bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2274: Development of bispecific antibodies using molecular imaging
Authors: Kamakura Daisuke , Yasunaga Masahiro , Asano Ryutaro , Matsumura Yasuhiro 
Published: September 2020

Abstract
(Background and purpose) A bispecific antibody (BsAb), as a next-generation therapeutic antibody, has two antigen binding sites in an antibody molecule. Many formats have been exploited for decades. Among them, we focused on T cell dependent BsAb (TDB), which can engage and redirect cytotoxic T cells against tumor cells and is expected to be effective in treating refractory cancer. However, although many studies revealed its potent antitumor effect in animal models, it has not been applied to solid tumors yet in clinics. In this context, we think that it is necessary to clarify pharmacokinetics (PK), pharmacodynamics (PD) and mechanism of action (MOA) of TDB, especially within tumor tissue. For this aim, we have decided to develop the molecular imaging-based systems for the evaluation of TDB in order to visualize antigen binding to two target antigens, BsAb delivery or immunological synapse formation.
(Materials a& Methods) We used hEx3 which is a humanized IgG-like antibody with bivalent Fv regions against each EGFR and CD3. We applied the TDB to colorectal cancer (CRC) cells with or without KRAS or BRAF mutation. In the first part, we visualized the BsAb binding to two antigens, EGFR on CRC cells and CD3 on T cells. Next, immunological synapse formation as a cutting-edge mechanism involving T cells-killing tumor cells, which is an important MOA of TDB, was visualized in combination with Granzyme staining. In the second part, we evaluated in vitro cytotoxicity and the in vivo antitumor effect of hEx3 in NOD-SCID mice bearing CRC xenografts with KRAS or BRAF mutation following human PBMC administration.
(Results) We found that CRC cells were damaged via Granzyme accumulation through immunological synapse. In the ELISA data, we also found that released gamma interferons can damage CRC cells. In vitro and In vivo studies showed that the hEx3 demonstrated a significant cytocidal effect and antitumor activity not only for KRAS wild but also mutant.
(Conclusion) we established a molecular imaging-based TDB evaluation system and visualized antigen-binding and immunological synapse formation as a MOA of TDB. Present data indicated that TDB can damage CRC cells in two distinct manners, namely immunological synapse-dependent and -independent manners using cytokines including a gamma interferon. TDB may thus be a promising next generation antibody therapy against CRC regardless KRAS status.
Citation Format: Daisuke Kamakura, Masahiro Yasunaga, Ryutaro Asano, Yasuhiro Matsumura. Development of bispecific antibodies using molecular imaging [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2274.
Abstract 2299: Sarcoma as second cancer in pediatric cancer survivors: Large population analysis
Authors: Makena Monish Ram , Nguyen Thinh H. , Yavvari Siddhartha , Kaur Maninder , Pham Teresia , Urias Eduardo , Panapitiya Narendra , Al-Rahawan Mohamad M. 
Published: September 2020

Abstract
Introduction: As the prognosis of a pediatric cancer continues to improve, the burden of long term therapy effects, including subsequent malignant neoplasm (SMN), in survivors is an increasing epidemiologic concern. The mortality rate from cancer in the pediatric population decreased from 6.5 per 100,000 in 1970 to 2.3 in 2015, indicating more chance of SMNs. Sarcoma as a SMN in pediatrics has important clinical significance and has been extensively reported globally. We quantified the percentage of sarcoma as second cancer and determined the primary cancer distribution for patients with sarcoma as second cancer.
Methods: The Surveillance, Epidemiology, and End Results (SEER) database, which includes 28% of the U.S population and data from 18 state cancer registries (SEER-18), was probed for the overall incidence of SMN in pediatric cancer survivors and the incidence of sarcoma as the SMN specifically.
Results: Our SEER database analysis found that out of 75,665 cases of primary pediatric malignancies, 1218 (1.61%) developed SMN. The second most common SMN was sarcoma, accounting for 14.37% of them in pediatric population. The breakdown of sarcoma into sub groups showed that osteosarcoma, fibrosarcoma, and rhabdomyosarcoma are the most common second sarcomas seen in pediatric cancer survivors. Finally, we looked at the distribution of primary cancer in pediatric cancer survivors who developed sarcoma as a SMN. We found that retinoblastoma, lymphoid leukemia, and Hodgkin lymphomas were the most common types of primary cancer. Similar results were reported among different racial groups around the world, which show a universal trend of sarcomas as second cancers in pediatric cancer survivors.
Conclusion: By analyzing the SEER database, we corroborated previous findings, suggesting that about 14% of SMN after a childhood cancer is encompassed by sarcoma. The exact etiology of cancer, be it primary predisposition or secondary to exposures, is uncertain. Radiation and chemotherapies used in patients with pediatric cancers can be carcinogenic. Our study highlights the need for development of novel non-DNA damaging or alternate antineoplastic therapies to avoid the long-term potential of development of SMN.
Citation Format: Monish Ram Makena, Thinh H. Nguyen, Siddhartha Yavvari, Maninder Kaur, Teresia Pham, Eduardo Urias, Narendra Panapitiya, Mohamad M. Al-Rahawan. Sarcoma as second cancer in pediatric cancer survivors: Large population analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2299.
Abstract 2321: Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank
Authors: Jee Yon Ho , Gao Chi , Kim Jihye , Park Seho , Jee Sun Ha , Kraft Peter 
Published: September 2020

