula Jayaprakasam , Qian Mark G. , Fretland Jennifer , Veiby O. Petter 
Published: August 2020

Abstract
Guanylyl cyclase C (GCC) is a unique therapeutic target with expression restricted to the apical side of epithelial cell tight junctions thought to be only accessible by intravenously administered agents on malignant tissues where GCC expression is aberrant. In this study, we sought to evaluate the therapeutic potential of a second-generation investigational antibody–dug conjugate (ADC), TAK-164, comprised of a human anti-GCC mAb conjugated via a peptide linker to the highly cytotoxic DNA alkylator, DGN549. The in vitro binding, payload release, and in vitro activity of TAK-164 was characterized motivating in vivo evaluation. The efficacy of TAK-164 and the relationship to exposure, pharmacodynamic marker activation, and biodistribution was evaluated in xenograft models and primary human tumor xenograft (PHTX) models. We demonstrate TAK-164 selectively binds to, is internalized by, and has potent cytotoxic effects against GCC-expressing cells in vitro. A single intravenous administration of TAK-164 (0.76 mg/kg) resulted in significant growth rate inhibition in PHTX models of metastatic colorectal cancer. Furthermore, imaging studies characterized TAK-164 uptake and activity and showed positive relationships between GCC expression and tumor uptake which correlated with antitumor activity. Collectively, our data suggest that TAK-164 is highly active in multiple GCC-positive tumors including those refractory to TAK-264, a GCC-targeted auristatin ADC. A strong relationship between uptake of 89Zr-labeled TAK-164, levels of GCC expression and, most notably, response to TAK-164 therapy in GCC-expressing xenografts and PHTX models. These data supported the clinical development of TAK-164 as part of a first-in-human clinical trial (NCT03449030).
Aurora A Inhibitor TAS-119 Enhances Antitumor Efficacy of TaxanesIn VitroandIn Vivo: Preclinical Studies as Guidance for Clinical Development and Trial Design
Authors: Sootome Hiroshi , Miura Akihiro , Masuko Norio , Suzuki Takamasa , Uto Yoshihiro , Hirai Hiroshi 
Published: August 2020

AbstractTAS-119 is a novel orally active, selective inhibitor of Aurora kinase A identified as a clinical candidate for efficacy testing in combination with taxanes. In vitro, TAS-119 enhanced cell growth inhibition of paclitaxel in multiple human cancer cell lines derived from various tissues, including paclitaxel-resistant cell lines. Interestingly, TAS-119 did not enhance paclitaxel antitumor activity in normal lung diploid fibroblast cell lines WI-38 and MRC5. In vivo, TAS-119 enhanced the antitumor efficacy of paclitaxel and docetaxel in multiple models at doses inhibitory to Aurora A in tumors. Moreover, the drug combination was well tolerated, and TAS-119 did not exaggerate clinically documented side effects of taxanes, neutropenia and neurotoxicity, in rats. The same TAS-119 concentration enhanced the cell growth inhibitory activity of three clinically approved taxanes, paclitaxel, docetaxel, and cabazitaxel. The degree of enhancement calculated as fold of change of the IC50 value for each taxane was almost the same among the three taxanes. We conducted in vitro and in vivo experiments to develop an optimized combination therapy regimen for TAS-119 with paclitaxel/docetaxel. Using in vitro and in vivo models, we tested the drug administration order for TAS-119 combined with paclitaxel and the TAS-119 treatment duration. The best regimen in preclinical models was combining paclitaxel or docetaxel treatment with 4 days of TAS-119 dosing, which was initiated on the same day as the paclitaxel or docetaxel administration or one day later. This information provided guidance for the design of a clinical trial of TAS-119 and paclitaxel or docetaxel combination.
Abstract A008: Barriers and facilitator to minorities' participation in cancer clinical trials: Perspectives from a safety-net hospital
Authors: Rivers Brian M. , Harris Monica , Cooper Dexter L. , Lisovicz Nedra , Durant Raegan , Hernandez Natalie D. , Rivers Desiree , McKinney Lawrence , Carmichael Bria , Rutland Sarah B. , Shamim Ainny 
Published: August 2020

