bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1210: Mifepristone abrogates repopulation of ovarian cancer cells in between courses of cisplatin treatment
Authors: Freeburg Elizabeth M , Goyeneche Alicia A , Telleria Carlos M. 
Published: May 2019

Abstract
Repopulation of cancer cells that escape cytotoxic chemotherapy is a critical factor that negatively impacts treatment success. Thus, any strategy that prevents this phenomenon from occurring would be beneficial for the outcome of the treatment. One such strategy to inhibit tumor cell repopulation is the use of cytostatic compounds among courses of cytotoxic therapy. In this study, we tested the hypothesis that mifepristone, a steroid compound displaying a potent cytostatic effect in ovarian cancer as recently demonstrated in our laboratory (Clin Cancer Res 2007, 13, 3370-3379), should be efficacious to induce cytostasis and to prevent ovarian cancer repopulation if given in between rounds of cisplatin therapy. We established an in vitro approach in which OV2008 cisplatin-sensitive ovarian cancer cells were exposed to three rounds of a cytotoxic dose (20 μM) of cisplatin for 1 h, twelve days apart. Every four days the number of cells, their viability, and their distribution within the cell cycle were assessed by micro-cytometry using exclusion fluorochromes and propidium iodide, respectively. Further, the colony-forming capacity of the viable cells was evaluated along the experiment. Although cisplatin killed the vast majority of OV2008 cells, there were cells that escaped cisplatin toxicity and repopulated the culture. This phenomenon occurred each one of the three times the cells were challenged by cisplatin during the 36 days the study lasted. Post-cisplatin repopulation was evidenced by the increase in number and clonogenic capacity of the viable cells, the normalization in the distribution of cells within the different phases of the cell cycle (S, G1 and G2/M), and the concomitant reduction in sub-diploid DNA content (as marker of cytotoxicity). Instead, when the cells were exposed to cisplatin for 1 h, but 5, 10 or 20 μM mifepristone was present in the culture medium after removal of the platinum agent, both number of cells and their clonogenic capacity were reduced in a dose-related manner. Remarkably, the cultures exposed to cisplatin for 1 h followed by chronic exposure to 20 μM mifepristone did not have remaining viable cells to allow performing the clonogenic survival assay by day 12 of the study, suggesting an added lethality to the cytostatic effect of mifepristone. In conclusion, this study demonstrates that presence of cytostatic concentrations of mifepristone prevents the repopulation of ovarian cancer cells surviving the lethality of cisplatin, and further suggests mifepristone may potentiate cisplatin toxicity. The scheduling of mifepristone between courses of cisplatin-based therapy for human ovarian cancer has potential for improving treatment success. Supported by NIH grant CA121991.
Abstract 1582: Identification of BCAR genes relevant for breast cancer progression and endocrine therapy resistance
Authors: Van Agthoven Ton , Veldscholte Jos , Sieuwerts Anieta , Smid Marcel , Meijer-Van Gelder Marion E , Look Maxime P , Foekens John A , Dorssers Lambert C. J. 
Published: May 2019