Abstract
Background: Informative and well-calibrated risk prediction models may be useful for precision breast-cancer screening. However, these models often have not been validated across diverse populations. Validation in East Asian populations is particularly lacking.
Objective: To evaluate the performance of breast cancer risk models developed in European-ancestry studies in a Korean population, both directly and after recalibration.
Methods: We compared discrimination and calibration of three multivariable risk models in a cohort of 77,457 women from the Korean Cancer Prevention Study-II. The first incorporated US breast-cancer incidence and mortality rates, US risk-factor distributions, and relative risk (RR) estimates from European-ancestry studies. The second recalibrated the first by using Korean incidence and mortality rates and Korean risk factor distributions, while retaining the European-ancestry RR estimates. Finally, we derived a Korea-specific model incorporating the RR estimates from Korean Cancer Prevention Study. The Individualized Coherent Absolute Risk Estimation (iCARE) software package was used to calculate 5 year predicted absolute risks of breast cancer and assess model performance.
Results: The US European-ancestry breast cancer risk model was well calibrated among Korean women &lt;50 years (E/O=1.124 (0.989, 1.278)) but markedly overestimated the risk for those ≥50 years (E/O=2.472 (2.005, 3.049)). Recalibrating absolute risk estimates using Korean breast cancer rates and risk distributions markedly improved the calibration in women ≥50 (E/O=1.018 (0.825, 1.255)). The model incorporating Korean-based RRs had similar but not clearly improved performance relative to the recalibrated model; this may reflect at most modest differences in the RRs between European and Korean populations and the relatively small sample used to estimate RRs among Korean women.
Conclusions: The poor performance of the US European-ancestry breast cancer risk model among older Korean women highlights the importance of tailoring absolute risk models to specific populations. Recalibrating the model using Korean incidence and mortality rates and risk factor distributions greatly improved performance; we anticipate the performance could be further improved by incorporating multivariable risk-factor RRs from large Korea-based studies.
Citation Format: Yon Ho Jee, Chi Gao, Jihye Kim, Seho Park, Sun Ha Jee, Peter Kraft. Validating breast cancer risk prediction models in the Korean Cancer Prevention Study-II Biobank [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2321.
Abstract 2341: Predictive analysis of gynecologic cancer risk factors using decision tree analysis
Authors: Bahrani-Mostafavi Zahra , Huber Larissa B. , Sha Wei , Richardson Christine 
Published: September 2020