Abstract
Introduction: Cancer clinical trials (CCTs) are vital to clinical oncology research, in that they provide a foundation for the development and implementation of effective cancer therapies. However, there is a disparity in CCT participation given that only 2.7% of all CCT participants in the U.S. are African-American (AA). Grady Memorial Hospital in Atlanta, Georgia, the setting for this study, is a safety-net hospital with over 80% of its patients on Medicare, Medicaid, or uninsured. The objective of this two-phase pilot study is to utilize a multilevel, qualitative approach to assess the clinical and nonclinical facilitators and barriers to AA participation in CCTs (Phase I) and develop and pilot a multilevel intervention (Phase II).
Methods: Study participants were recruited from a cancer center at a safety-net hospital in Atlanta, GA. Twenty key informant interviews were conducted with key stakeholders at the safety-net hospital and 2 focus groups with AA cancer survivors. Interview guides were adapted from the NIH-funded EMPACT study. The interviews and focus groups were recorded on digital devices upon which the data was transcribed and subsequently analyzed using NVIVO 11 software.
Results: The interview transcripts were analyzed using a combination of hand coding and NVIVO 11 software. Content analysis was conducted using an immersion/crystallizing analysis plan. Common themes regarding Barriers and Facilitators within the context of Institution-level, Participant-level, System-level, and Trial-level will be presented.
Conclusion: These findings will assist in the development and testing of culturally appropriate resources and interventions to increase AA participation in CCTs.
Citation Format: Brian M. Rivers, Monica Harris, Dexter L. Cooper, Nedra Lisovicz, Raegan Durant, Natalie D. Hernandez, Desiree Rivers, Lawrence McKinney, Bria Carmichael, Sarah B. Rutland, Ainny Shamim. Barriers and facilitator to minorities' participation in cancer clinical trials: Perspectives from a safety-net hospital [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A008.
Abstract A009: Validation of an instrument to measure health professionals' health literacy competence
Authors: Dawkins-Moultin Lenna , McKyer Lisako 
Published: August 2020

Abstract
Introduction: Health literacy (HL) has been identified as a significant predictor of outcomes across the health continuum, including cancer care. As a result it is recommended that all health professionals receive health literacy training. Some institutions have begun integrating health literacy into training programs, but there is a dearth of reliable assessment tools to measure learners' knowledge. Only one validated instrument (Health Literacy Knowledge and Experience Scale (HL-KES)) exists that specifically assess health professionals' health literacy competence, but it was validated for use among nurses. The purpose of this study was to evaluate the reliability and validity of the HL-KES as a suitable measure for assessing the HL knowledge and experience of health promotion professionals.
Methods: Advanced (junior and senior) students (n=250) enrolled in bachelor-level health promotion programs in three large public universities in Texas completed the 29-item HL-KES. Exploratory and confirmatory factor analyses were conducted to test the factor structure. Reliability estimates of the overall scale and subscales were assessed using the item covariance method with coefficient alpha (α).
Results: The analyses identified three factors that accounted for 62% of the total variance. Twelve items loaded on factor 1 (Knowledge of HL challenges), four items loaded on factor 2 (knowledge of HL assessment strategies), and three items loaded on factor 3 (knowledge of HL principles for written healthcare materials). Results from the test of internal consistency indicated the HL-KES had acceptable reliability for the overall knowledge scale (Cronbach's alpha = 0.77). The sub-scales had Cronbach's alphas ranging from .31 to .52.
Conclusion: The results suggest the HLKES is a reliable instrument for assessing health promotion professionals' health literacy knowledge. As a whole, the Cronbach's alpha for the instrument falls within the acceptable range (.65 - .90). The subscales, however, have low reliability coefficients. Cronbach's alpha is a function of test length and inter-item correlation and a couple of subscales had just a few items. Reduction in the number of items no doubt attenuated the internal consistency.
Citation Format: Lenna Dawkins-Moultin, Lisako McKyer. Validation of an instrument to measure health professionals' health literacy competence [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A009.
Abstract A016: [Advocate Abstract] Journey of life
Authors: Barefield Brian L. 
Published: August 2020

Abstract
I never knew much about colorectal cancer until it found its way into my home. The one thing I was always told was that it is an “Old Person's” disease and you shouldn't even check for it until after 50. Well, I found out that was not true as my wife was diagnosed at age 36 and passed at age 39. My sole purpose in life is to make young adults aware that they should get checked at an earlier age or when they see even the smallest symptoms. I never want anyone else to suffer from lack of knowledge.
Citation Format: Brian L. Barefield. [Advocate Abstract] Journey of life [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A016.
Abstract A024: Planning for scale-up of an evidence-based intervention in community settings: Project HEAL insights from the SPRINT Initiative
Authors: Jones Laundette P. , Slade Jimmie L. , Davenport Felicia , Santos Sherie Lou Z. , Holt Cheryl L. 
Published: August 2020