Abstract
Endocrine therapy of breast cancer is effective and widely applied. In advanced disease, about half of the patients will experience a clinical benefit from tamoxifen treatment, but ultimately the disease will progress into a resistant phenotype. The molecular basis of this general failure of endocrine therapy is not understood yet. Although gene expression profiling experiments provide gene lists to identify patients who may benefit from specific treatments, these genes mostly do not define the underlying molecular mechanisms. We have executed a functional screen for the identification of BCAR genes causing anti-estrogen resistance in a human breast cancer model and evaluated their role in a large breast cancer cohort.
Estrogen-dependent ZR-75-1 human breast cancer cells were subjected to insertion mutagenesis with replication-defective retroviruses and selected for proliferation in the presence of 4-hydroxy tamoxifen. In our panel of 79 tamoxifen-resistant cell lines, the target genes of the retroviruses have been identified and were functionally tested following transfection into ZR-75-1 cells. Seven BCAR genes (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7 and TRERF1) causing the tamoxifen-resistant phenotype were identified. Furthermore, additional putative BCAR genes and loci have been pinpointed.
To determine the relevance of the identified genes in clinical breast cancer, we have studied 561 estrogen receptor-positive primary breast cancers for tumor aggressiveness and tamoxifen therapy resistance. Quantitative RT-PCR of ten genes was performed to measure the tumor mRNA levels. The endpoint for tumor aggressiveness was metastasis-free survival (MFS) of a cohort of lymph node-negative patients. Therapy resistance was evaluated in a group of patients treated with tamoxifen as first-line therapy for recurrent disease and the endpoint of this analysis was progression-free survival (PFS). Statistically significant associations with MFS were found for AKT2, EGFR, TLE3 and TRERF1 mRNA levels. In multivariate analyses including the traditional prognostic factors, AKT2, EGFR and TRERF1 were independent prognostic factors for MFS and thus are associated with tumor aggressiveness. In the analyses of PFS, mRNA levels of BCAR3, ERBB2, GRB7, TLE3 and TRERF1 were associated with the duration of clinical benefit of tamoxifen therapy, independently of the classical predictive factors.
Our functional screen identified a set of clinically relevant BCAR genes offering insight in the molecular and cellular pathways of breast tumor aggressiveness and tamoxifen resistance, and thereby provides novel targets for personalized treatment and prevention strategies.
Supported by the Dutch Cancer Society, the Susan G Komen Breast Cancer Foundation and the Association for International Cancer Research.
Abstract 1604: Dietary energy balance modulates multistage epithelial carcinogenesis in mouse skin
Authors: Moore Tricia , Carbajal Steve , Jiang Anna , Beltran Linda , Hursting Stephen , DiGiovanni John 
Published: May 2019

Abstract
Dietary energy balance refers to the balance between caloric intake and energy expenditure. Findings from both epidemiological and experimental studies suggest chronic positive energy balance, which can lead to obesity, heightens the risk of developing multiple cancers, while a negative energy balance state, as induced by calorie restriction (CR), decreases these risks. In the present study, we used the two-stage skin carcinogenesis model to examine the effect of dietary energy balance manipulation on both the promotion and progression stages of skin tumorigenesis. Groups of female ICR mice (n=30) were initiated with 25 nmol DMBA and then placed on one of four dietary treatment regimens: 30% CR, 15% CR, 10Kcal% fat (control), or 60Kcal% fat [diet-induced obesity (DIO) diet]. Following four weeks on diet, mice were then promoted with either acetone or 6.8 nmol TPA twice-weekly for the duration of the study. Chronic CR (30% CR) led to a statistically significant inhibition of papilloma formation in the TPA treated group compared to the other TPA treated diet groups. In contrast, while there was a slightly higher number of papillomas per mouse in the DIO diet group treated with TPA, this was not statistically different from the control and 15% CR groups treated with TPA. This experiment is currently being carried to carcinoma development to determine the impact of dietary energy balance manipulation on the conversion of papillomas to carcinomas in this model of epithelial multistage carcinogenesis. Mechanistic studies have been performed to examine the impact of dietary energy balance manipulation on epidermal cell signaling pathways related to TPA-mediated skin tumor promotion. In this regard, CR reduced whereas DIO increased activation of both epidermal Akt and mTOR (assessed by Western blot analysis of phosphorylated proteins) both in the absence and presence of TPA. Furthermore, activation of both the EGFr and IGF-1R was modulated in a similar manner by the different diets. These results suggest that dietary energy balance may modulate tumor promotion in part through modulation of critical signaling pathways downstream of cell surface receptors such as the EGFr and IGF-1R.
Abstract 1795: Noninvasive genetic detection of head and neck squamous cell carcinoma
Authors: Sethi Seema , Benninger Michael S , Lu Mei , Havard Shaleta , Worsham Maria J 
Published: May 2019