Abstract
Introduction: Gynecologic cancer (GYNC) accounts for 6.3% of all cancers and is the fourth leading cause of cancer death for women in the U.S. Autoimmune diseases (AD) are among the top ten leading causes of death among U.S. women age 65 and under. This high mortality rate among women with AD has been linked to cancer and other causes. Considering cancer and AD are the accumulative effect of genetics and lifestyle, and 90-95% of all cancers are linked to lifestyle and environmental factors, a study to investigate the association between patient-level predictors and GYNC among AD patients in the U.S. was imperative.
Methods: 2007-2013 data from Florida State Inpatient samples of the Healthcare Cost and Utilization Project were used. The study population (n=836,717) was restricted to women who had any AD. The outcome variable was diagnosis of GYNC. 36 categorical transformed variables including race/ethnicity, age, insurance type, income level, GYN procedures, and comorbidities were analyzed as predictive variables (PV). Bootstrap Forest (JMP pro13) were was used to create a 10,000-decision tree (DT) model to identify independent predictors of GYNC. Multiple outputs such as confusion matrix, column contribution, and ROC was created for predictive analytics.
Results: The analytical model used was confirmed by evaluating criteria such as AUC (0.82), sensitivity (0.68), specificity (0.82), false positive rate (0.18), wrongly predicted value (0.24), and overall accurate prediction (0.76) of the model. Using column contribution and single DT, the PV hysterectomy was the highest predictor of GYNC, followed by PV age;, and comorbidities such as diabetes, and obesity; along with race/ethnicity; and income level. Also, subpopulations of AD patients at risk for GYNC based on unique combinations of risk factors were established, including subpopulations such as women with AD, involved glandular disorders who had hysterectomy, and comorbidities such as diabetes and fluid and electrolyte disorders.
Discussion: Both GYNC and AD are major chronic diseases among women. Because of high prevalence of AD among women, more elucidation on the association between GYNC and AD is essential for GYNC management. The unique combinations of characteristics that describe subgroups of patients at risk for GYNC among AD patients can be used as a potential risk assessment, as well as an early detection and/ or prevention tools for GYNC.
Citation Format: Zahra Bahrani-Mostafavi, Larissa B. Huber, Wei Sha, Christine Richardson. Predictive analysis of gynecologic cancer risk factors using decision tree analysis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2341.
Abstract 2365: Does a combination of type 2 diabetes mellitus and increased alcohol intake affect prospective total adenoma accumulation
Authors: Tobi Martin , Antaki Fadi , Judd Stephanie , Sochacki Paula , Rambus MaryAnn , Talwar Harvinder , Lawson Michael , Levi Edi , McVicker Benita 
Published: September 2020

Abstract
Introduction: Adenoma formation data in diabetics is inconclusive. Alcohol intake (AI), associated with colorectal neoplasia (CRN) has not been systematically studied in diabetes. We investigated effects of diabetes and AI in a prospective patient cohort at increased CRN risk.
Methods: Diabetes diagnoses based on patients' problem list, corroborated by HbA1c and glucose levels. Self-reported AI was quantified as more than occasional/social. Cumulative adenoma number were computed using available records. In a subset of patients, CRN-related Paneth cell marker p87 was used to semi-quantify immunohistochemically the colonic regions binding this label.
Results: 680 patients (348 diabetics 332 non-diabetic) were ascertained with 12.4-year median follow-up. Diabetics had more adenomas than non-diabetics (2.3±3.54 versus 1.81±2.91, p=0.05) and p87 levels were significantly higher in the descending colon (p&lt;0.03) and rectum (p&lt;0.008). Significant demographic differences of increased black ethnicity, lesser survival, increased BMI and increased smoking were appreciated in diabetics. In non-drinking patients, adenomas were also similarly increased in diabetics and demographics and p87 levels were as reported above without significant smoking differences. Comparing diabetics who drank actively with non-diabetics who did not, the diabetics had increased polyp accumulation (2.90±4.29 versus 1.62±2.45 p&lt;0.012), increased proportion of black ethnicity, increased BMI and were younger. Rectal p87 was significantly increased (p&lt;0.04) without smoking effects on polyp number.
Conclusion: Diabetics accumulate more adenomas than controls which is reflected in the increase of left-sided p87 expression. A combination of increased AI and diabetes particularly increases adenoma formation seemingly independent of factors such as age and smoking.
Citation Format: Martin Tobi, Fadi Antaki, Stephanie Judd, Paula Sochacki, MaryAnn Rambus, Harvinder Talwar, Michael Lawson, Edi Levi, Benita McVicker. Does a combination of type 2 diabetes mellitus and increased alcohol intake affect prospective total adenoma accumulation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2365.
Abstract 2391: Centromeric chromatin alteration is associated with increase in alphoid array replication fork speed in ovarian cancer cell lines
Authors: Erliandri Indri , Redon Christophe , Kim Jung-Hyun , Fu Haiqing , Aladjem Mirit , Reinhold William , Larionov Vladimir 
Published: September 2020