Abstract
Project HEAL (Health through Early Awareness and Learning) is an evidence-based intervention rooted in health behavior change theory and aiming to increase cancer awareness and early detection through African American faith-based organizations. This study explored the potential for broader scale-up and dissemination of Project HEAL through the team's participation in a training program called Speeding Research-tested INTerventions (SPRINT). The SPRINT training was framed using tools from the Business Model Canvas and the Value Proposition Canvas to guide trainees in designing (1) compelling value propositions, (2) a minimal viable product, and (3) questions to gain critical insight from various stakeholders during a process called Customer Discovery. We report on our experiences in the SPRINT training and insights on intervention scale-up that we gained from the training, including key findings from 41 discovery interviews conducted with various stakeholders of the church ecosystem. We learned several valuable lessons from the discovery interviews, including the realization that scale-up will likely be more incremental than immediate. Additional refinement will be needed to scale up the intervention for “real world” application, including making our technology more user-friendly and including additional health topics beyond cancer. The SPRINT training helped our team consider broader scale-up and dissemination in a constituent-informed way. We discuss how insights from the training helped to refine our plans for future intervention scale-up.
Citation Format: Laundette P. Jones, Jimmie L. Slade, Felicia Davenport, Sherie Lou Z. Santos, Cheryl L. Holt. Planning for scale-up of an evidence-based intervention in community settings: Project HEAL insights from the SPRINT Initiative [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A024.
Abstract A027: [Advocate Abstract] How to promote diversity and inclusion in the community
Authors: Hauge Winona Hollins 
Published: August 2020

Abstract
Reaching underserved communities is not always easy but it remains a critical area of need. To become an effective champion there are three critical areas that you must clearly define before you start your research. One important factor is understanding the population that you are attempting to reach into. Will your research harm or create any unclear expectations? Did you consult with the community to discern what they think they need or would like to see implemented in their area? At the end of the study or the program, will the community see how their cooperation and engagement has made a impact or a difference?
Citation Format: Winona Hollins Hauge. [Advocate Abstract] How to promote diversity and inclusion in the community [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A027.
Abstract A037: [Advocate Abstract] The benefits of partnering to combat disparities
Authors: Townsend Virgie 
Published: August 2020

Abstract
My poster will focus on partnering and working together to fight or eliminate disparities. It will focus on the need for health systems, comunity groups and public organizations to come together in working to educate and bring together prevention and treatment.
Citation Format: Virgie Townsend. [Advocate Abstract] The benefits of partnering to combat disparities [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A037.
Abstract A046: Colorectal cancer screening among Chamorro on Guam: Barriers and access to care
Authors: Diaz Tressa P. 
Published: August 2020

Abstract
Colorectal cancer (CRC) is the second most common cause of cancer death on Guahan (Guam). Chamoru, the Indigenous peoples of Guahan, have the highest mortality rates in CRC on the island, which implicates the need for earlier detection. Limited research has been conducted on CRC screening behavior among Chamoru. To address the gap, this study seeks to understand, explore, and predict factors associated with CRC screening among Chamoru, and to address the research questions: (1) How does access to care impact colorectal cancer screening among Chamoru on Guam, and (2) What are barriers to colorectal cancer screening among Chamoru on Guam? Guided by Andersen's Behavioral Model of Health Service Utilization, individual predictors were categorized as predisposing, enabling, and need factors that facilitate or hinder CRC screening. A mixed quantitative and qualitative methods approach was utilized. First, screening data from the 2010 Guam Behavioral Risk Factor Surveillance System were used to model the association between CRC screening and predisposing, enabling, and need factors. Second, semistructured in-depth interviews with Chamoru men and women were conducted on why they opted for or against CRC screening. Purposive and snowball sampling was implemented to recruit participants due to the potentially sensitive and stigmatizing subject of colon/rectum screening processes. Binary logistic regression was used in quantitative analysis to determine significant predictors of CRC screening utilization. Qualitative analysis implemented grounded theory to determine relevant themes and key findings. Quantitative results show that having an annual check-up and educational attainment of high school or greater significantly predicted CRC screening. Qualitative analysis points to five themes in CRC screening decision-making: (1) being proactive in one's health care; (2) intergenerational consciousness of cancer diagnosis and related screening behaviors; (3) social stigma associated with colonoscopies; (4) “If I'm gonna die, I'm gonna die”; and (5) negative perceptions of the medical system. Findings provide insight toward cultural and health beliefs as facilitators and barriers to CRC screening with broader implications for political status as a determinant of health. Further research toward culturally tailored screening interventions is recommended to address cancer disparities in the context of health care access and health equity for Chamoru.
Citation Format: Tressa P. Diaz. Colorectal cancer screening among Chamorro on Guam: Barriers and access to care [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A046.