Abstract
Purpose of the study: To develop and evaluate a noninvasive approach for head and neck squamous cell carcinoma (HNSCC) based on genomic alterations of loss and gain of gene copy number.
Experimental Procedures: The study cohort comprised 37 subjects, 27 HNSCC patients and 10 healthy controls. DNA extracted from saliva of the study subjects was interrogated by multiplex ligation-dependent probe amplification (MLPA) assay for gene copy number alterations (losses and gains) using two panels of 82 gene probes with known associations to HNSCC. MLPA permits evaluation of 41 different genes in one PCR reaction using scant amounts of DNA. The data were analyzed using the Classification and Regression Tree (CART) to determine whether gene alterations detected in saliva DNA discriminated HNSCC patients from normal controls. Results were validated using the leave-one-out validation approach.
Results: Of the 82 genes analyzed, 11 genes, ERBB2, ABCC4, UTY, DNMT1, PMAIP1, CDKN2B, CDKN2D, NFKB1, TP53, PTPN1, DCC, had the highest individual predictive ability for HNSCC. CART analysis revealed gain of PMAIP1 (18q21.31) solely or in conjunction with gain of PTPN1 (20q13.13) genes classified all 27 HNSCC patients with 100% sensitivity and 100% specificity. Validation results showed a sensitivity and specificity of 96% and 90% respectively.
Conclusions: Gain of PMAIP1 (18q21.31) and PTPN1 (20q13.13) genes definitively separated HNSCC patients from normal controls, providing proof of concept that saliva based gene algorithms may have clinical utility for noninvasive HNSCC detection.
Keywords: Genetic alterations; Head and neck squamous cell carcinoma (HNSCC); Multiplex Ligation-dependent Probe Amplification Assay (MLPA); Classification and Regression Tree (CART).
Support:
HFHS Dev Grant 06 (SS), R01 NIH DE 15990 (MJW).
Abstract 2029: Identification and characterization of cancer stem cells in ovarian cancer
Authors: Mor Gil , Chen Rui , Fu Han Hsuan , Montagna Michele , Visintin Irene , Silasi Dan , Schwartz Peter , Azodi Masoud , Rutherford Thomas , Alvero Ayesha 
Published: May 2019

Abstract
Introduction: One of the major burdens in the treatment of epithelial ovarian cancer (EOC) is the high percentage of recurrence characterized by chemoresistance. The biology underlying the tumor’s high capacity for recurrence has not been elucidated. Tumors are made of a heterogeneous cell population consisting of both cancer and non-cancer cells. New data suggest that even the cancer cell population is heterogeneous and contains a small subset of cells, the cancer stem cells (CSC), which constitute a reservoir that can self-renew and therefore maintain the tumor. CSC can divide and expand their pool and also differentiate into non-CSC, which constitute the bulk of the tumor. Contrary to CSC, the non-CSC are rapidly dividing and therefore sensitive to therapies, which target highly proliferative cells. In the present study we identified and characterized the CSC of EOC.
Methods: EOC cells were isolated from malignant ovarian cancer ascities and solid tumors (n=80). Marker expression was determined using Flow Cytometry, Western Blots and Immunocytochemistry. Xenograft nude mice model was used for tumor growth by injecting cancer cells either s.c. or i.p. Isolation of CD44+ population was done using FACS. Cancer cells were maintained in culture as previously described {Kamsteeg, 2003 #358}
Results: CSC were identified in EOC cells isolated form ascites and solid tumors with the following characteristics: 1) cellular markers: CD44+, MyD88+, constitutive NFκB activity and cytokine and chemokine production, high capacity for repair, chemoresistance to conventional chemotherapies, resistance to TNFα-mediated apoptosis, capacity to form spheroids in suspension, and unique microRNA phenotype; 2) tumor formation in animals: 100% CD44+ cells formed tumors which contained 10% CD44+ and 90% CD44-negative cells. Re-injection of isolated CD44+ cells from previous engraftment was able to again recapitulate the original tumor phenotype. Isolation and in vitro treatment of CD44+ cells from fresh samples showed resistance to carboplatin and paclitaxel. In contrast, the sorted CD44-negative cell population from the same sample/patient was chemosensitive.
Conclusion: Present chemotherapy modalities eliminate the bulk of the tumor but it leaves a core of cancer cells with high capacity for repair and renewal. CSC corresponds to the core of malignant cells that promotes recurrence and chemoresistance. Identification of these cells represents the first step in the development of therapeutic modalities that can eliminate not only the bulk of the tumor but its source. Prevention of recurrence will be achieved only with therapies targeting this cell population.
Abstract 2539: CTLA-4 blockade for hormone refractory prostate cancer: Dose-dependent induction of CD8+ T cell activation and clinical responses
Authors: Fong Lawrence , Kwek Serena , Kavanagh Brian , O'Brien Shaun , McNeel Douglas , Weinberg Vivian , Rini Brian , Small Eric J. 
Published: May 2019