Abstract
The centromere is well known as the center point of cell division, with aberrant centromeric function leading to mitotic dysfunction and chromosomal abnormalities. These abnormalities may in turn lead to diseases, including cancer and premature aging. Binding of CENPB to the CENPB box is orchestrated epigenetically, and has emerged as an important factor in the regulation of the centromeric-chromatin structural landscape. CENP-B depletion that resulted in euchromatization of the alphoid centromere array, also is associated with elevated centromeric DNA replication activity. Observation in two ovarian cancer cells from NCI-60 collection; OVCAR3 and SKOV3, identified as having low and high expression of CENPB RNA respectively, indicates the different level of centromeric DNA instability. Centromeric DNA damage fraction is more abundant and replication fork velocity is elevated in less CENPB expresser cells, indicates alphoid array alteration. We conclude that CENP-B is required for maintenance of centromeric chromatin structure and centromeric DNA integrity.
Citation Format: Indri Erliandri, Christophe Redon, Jung-Hyun Kim, Haiqing Fu, Mirit Aladjem, William Reinhold, Vladimir Larionov. Centromeric chromatin alteration is associated with increase in alphoid array replication fork speed in ovarian cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2391.
Abstract 2440: The epigenetic influence of maternal diet on prevention of high-fat diet induced obesity and breast cancer in later life
Authors: Li Yuanyuan , Chen Min , Tollefsbol Trygve 
Published: September 2020

Abstract
Breast cancer is one of the most lethal diseases in women. Individual epigenetic profiles that are initially established in utero and postnatal environmental exposures contribute to later-life breast cancer incidence. Intervention on environmental factors such as diets during these sensitive periods provides excellent opportunities to re-program epigenetic profiles leading to cancer prevention. The bioactive dietary compound, genistein (GE) enriched in soybean products such as soymilk, soy protein and tofu, has been widely accepted as a potent anticancer reagent through regulation of epigenetic mechanisms. Our pilot study indicates that maternal dietary GE exposure effectively prevents later-life breast cancer development through epigenetic reprogramming in transgenic breast cancer mouse models. More importantly, we found that maternal GE significantly inhibited a postnatal overnutrition stimulus such as high-fat diet (HFD)-induced breast cancer promotion and metabolic disorders in mouse offspring. Diets with high saturated fat such as the Western diet and its related obesity are considered major risk factors for breast cancer. Importantly, we found that maternal dietary GE reversed HFD-induced lipid panel abnormalities, reduced obesity-related biomarkers and influences gut microbiome profiles through epigenetic regulations. Overnutrition-induced metabolic disorders such as overweight and obesity are a global epidemic that impair human life quality and increases risk of development of many human diseases including breast cancer. Elucidation of the key mechanisms and interactions between nutrition stress and breast cancer and exploration of a novel in utero preventive strategy through natural bioactive products will have global impact.
Citation Format: Yuanyuan Li, Min Chen, Trygve Tollefsbol. The epigenetic influence of maternal diet on prevention of high-fat diet induced obesity and breast cancer in later life [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2440.
Abstract 2449: A novel function of FTO in ovarian cancer stem cells through m6A RNA demethylation
Authors: Huang Hao , Wang Yinu , Kandpal Manoj , Zhao Guangyuan , Cardenas Horacio , Ji Yanrong , Tanner Edward , Chen Jianjun , Davuluri Ramana , Matei Daniela 
Published: September 2020

Abstract
Introduction: N6-Methyladenosine (m6A) is the most abundant internal modification in mammalian messenger RNAs (mRNAs). Although previous studies have showed that RNA methylation is reversible and plays important roles in various cellular processes, such as metabolism, stem cell development, and self-renewal, its functions in cancer remain elusive. The fat mass- and obesity-associated protein (FTO) is an m6A demethylase and was described as an oncogenic factor in leukemia and brain tumors. We hypothesized that RNA demethylation could be involved in the process of ovarian cancer initiation or progression.Methods: Here we measured FTO expression in ovarian tumors compared to fallopian tube epithelium (FTE) and in ovarian cancer stem cells (CSCs) compared to non-CSCs. To investigate its functions we used overexpression and siRNA-mediated knockdown. Colony, sphere formation and tumor initiation assays were carried out. RNA-Seq and MeRIP-Seq were used to investigate the mechanism by which FTO-mediated m6A modifications altered stemness in OC cells. Results: FTO was expressed at lower levels in ovarian tumors compared to FTE and in ovarian CSCs compared to non-CSCs (P&lt;0.01). Overexpression of FTO inhibited the tumorigenic CSC population, its ability to form colonies and spheres, and to initiate tumors in vivo. This phenotype was not recapitulated by overexpression of mutant FTO, lacking enzymatic activity. Integrated RNA-sequencing and genome wide m6A mapping revealed significant transcriptomic changes associated with FTO overexpression and loss of m6A, involving pathways related to cell stem signaling, RNA transcription, DNA repair, and mRNA splicing. FTO augmented second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) signaling and suppressed stemness features of ovarian cancer cells by reducing mRNA stability of two phosphodiesterase genes (PDE1C and PDE4B). Conclusions: Our results point to a new function of FTO in high grade serous ovarian cancer as a regulator of cAMP hydrolysis through post-transcriptional gene modifications.
Citation Format: Hao Huang, Yinu Wang, Manoj Kandpal, Guangyuan Zhao, Horacio Cardenas, Yanrong Ji, Edward Tanner, Jianjun Chen, Ramana Davuluri, Daniela Matei. A novel function of FTO in ovarian cancer stem cells through m6A RNA demethylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2449.
Abstract 2491: Targeted next generation sequencing identifies somatic variants in Egyptian breast cancer patients
Authors: Nassar Auhood , abouelhoda Mohamed , Bahnassy Abeer , El-Din Youssef Amira Salah , Lotfy Mai M. , Ahmed ola S. , Ismail Hoda , Zekri Abdel-Rahman N. 
Published: September 2020

Abstract
Breast cancer (BC) is the leading cause of cancer-related death in women worldwide and its incidence is progressively increasing in Egypt. Recent advances in next generation sequencing have been used to detect the acquired somatic mutations driving BC. However, there is insufficient knowledge of the acquired somatic mutations in Egyptian BC patients which limit our understanding of disease progression. Up to our knowledge, this is the first Egyptian cohort to sequence a multiple-gene panel of cancer related genes on BC patients.
409 cancer related genes were sequenced in 46 fresh breast tumors of Egyptian BC patients to identify somatic mutations and their frequencies, using the Ion Ampliseq Comprehensive Cancer Panel based on the Ion torrent DNA sequencing technology. The identified sequences were mapped to the human reference genome (hg19) and the detected genetic variants were annotated against different reference databases. The average depth of coverage is 668X and the average of the aligned reads which cover the target regions is 99.6%.
Our results showed that TP53 and PIK3CA were the most top two frequently mutated genes. We detected 15 different somatic mutations in TP53 and 8 different ones in PIK3CA, each in 27 samples (58.7%). Most of the detected somatic mutations in TP53 and PIK3CA are pathogenic and well established in known hotspot regions. According to Clinvar database; we found 19 pathogenic somatic mutations: 7 in p53, 5 in PIK3CA, and single variants of VHL, STK11, AKT1, KRAS, IDH2, PTEN and ERBB2. We also identified 5 variants with uncertain significance (4 in TP53 and 1 in CEBPA) and 4 variants with conflicting interpretations of pathogenicity (2 in TP53 and 1 in each of APC and JAK3). Moreover, 4 novel variants were identified in JAK2, MTOR, KIT and EPHB.
In this cohort, we shed the light on the most frequently detected somatic mutations in Egyptian BC patients which allows for more knowledge about BC progression.
Citation Format: Auhood Nassar, Mohamed abouelhoda, Abeer Bahnassy, Amira Salah El-Din Youssef, Mai M. Lotfy, ola S. Ahmed, Hoda Ismail, Abdel-Rahman N. Zekri. Targeted next generation sequencing identifies somatic variants in Egyptian breast cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2491.