bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5030: Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages
Authors: Bejestani Elham Pishali , Lloyd G. Kenneth , Buchi Melanie , Ritschard Reto , Herzig Petra , Mohanlal Ramon , Huang Lan , Tonra James R. , Zippelius Alfred , Kashyap Abhishek 
Published: August 2019

Abstract
The M2 phenotype is dominant in tumor associated macrophages (TAMs) and correlates with poor prognosis. As M1 polarized macrophages possess anti-tumor functions, in vivo reprogramming of macrophages is a promising strategy for cancer treatment. We recently demonstrated that microtubule destabilizing chemotherapeutic agents such as plinabulin induce potent dendritic cell maturation and thereby augment anti-tumor immune responses; yet the effects of plinabulin on macrophage polarization remain unknown. Here we demonstrate that plinabulin, which is currently being investigated for both its anti-tumor effect and prevention of chemotherapy-induced neutropenia in phase II/III clinical trials,induces M1 polarization of ex vivo cultured human monocyte-derived M2 macrophages. This was characterized by a reduction in the cell surface expression of M2 markers CD163 and CD206 and an increase in the expression of co-stimulatory M1 markers CD80 and CD86. Phenotypically, plinabulin-polarized human M1 macrophages secreted increasing levels of iNOS and inflammatory cytokines IL-1β, IL-6 and IL-12 while IL-10 and IL-4 secretion decreased. This suggests a functional skewing from immunosuppressive M2 to pro-inflammatory M1 macrophages upon exposure to plinabulin. Similarly, plinabulin induced the M1 polarization of murine FACS sorted F4/80+ intratumoral M2-TAMs, characterized by increased CD80 and decreased CD206 expression. Moreover, systemic treatment (i.p.) of tumor bearing mice with plinabulin led to a significant reduction in the number of tumor-infiltrating TAMs with a concomitant M1 polarization of the remaining TAMs. Indeed, plinabulin treatment of mice bearing subcutaneous MC38 colon cancer or orthotopic EMT6 breast cancer tumors significantly delayed tumor growth. This efficacy of plinabulin remained unaltered in Rag2-/- mice lacking T cells, suggesting that macrophages are required for its anti-tumor activity. These results identify targeting of TAMs by plinabulin as a promising therapeutic strategy. Testing of plinabulin in combination with other macrophage targeting drugs are currently being explored to investigate the dual effect in reprogramming the tumor immune microenvironment.
Citation Format: Elham Pishali Bejestani, G. Kenneth Lloyd, Melanie Buchi, Reto Ritschard, Petra Herzig, Ramon Mohanlal, Lan Huang, James R. Tonra, Alfred Zippelius, Abhishek Kashyap. Microtubule destabilization by plinabulin generates anti-tumor immune response through repolarization of intratumoral macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5030.
Abstract 5042: Folate and other B-vitamins and the risk of breast cancer in younger women
Authors: Houghton Serena C. , Eliassen A Heather , Zhang Shumin , Selhub Jacob , Rosner Bernard A. , Willett Walter C. , Hankinson Susan E. 
Published: August 2019

Abstract
Purpose: Prior epidemiologic cohort studies have generally found no associations of folate and other B-vitamins with breast cancer overall, but differences by menopause status have been suggested. However, prior studies have been limited by small numbers to examine the relationship between different plasma measures and related polymorphisms and breast cancer risk among younger women. Therefore, we examined the association of plasma B-vitamins and metabolites, and related genetic variants, with risk of breast cancer among predominantly premenopausal women.
Methods: We conducted a nested case-control study within the Nurses’ Health Study II. From blood samples collected in 1996-1999 and follow-up through 2007, plasma measures were available for 610 cases and 1,207 controls. Unconditional multivariable logistic regression was used to estimate relative risks (RR) of breast cancer and 95% confidence intervals (CIs). We examined whether associations varied by methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase polymorphisms, breast cancer risk factors, or tumor characteristics.
Results: Plasma vitamin B12 was associated with a 71% increase in risk of breast cancer comparing the highest versus lowest quintile (95%CI=1.22-2.39, p-trend=0.02). Plasma folate (comparable RR=1.20, 95%CI=0.85-1.68), pyridoxal 5’-phosphate (RR=1.19, 95%CI=0.85-1.65), cysteine (RR=1.15, 95%CI=0.81-1.63), homocysteine (RR=0.90, 95%CI=0.65-1.25), and cysteinylglycine (RR=0.92, 95%CI=0.65-1.31) were not associated with overall breast cancer risk. Folate was significantly positively associated with invasive (RR highest tertile vs. lowest=1.48, 95%CI=1.09-2.01) and estrogen receptor-positive/progesterone receptor-positive breast cancer (RR T3 vs. T1= 1.59, 95%CI= 1.12-2.27) and the invasive association was suggestively stronger for bloods collected post-fortification (p-heterogeneity=0.19). Several nutrient/breast cancer associations varied across subgroups defined by age, smoking, alcohol, multivitamin use and MTHFR status (p-interaction&lt;0.05).
Conclusions: Overall, plasma B-vitamins and metabolites were not consistently associated with lower breast cancer risk. For increasing plasma folate and B12 levels higher risk of invasive breast cancer was observed. Additionally, there may be associations in subgroups defined by related genetic variants, breast cancer risk factors, and tumor factors. Future studies in younger women are needed to confirm findings.
Citation Format: Serena C. Houghton, A Heather Eliassen, Shumin Zhang, Jacob Selhub, Bernard A. Rosner, Walter C. Willett, Susan E. Hankinson. Folate and other B-vitamins and the risk of breast cancer in younger women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5042.
Abstract 5048: Determination of haptoglobin, hemoglobin genotypes and malaria incidence in Nigerian breast cancer patients
Authors: Dokunmu Titilope M. , Obi Patience , Rotimi Oluwakemi A. , Fatiregun Omolara A. , Agodirin Sulaiman O. , Rotimi Solomon O. 
Published: August 2019

Abstract
Breast cancer is the second leading cause of cancer morbidity and mortality globally. Cancer chemotherapy commonly result in hemolysis, which impacts patient overall health. There is a need to determine genetic factors associated with hemolysis in breast cancer patients. Haptoglobin (Hp), a polymorphic protein plays important role in hemoglobin clearance and disease predisposition, but has been reported to have no prognostic factor in breast cancer. However, understanding selection pressure that drives certain gene mutations in specific populations and how it confers protection or susceptibility to diseases is crucial. In Nigeria, breast cancer, malaria infection and sickle cell disease are prevalent and associated with hemolysis, but little is known of their association in breast cancer patients. This study aims to determine relationship between haptoglobin, hemoglobin genotypes and submicroscopic malaria co-morbidity in clinically diagnosed breast cancer and healthy Nigerian women. DNA was extracted from blood using standard methods. Haptoglobin 2 and hemoglobin genotypes were detected by RFLP-PCR, while Plasmodium falciparum infection was detected by primer specific amplification of plasmodium cytochrome oxidase III gene (cox III) in 75 clinically diagnosed breast cancer (BC) and 287 healthy women (control; HC). Proportions were determined and compared in the two groups and test of association was carried out with significance level set at P &lt;0.05. In BC groups, 3 (4.1%) of 72 Hp 2-2 phenotypes was detected compared to a significantly higher occurrence of 48 (16.7%) of 287 in HC group (p &lt;0.05). Conversely, malaria infection was detected in 68 (94.4%) BC versus 255 (88.9%) in HC group. A similar proportion had Hp deletions (2 in BC and 8 in HC group). There was a low prevalence of hemoglobin S genotype in the entire population and relative risk for Hp 2-2 polymorphism in hemoglobin genotypes was not significantly different. In conclusion, this study reports in breast cancer and healthy women an inverse correlation of haptoglobin (Hp2-2) genotype with malaria incidence in southwest Nigeria. The results imply a possible protection against hemolysis and can play significant role in determining choice of cancer therapy for good patient treatment outcomes.
Citation Format: Titilope M. Dokunmu, Patience Obi, Oluwakemi A. Rotimi, Omolara A. Fatiregun, Sulaiman O. Agodirin, Solomon O. Rotimi. Determination of haptoglobin, hemoglobin genotypes and malaria incidence in Nigerian breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5048.
Abstract 5059: Early life risk factors and childhood cancer risk
Authors: Stacy Shaina L. , Buchanich Jeanine M. , Ma Zhen-qiang , Mair Christina , Robertson Linda , Sharma Ravi K. , Talbott Evelyn O. , Yuan Jian-Min 
Published: August 2019

Abstract
Prenatal exposures, including maternal, delivery, and newborn characteristics, may affect childhood cancer risk. Our objective was to examine whether such birth certificate-derived factors are associated with increased risk of subsequent cancer development, including leukemia and central nervous system (CNS) tumors, in children ages zero to 13. Pennsylvania state birth and cancer registry files obtained from the PA Department of Health were linked to create a cohort of children born from 2003 to 2015 who developed cancer from 2003 to 2016. After exclusions, 1,834,796 infants were included with a total of 13,785,309 person-years of observation. Among these, there were 2,355 children diagnosed with any cancer, 748 with leukemia, and 545 with CNS tumors. Older maternal age increased the hazard of developing any childhood cancer, leukemia, and CNS tumors. Children born to severely obese mothers (body mass index ≥40 kg/m2) were at over 50% higher hazard of leukemia (P=0.01) after adjustment for age and other significant risk factors; however, maternal obesity did not significantly increase the risk of childhood CNS tumors. Among the infant characteristics, having a fetal growth ratio 30% higher than expected was significantly associated with increased hazard of any childhood cancer, leukemia, or CNS tumors (hazard ratios 2.19, 1.79, and 1.77, respectively). Other fetal and newborn factors associated with higher risk of total childhood cancer included fetal intolerance of labor, lower gestational age, and having a low Apgar score at birth. This analysis demonstrated significant and independent impacts of maternal obesity and fetal growth rate on childhood cancer development, particularly leukemia, after accounting for multiple risk factors. If confirmed, weight control during pregnancy would be an effective means of childhood cancer prevention.
Citation Format: Shaina L. Stacy, Jeanine M. Buchanich, Zhen-qiang Ma, Christina Mair, Linda Robertson, Ravi K. Sharma, Evelyn O. Talbott, Jian-Min Yuan. Early life risk factors and childhood cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5059.
Abstract 5064: Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin
Authors: Fu DongJun , Yokoyama Noriko N. , Tippin Mattew , Zi Xiaolin 
Published: August 2019

Abstract
Sirtuin 6 (SIRT6) plays an important role in longevity, metabolism, DNA-repair, and inflammatory response. In human urothelial cancer, a high level of SIRT6 expression predicts a better survival for patients. We found that overexpression of SIRT6 in human muscle-invasive bladder cancer cell line J82 reduced cell migration and invasion, but didn’t reduce the in vitro cell growth. Kava is a traditional psychotropic beverage made from the rhizomes of Piper methysticum G. Forst. Previous epidemiological studies have shown an inverse relationship between cancer incidence and kava consumption in South Pacific Island Nations. We have shown that Methysticin, a major kavalactone in the Kava plant, inhibits the growth, migration and invasion of bladder cancer lines. However, these anti-cancer activities of Methysticin are attenuated in cells with low expression of SIRT6, expression of enzymatically mutant SIRT6 or SIRT6 knockout, which suggested that the anti-cancer activities of Methysticin are at least in part dependent on SIRT6 expression. Molecular modelling indicates that Methysticin docks into the site next to a loop near the acetylated peptide substrate binding site of SIRT6. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that Methysticin significantly decreased heat-induced protein degradation of SIRT6. Treatment of J82 cells with Methysticin also resulted in a dose-dependent reduction of H3K18 acetylation. Taken together, these results suggest that Methysticin acts a novel SIRT6 activator for its anti-bladder activity. Further studies have demonstrated that Methysticin activates the TBK1/IRF3/STING pathway by increasing the protein expression of TBK1 and the phosphorylation of TBK1 and STING, which suggest that Methysticin may be able to enhance anti-tumor immunity. Therefore, our results support further investigation of Methylation for bladder cancer prevention.
Note: This abstract was not presented at the meeting.
Citation Format: DongJun Fu, Noriko N. Yokoyama, Mattew Tippin, Xiaolin Zi. Sirt6 is a novel tumor suppressor in human urothelial cancer and activated by methysticin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5064.
Abstract 5083: BSCHL-2046, a lead chalcone derivative from a newly synthesized library, is a potent neddylation inhibitor against the growth of prostate cancer cell lines
Authors: Tippin Matthew A. , Fu Dong Jun , Song Liankun , Pham Victor , Zi Xaolin 
Published: August 2019

Abstract
Members of the chalcone family of molecules and their derivatives have been shown to inhibit various forms of cancer cells. In particular, Flavokawain A has been shown to inhibit prostate cancer cell lines. In order to capitalize on the bioactive nature of chalcone derivatives, we created a library of chalcone derivatives based on the scaffold of Flavokawain A but with an additional anti-cancer moiety. Here we have demonstrated that BSCHL-2046, the most potent member of the library, inhibits cell growth of prostate cancer cell lines including LNCaP, C4-2B, DU145, 22Rv1, and PC3 with IC50’s ranging from 0.44µM-7.5µM. BSCHL-2046 inhibited Ubc12 neddylation in an in vitro assay at an IC50 of 1.5µM and demonstrated complete inhibition at a concentration of 6µM. BSCHL-2046 also reduced Nedd-8 conjugations to both Cullin-1 and Ubc12 in vivo in DU145 cells. The inhibition of neddylation by BSCHL-2046 resulted in an increased expression of p27 and CDT-1. Using molecular modeling, BSCHL-2046 was predicted to bind directly to the Cullin-RING E3 ligase complex. The Cellular Thermal Shift Assay (CETSA, an in vivo assay) demonstrated that BSCHL-2046 significantly decreased heat-induced protein degradation of E3 subunits, supporting BSCHL-2046 directly binding to the complex. Furthermore, BSCHL-2046 at a concentration of 500nM and 1.25µM displayed a 75% to complete inhibition of colony formation of C4-2B cells in soft agar. Taken together, these results demonstrate BSCHL-2046 and its structural analogs are potent neddylation inhibitors that deserve further investigation for the prevention and treatment of prostate cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Matthew A. Tippin, Dong Jun Fu, Liankun Song, Victor Pham, Xaolin Zi. BSCHL-2046, a lead chalcone derivative from a newly synthesized library, is a potent neddylation inhibitor against the growth of prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5083.
Abstract 5087: Carvedilol prevents skin cancer independently of its antioxidant property
Authors: Chen Mengbing , Liang Sherry , Andresen Bradley , Huang Ying 
Published: August 2019

Abstract
Carvedilol is an FDA approved β-blocker traditionally prescribed for cardiovascular diseases. Our previous work demonstrated that carvedilol has preventive activity against ultraviolet radiation (UVR)-induced skin damage, inflammation, and carcinogenesis. However, the photoprotective mechanism for carvedilol remains unknown. Interestingly, not all β-blockers have cancer preventive activity, suggesting that targeting the β-adrenergic receptors may not be responsible for carvedilol’s anticancer activity. Since carvedilol has been shown as a potent antioxidant and such property is not shared by majority of other β-blockers (e.g., metoprolol), we hypothesized that the antioxidant property may be, in part, responsible for carvedilol’s protective activity against photocarcinogenesis. The nontumorous mouse epidermal JB6 P+ cells were subjected to various doses of UVR exposure and H2O2 treatment to identify the optimal doses to examine protective activity. UVR and H2O2dose-dependently reduced cell viability. 25mJ/cm2 UVR and 100 μM H2O2 reduced cell viability detected by Trypan blue exclusion assay to 58.1% and 60.6%, respectively. 25mJ/cm2 UVR and 300 μM H2O2 increased the formation of intracellular fluorescent 2',7'-dichlorofluorescein (DCF) fluorescence, a marker of reactive oxidative species (ROS) detected by flow cytometry, to 5- and 4-fold compared to non-treated control, respectively. The cells were treated before or after UVR and H2O2 exposure with metoprolol, carvedilol or 4-hydroxycarbazole (4-OHC). 4-OHC is an intermediate compound for carvedilol synthesis that possesses an identical UV absorption profile as carvedilol. Additionally, the carbazole moiety is likely responsible for the antioxidant activity of carvedilol. Carvedilol, but not metoprolol and 4-OHC, was able to inhibit EGF-induced JB6 transformation in soft agar. Carvedilol, but not metoprolol and 4-OHC, also attenuated UVR and H2O2 induced cell death. Carvedilol, but not 4-OHC, inhibited UVR-induced NF-κB and AP-1 promoter activity. In addition, unlike carvedilol, 4-OHC failed to prevent chronic UVR induced skin carcinogenesis in SKH-1 mice. However, 4-OHC and carvedilol similarly attenuated UVR- and H2O2-induced ROS formation in JB6 P+ cells, while metoprolol had no effect. These results indicate that the photoprotective effects of carvedilol are primarily due to an unknown mechanism that is independent of β-adrenergic receptors and reactive oxygen species scavenging.
Citation Format: Mengbing Chen, Sherry Liang, Bradley Andresen, Ying Huang. Carvedilol prevents skin cancer independently of its antioxidant property [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5087.
Abstract 5090: Epitope mapping of mouse TERT for vaccine development
Authors: Song Yurong , Marshall Jason , Kerr Travis , Pinto Ligia , Sei Shizuko , Shoemaker Robert 
Published: August 2019

Abstract
Telomerase reverse transcriptase (TERT) is one of two essential components of telomerase, an enzyme complex that generates and maintains telomeres. Telomerase is expressed mainly in embryonic and adult stem cells. Telomere biology has recently been implicated in the pathogenesis of a variety of diseases, and mutations in telomerase components result in a predisposition to solid malignancies. More recent findings show that TERT is not only expressed in late stage primary tumor cells and metastatic cells, but also expressed in incipient cancer stem cells and/or tumor-initiating cells, indicating that TERT has essential roles at every stage of tumorigenesis. However, the clinical benefit of a TERT (hTERT)-targeting vaccine, given as a single agent or in combination with chemotherapeutic agents, has been limited in patients with advanced cancer, possibly due to insufficient epitope coverage as well as tumor-induced immune suppression. Thus, targeting TERT in tumor-initiating cells in early stage lesions may be more effective in preventing cancer development and progression. To develop cancer preventive TERT vaccines, novel immunogenic epitopes must be first identified and evaluated in a relevant preclinical model of tumorigenesis. The goal of this project is to identify the epitopes of mouse TERT with high immunogenicity using MHC I-peptide binding assay by flow cytometry analysis. The in vitro peptide-induced MHC Class I stabilization assay was carried out using RMA/S cell line, which was derived from a Rauscher leukemia virus-induced C57BL/6 T cell lymphoma and is deficient in transporter associated with antigen processing (TAP). Results of screening the overlapping peptide library will be presented.
Funded by NCI Contract No. HHSN261200800001E
Citation Format: Yurong Song, Jason Marshall, Travis Kerr, Ligia Pinto, Shizuko Sei, Robert Shoemaker. Epitope mapping of mouse TERT for vaccine development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5090.