Abstract
CTLA-4 is a costimulatory molecule expressed on activated T cells that delivers an inhibitory signal to these T cells. CTLA4 blockade with antibody treatment has been shown to augment T cell responses and anti-tumor immunity in animal models and is being developed as an immunotherapy for cancer patients. We performed a phase I trial in patients with metastatic, hormone refractory prostate cancer (HRPC) where sequential cohorts of 3-6 patients were treated with escalating doses (0.5, 1.5 or 3 mg/kg) of ipilimumab, a fully human anti-CTLA-4 antibody (Medarex/BMS), given IV on day 1 of each 28-day cycle x 4 cycles. Patients also received GM-CSF (sargramostim, Berlex) 250 mg/m2/d SC on days 1-14 of the 28-day cycles. Patients were monitored for toxicity as well as for T cell activation. PSA and radiographic tests were performed at baseline and through therapy to evaluate for clinical response. 24 patients have been treated in the initial phase of this study. Of 6 patients treated on the highest dose level (3.0 mg/kg x 4), 3 (50%) had confirmed PSA declines of &gt;50%, and one of these patients had a partial response in hepatic metastases. Immune-related adverse events associated with ipilimumab treatment were also seen more frequently at higher doses of treatment. Expansion of CD25+CD69+ CD8 T cells was also seem primarily at the highest dose level. The treatment also induced an antibody and CD8 T cell immune response to NY-ESO-1. These results demonstrate that CTLA-4 blockade induces not only the expansion of activated effector CD8 T cells in vivo in cancer patients, but also can induce from the endogenous T cell repertoire of these patients T cells that are specific for tumor-associated antigens. CD8 T cell activation, toxicity, and clinical responses also appear to be dose-dependent. Supported by NIH P50 CA89520.
Abstract 4188: Dietary energy balance impacts spontaneous pancreatic lesions in the K5.COX-2 transgenic model of pancreatic cancer
Authors: Lashinger Laura M , Malone Lauren , Daniels Elizabeth , Smith Nicole C. , Pavone Amy , Colby Jennifer L. , Fischer Susan M. , Hursting Stephen D. 
Published: May 2019

Abstract
Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States. Obesity, which has increased dramatically over the past 40 years, has emerged as an important risk factor for pancreatic cancer, although the mechanisms underlying the obesity-pancreatic cancer association have not been identified. Calorie restriction (CR), a dietary strategy for inducing negative energy balance and preventing or reversing obesity, has significant anti-cancer effects in several species, for a variety of tumor types, and for both spontaneous and chemically-induced tumors. However, the effects of dietary energy balance modulation on pancreatic tumor formation have not been well studied. We hypothesized that spontaneous tumor development in the K5.COX-2 transgenic mouse model of pancreatitis-driven pancreatic cancer would be reduced in lean mice, relative to overweight or diet-induced obese (DIO) mice. In order to test this hypothesis, we placed 6-8 week old K5.COX-2 transgenic mice on one of three diets for 14 weeks (n=12/group): lean (30% CR), overweight (AIN-76A diet fed ad libitum), or a high calorie/high fat DIO regimen. K5.COX-2 transgenic mice develop spontaneous pancreatic lesions as early as 4 weeks with 100% becoming moribund within 6-8 months. Based on histologic analysis of the percentage of pancreas that is comprised of enlarged and dilated ductal lesions, the CR animals were significantly protected from spontaneous pancreatic lesion formation (7.5%±1.44) as compared to the overweight (45%±10.5) and DIO (57.5%±9.46) groups. Furthermore, CR mice had smaller lesions at time of harvest with none exhibiting signs of moribundity. Conversely, the DIO group generally had the largest lesions, although there was no statistical difference between the overweight and DIO groups. In addition, several mice in the overweight and DIO groups had to be sacrificed early due to extensive abdominal distention, morbidity from enlarged cystic lesions, and other signs of distress. Further investigation is needed to discern how CR exerts its effects. Preliminary analyses suggest that IGF-1 may be playing a significant role. Moreover, pro-inflammatory cytokines were shown to be significantly reduced in sera of CR-animals as compared to the other two groups. In conclusion, using a model of pancreatitis-induced pancreatic tumorigenesis, our findings indicate that dietary energy balance modulation can alter the development of pancreatic cancer. This could have direct implications for the prevention and control of pancreatic tumors due to chronic inflammation and/or obesity.
Abstract 4741: Application of nanotechnology for enhanced early detection of prostate cancer in African-American men
Authors: Phelan Catherine M , Ostapenko Sergei , Chornokur Anna , Tanner Richard , zhang jin , Pow-Sang Julio , Steel John Jack , Sellers Thomas 
Published: May 2019

Abstract
Background: African American men in the US have the highest incidence and mortality from prostate cancer in the world. Five-year survival rates are almost 100% of African American men diagnosed with early stage prostate cancer but only 29% for men diagnosed in the late stages of the disease. Early detection is thus the key to improved mortality and morbidity. We are investigating nanotechnologies to enhance the detection of prostate cancer biomarkers at extremely low levels in blood serum. Our goal is to engineer a multi-biomarker panel that will provide sufficiently high sensitivity and specificity such that it can be applied as a screening test and decrease prostate cancer morbidity and mortality among African-American men.
Objectives: 1.To engineer quantum dot - antibody conjugates targeting established prostate cancer biomarkers (antigens): prostate specific antigen (PSA), Kallikrein 2 (KLK2), Kallikrein 14 (KLK14), Osteoprotegerin (OPG), Antip53Ab, Caveolin-1 (Cav-1) and Interleukin-6 (IL-6) 2. To define the photoluminescence signatures of bound versus unbound QDs, reflecting antigen-antibody complex formation. 3. To derive optimal cutpoints for the sensitivity and specificity of the novel QD-conjugated biomarkers individually, and in combination, for the early detection of prostate cancer in African-American men.
Results: We have established an African American prostate cancer case-control collection. We have successfully conjugated antibodies to the above biomarkers to quantum dots and these are undergoing characterization. We have observed that the bio-conjugated QD shows a spectral shift of the maximum position on average by 4 nm in comparison to non-conjugated QDs. The shift is towards a shorter wavelengths “blue” shift for conjugated quantum dots. Its existence was confirmed with repetition of the conjugation scheme with identical parameters and the “blue” shift was observed in all repeated experiments. The PL spectral shift observed on bio-conjugated QDs with antigens may be attributed to the existence of an external local electric field that is imposed by the surrounding biomolecules (Stark effect). The shift varied depending on the different antibodies attached and on QDs of different wavelengths.
Conclusions: We have observed a spectral shift of the bio-conjugated quantum dots compared to unconjugated quantum dots. The benefit of this observation may lie in the fact that the shift is different for each antibody, thus will show a peak at different wavelengths. This effect may provide a powerful tool for multiplexing proteins for early cancer detection. This study has enormous potential impact on improved detection of this disease in the early and more curable stage which in turn would lead to decreased morbidity and mortality.
Abstract 512: Gene expression profiling reveals tumor immunobiological differences in prostate cancer between African-American and European-American men
Authors: Wallace Tiffany A , Prueitt Robyn L , Yi Ming , Stephens Robert M , Ambs Stefan 
Published: May 2019

Abstract
The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared to European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed 162 transcripts to be differentially expressed between African-American and European-American prostate cancer patients at a false discovery rate of 5% or less. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differentially expressed genes clustering in immune response, defense response, antigen presentation, B-cell/T-cell function, cytokine signaling, and inflammatory response pathways. Most commonly, the genes involved in these pathways were more highly expressed in tumors of African-American patients when compared with those of European-American patients. Amongst the immune-specific genes over-expressed by African-American patients was indoleamine 2,3-dioxygenease, HLA-E, and HLA-G. All three of these genes are well-known contributors of immunologic tolerance in tumors. Furthermore, a distinctive interferon signature was identified in the African-American prostate tumors, suggesting the possibility of viral involvement in disease etiology in this African-American population. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups.