bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4987: Identification of novel genes and pathways involved in resistance to HER2-targeting agents in breast cancer
Authors: Wetterskog Daniel , Shiu Kai-Keen , Chong Irene , Meijer Titia , Natrajan Rachael , Lord Christopher J. , Ashworth Alan , Reis-Filho Jorge S. 
Published: June 2012

Abstract
The HER2 gene ERBB2 is amplified and/ or overexpressed in up to 15% of all invasive breast cancers. These cancers are characterised by an aggressive phenotype and poor clinical outcome. HER2 positive tumours often display multiple high level amplifications of genes in addition to HER2. Although targeted therapies to HER2 have proven clinical benefit, a substantial number of patients have tumours that are either de novo resistant or acquire resistance over time to these agents. Reasons for this are still largely unknown. By using a high throughput siRNA screen we sought to determine whether genes recurrently amplified and overexpressed in HER2-amplified breast cancer mediate resistance to HER2-targeting agents. We profiled 45 HER2-amplified primary breast cancers and 13 HER2-amplified cell lines with high resolution microarray-based comparative genomic hybridisation (aCGH) and Illumina WG6 v2 arrays. Overlaying of aCGH and gene expression data led to the identification of 369 genes recurrently amplified and overexpressed when amplified. Lapatinib-resistant HER2-amplified breast cancer cell lines were treated with lapatinib, a HER2 small molecule inhibitor, and screened with an RNA interference (RNAi) library targeting these 369 genes and controls. This RNAi screen and subsequent validation screens identified eight genes that when silenced lead to a significant sensitization to lapatinib. The mechanisms of resistance conferred by the identified genes were further investigated and pointed to the involvement of NF-kappaB-signalling, Wnt-signalling and reactive oxygen species scavenging. Our results indicate that specific amplified and overexpressed genes found in HER2 positive breast cancers mediate resistance to anti-HER2 agents. These findings might be used to identify patients likely to be de novo resistant to lapatinib and provide new targets for combined targeted therapies to overcome resistance to anti-HER2 therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4987. doi:10.1158/1538-7445.AM2011-4987
Abstract 4995: Lung specific target gene inhibition following intravenous delivery of siRNA nanocomplexes
Authors: Fewell Jason , Sparks Jeff , Congo Richard , Slobodkin Gregory , Rea-Ramsey Angela , Pence Casey , Matar Majed , McClure Diane , Rice Jennifer , Brunhoeber Elaine , Wilkinson Leslie , Anwer Khursheed , Polach Kevin 
Published: June 2012

Abstract
RNA interference offers the promise of a new class of therapeutics that can specifically target many diseases that have aberrant gene expression as the root cause. This is potentially true even for diseases that are currently considered non-druggable by small molecules or other conventional therapies. The means to efficiently deliver RNAi based therapeutics into target cells still poses arguably the most significant barrier to overcome for this platform technology. Cationic systems (lipids and polymers) have been extensively used for siRNA delivery and a wide range of experimental approaches have indicated that siRNA specific knockdown in vivo can be achieved using these systems. However, there is considerable concern that the dose levels required to achieve therapeutically relevant knockdown will result in unacceptable toxicity. This is particularly relevant when applied to systemic delivery. To address this issue we have developed a novel core cationic lipopolyamine structure that is chemically flexible allowing for incorporation of active moieties that improve safety, stability, and efficiency, creating a family of functionalized RNAi delivery systems. Here we show that systemic (intravenous) administration of siRNA nanocomplexes formulated with one of these functionalized systems produces significant target gene knockdown specifically in the lung with duration of at least 7 days following a single injection. Administration was well tolerated with no indications of acute or long term toxicities. Detailed biodistribution analysis reveals that siRNA is initially distributed primarily to lungs, liver and spleen, with the majority of the siRNA accumulating in the liver. Lung specific knockdown is explained through the observed rates of siRNA clearance, which are considerably faster for the liver and spleen than those observed in the lung. This results in higher lung siRNA concentrations on the timescale of RNAi mediated transcript knockdown. In a model of metastatic lung cancer administration of siRNA targeting STAT3 resulted in significant transcript depletion in the lungs and a significant reduction in tumor burden. These results support the continued evaluation of this delivery system as a potential siRNA based therapeutic approach for a variety of diseases of the lung.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4995. doi:10.1158/1538-7445.AM2011-4995
Abstract 5002: Posttranslational modification of E2F1 during melanoma progression
Authors: Meng Peng , Ghosh Rita 
Published: June 2012

Abstract
Melanoma, the malignant tumor of melanocytes, accounts for approximately 78% of skin cancer related deaths. No current treatment significantly enhances disease-free survival once distant metastases have established. To facilitate the development of effective treatment strategies, it is imperative that we obtain a better understanding of the biology of melanoma cells as they progress through the various stages of disease. Previous studies have shown that E2F1, a transcription factor, is over-expressed in melanoma cells. Interaction between E2Fs and tumor suppressor, Rb is essential for regulation of cell cycle progression. E2F1 is known to be involved in other important biological processes, including DNA damage, DNA repair, differentiation, development, autophagy and apoptosis. However, the mechanism through which E2F1 is elevated in melanoma remains unknown. In normal cells in late S phase, E2F1 is recognized by the E3 ligase p45 SKP2, undergoes ubiquitination and is finally degraded in 26S proteasome. Since multiple post-translational modifications have been reported to affect the stability and functions of E2F1, we have hypothesized that during melanoma progression E2F1 fails to undergo degradation and this failure is due to post-translational modification of E2F1. In this study we have used melanoma cells of increasing disease progression. Our results show that primary melanoma cells have high level of E2F1 message and protein. We also found that E2F1 protein levels are not tightly regulated during cell cycle progression. Levels of E2F1 remain constantly high during cell cycle progression in the less metastatic melanoma cells. Consistent with these results, phosphorylation of E2F1 at Serine 337 is almost unchanged during cell cycle progression in the less metastatic melanoma cells. These results taken together suggest that this post-translational modification site may play an important role in stabilization of E2F1 in the primary melanoma cells that represent the radial and vertical growth phases of melanoma. Since modifications usually induce conformational changes, which may affect any following modifications, it is necessary to study the crosstalk among different modifications like acetylation and phosphorylation. The modifications towards the same direction may generate a specific array of modifications that can induce markedly stronger functional effects compared with those produced by the sum of single modifications. Therefore, it is intriguing to detect the coordination of different modifications and determine if there is such a modification array that regulates the stabilization and degradation of E2F1 resulting in the elevated E2F1 levels in melanoma cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5002. doi:10.1158/1538-7445.AM2011-5002
Abstract 5017: Comprehensive analyses of the T cell-mediated adaptive immune function in the elderly melanoma patients
Authors: Hegde Upendra P. , Yadav Meeta , Chakraborty Nitya G. 
Published: June 2012

Abstract
Introduction: The incidence of melanoma is rising at a rapid rate in elderly population. Melanoma is an immunogenic tumor but T lymphocyte in the elderly persons are believed to be hypo/dysfunctional. Methods: HLA-A2 positive eleven elderly and eight young patients (median age 82 Y and 48 Y respectively) participated in the IRB approved study following informed consent. Peripheral blood (PB) derived CD8+ cytotoxic T lymphocytes (CTL), CD4+ helper T lymphocytes (TL) and CD4+CD25+ natural regulatory (nTreg) were used. Mart-1 and flu peptide was presented through PB derived antigen presenting cells (APC) to respective autologous CD8+ T cells to generate antigen specific CTL. The respective CD8+ and CD4+ cells from six elderly and 5 young patients, were engineered to express MHC class I restricted Mart-1 specific TCR and tested in functional assays. nT reg cells were tested for suppressive effect upon anti-CD3 mediated proliferation of autologous CD4+CD25- cells. Results: We found no significant differences in transduction efficiencies of Mart-1 specific TCR between young and old patients. Both Mart-1 and Flu specific CTL could be generated from all the 11 elderly and eight young patients. In vitro expanded antigen specific T effector cell responses were also comparable with inherent and engineered TCR between the two age groups. The elderly group, however, exhibited a significantly lower suppressive nTreg activity (94.4 % in young vs.16.7% suppression in elderly of CD4+TL stimulated by anti CD3 antibody). Conclusion: Our studies show that the CTL function is comparable between the two groups of patients but the nTreg activity in elderly patients is significantly reduced. More critical studies will be needed in larger number of patients to develop a comprehensive understanding of the T cell-mediated function that is important for immune based treatment of elderly melanoma patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2011-5017
Abstract 5021: Physical health scores and breast cancer outcomes in the ABC Pooling Project
Authors: Pierce John P. , Flatt Shirley W. , Natarajan Loki , Shu Xiao O. , Nechuta Sarah , Lu Wei , Caan Bette , Chen Wendy Y. 
Published: June 2012

Abstract
Background: Of the two health-related quality of life domains measured by the SF-36 (mental health and physical health), the physical health score (PHS) has been associated with all cause mortality, and recently with additional breast cancer events. This PHS includes subscales for self-perceived physical functioning, general health, bodily pain, and role limitations due to physical problems and is known to be a marker for a number of co-morbidities. Methods: Three of the four cohorts that form the After Breast Cancer (ABC) Pooling Project measured health-related quality of life using the SF-36 after cancer diagnosis. These cohorts were the Women's Healthy Eating and Living (WHEL) Study, the Nurses’ Health Study (NHS), and the Shanghai Breast Cancer Survival Study (SBCSS). Using Cox proportional hazards models controlled for cancer stage and grade, we examined the relationship between PHS with disease-free and overall survival in 9387 early stage (I-III) breast cancer survivors. The post-diagnosis SF-36 measurement took place between 1991 and 2006 and the median follow-up time was 7.8 years. Poor physical health was defined as a non-normalized score of 76.4 as previously published by the WHEL study. We also report the association between PH and co-morbidities. Results: The pooled HR (95% CI) for additional breast cancer events was 1.27(1.12, 1.44) with significant findings in each of the two US cohorts: Nurses’ Health Study 1.31(1.07-1.61) and WHEL study 1.28(1.08-1.51). A similar effect size was seen in SBCSS only, with the measurement taken during or immediately after cancer treatment. However, mostly likely due to the much shorter follow-up in this study, it did not reach statistical significance (HR=1.22 95% CI 0.80-1.86). In all cohorts, low PHS was strongly associated with higher BMI. In overweight/obese WHEL participants, low compared to adequate PHS scores were significantly associated with much lower levels of physical activity (p&lt;.0001), 64% higher reported insomnia, a 50% higher prevalence of hypertension and diabetes, and a twofold higher prevalence of arthritis. Conclusion: The importance of the PHS as a predictor of future breast cancer events and overall survival appears to be confirmed in these observational studies. Interventions to improve the PHS and prognosis might target weight control, physical activity and sleep management.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2011-5021
Abstract 5055: The role of estrogens and vascular endothelial growth factor (VEGF) in premenopausal breast cancer carginogenesis and disease progression
Authors: Recchia Francesco , Candeloro Giampiero , Desideri Giovambattista , Necozione Stefano , Rea Silvio 
Published: June 2012

Abstract
Background. Estrogen is important in breast cancer development and there is evidence in vitro, that it modulates VEGF expression in breast cancer cells through transcriptional activation. However few clinical studies have investigated the association between VEGF and estrogens in humans. Objective of this study was to evaluate weather estrogen suppression with an LH-RH analogue was able to downregulate VEGF expression, and thus decrease its plasma concentration, in premenopausal patients with high-risk early breast cancer.
Patients and methods: From April 2003 to October 2008 we conducted this study on 100 premenopausal early breast cancer patients. At baseline, after surgery, before any type of therapy, plasma VEGF and sex hormones (estradiol, progesterone, FSH, LH) were evaluated. Evaluation was repeated each year. Patients received an LH-RH analogue for 5 years, a chemotherapy that was tailored to the biological characteristics of each patient, radiation therapy, and hormonal therapy in estrogen receptor positive (ER+) tumors. Primary end point was the evaluation of VEGF. Secondary end points were progression-free survival (PFS) and overall survival (OS).
Results: Median age was 43 years (range 26-45); mean number of positive axillary nodes was 3.3. (Range 0-25). Fifty-three patients were ER+ and progesterone receptor positive (PGR+), 17 were ER negative (−) and PGR-, 30 were ER+ and PGR-, Median KI-67 was 33% (range 15%-100%). Twenty patients were Herb-2 positive by FISH. A statistically significant decrease of VEGF was observed after 1 year. At 5 years and during the study period, plasma VEGF continued to decrease (p&lt;0.001) in 94% of patients that were disease-free, while in 6% of patients with disease relapse, VEGF increased with respect to baseline values. No unexpected toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogues administration. After a median follow-up of 50 months (range 24-90), 8-year disease free survival and overall survival rated were 94% and 100%, respectively.
Conclusion: Estrogen deprivation with an LH-RH analogue is able to decrease plasma VEGF levels in premenopausal high risk breast cancer patients. These data show how estrogens, through VEGF modulation, may be responsible for the worst prognosis that is observed in premenopausal breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5055. doi:10.1158/1538-7445.AM2011-5055
Abstract 5097: Proteomic characterization of non-small cell lung cancer (NSCLC): Discovery and validation of NSCLC protein signatures and signaling networks
Authors: Wei Yuhong , Taylor Paul , Tong Jiefei , Strumpf Dan , Ignatchenko Vladimir , Pham Nhu An , Thyparambil Sheeno , Tsao Ming-Sound , Kislinger Thomas , Moran Michael F. 
Published: June 2012

Abstract
Lung cancer is the leading cause of cancer death worldwide. Non-small cell lung carcinoma (NSCLC) accounts for 80% of lung cancers. The most prevalent subtypes of NSCLC are adenocarcinoma (ADC) and squamous cell carcinoma (SCC), which combined account for approximately 90%. Ten resected NSCLC patient tumors (5 ADC and 5 SCC) were directly introduced into severely immune deficient (NOD-SCID) mice, and the resulting xenograft tumors (XT) were analyzed by standard histology and immunohistochemistry (IHC) and by proteomics profiling. Mass spectrometry (MS) methods involving 1- and 2-dimensional LC-MS/MS, and multiplexed selective reaction monitoring (mSRM, or MRM), were applied to identify and quantify the xenograft proteomes. Hierarchical clustering of protein profiles distinguished between the ADC and SCC subtypes. The differential expression of &gt;175 proteins was found to constitute a distinctive proteomic signature associated with NSCLC subtype, and an mSRM method was developed that provided relative quantification of a subset of highly differentially expressed proteins (i.e. &gt;10-fold; p &lt;0.05) that distinguished ADC and SCC subtypes. The mSRM assay was further developed for the absolute quantification of tumor signature proteins, and also the epidermal growth factor receptor (EGFR) and phosphorylated EGFR, and was successfully applied with formalin-fixed paraffin-embedded tissue sections following laser micro dissection and Liquid Tissue® processing (Expression Pathology, Rockville, MD). To further validate the XT models and to define tumor-specific protein signatures, proteomic profiles encompassing ∼1500 proteins were compared between 5 (each) resected NSCLC patient tumors (PT), corresponding XT, and normal lung tissue (N). Subsets of proteins were identified that, based on their quantified differential expression patterns, distinguished between N and PT, and validated the fidelity of tumor signatures in the XT models. Protein quantifications by mSRM were associated with superior dynamic range and reproducibility but were otherwise consistent with orthogonal methods including IHC and Western immuno blotting. These findings illustrate the potential to develop a comprehensive MS-based platform in oncologic pathology for better classification and potentially treatment of NSCLC patients.
Expression Pathology Inc. 9620 Medical Center Dr. Rockville, MD 20850
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5097. doi:10.1158/1538-7445.AM2011-5097
Abstract 510: Do adipocytes in the tumor microenvironment influence the growth of pancreatic cancer
Authors: White Patrick , Swartz-Basile Deborah , Ziegler Kathryn , Wang Sue , Pitt Henry , Zyromski Nicholas 
Published: June 2012

Abstract
Introduction: Pancreatic cancer develops more frequently and progresses more rapidly in obesity. The mechanisms influencing this association are incompletely understood. Using our murine model of pancreatic cancer in diet-induced obesity, we hypothesized that changes in the immune profile and tumor microenvironment may contribute to accelerated pancreatic cancer growth in obesity.
Methods: Thirty male C57BL/6J mice were studied. At 5 weeks of age, 20 mice were fed high fat diet (60% fat; HFD) and 10 were fed low fat (10% fat) diet. At 19 weeks of age all mice were inoculated in the flank with 2.5 x105 Pan02 murine pancreatic cancer cells. After 5 weeks of tumor growth, spleens and tumors were collected, splenic flow cytometry evaluated lymphocyte population, proliferation was determined by PCNA staining, and tumor infiltrating lymphocytes (TIL), both B and T, were scored by immunohistochemistry. Intratumoral adipocyte volume was assessed by H&E staining. Students's t-test and Pearson's correlation were applied where appropriate. P value &lt;0.05 was accepted as statistically significant.
Results: Mice were segregated into overweight (OW – heavier than the mean body weight of the HFD mice – 35.5g, n=15) and lean (&lt;35.5g, n=14). OW mice were significantly heavier (37.3±0.2g vs. 33.9±0.3g, p&lt;0.001). Tumors were twice as large in OW mice as in lean mice (1.23±0.2g vs. 0.6±0.1g; p=0.001). The peripheral lymphocyte profile was similar in both OW and lean animals (T cells: 51.2±2.5% vs. 49.2±2.3%, p=0.59; B cells: 32.9±1.0% vs. 32.0±1.9%, p=0.73). TIL were observed in similar numbers in both OW and lean groups (T cell: 1.31±0.18 vs. 1.54±0.16, p=0.35; B cell: 0.63±0.08 vs. 0.91±0.15, p=0.33). Tumor proliferation as measured by PCNA was similar in both groups (139±18 OW vs. 143±14 lean, p=0.85). Interestingly, adipocyte volume was significantly greater in the OW tumor microenvironment than in the lean tumors (3.7%±0.7 vs. 2.2%±0.3, p&lt;0.05).
Conclusions: These results demonstrate that: 1) tumor weight was significantly greater in OW mice; 2) peripheral and tumor infiltrating lymphocyte profile was similar in OW and lean animals; and 3) adipocyte volume was significantly greater in the tumor microenvironment of OW mice. We conclude that obesity accelerates the growth of pancreatic cancer, and adipocytes in the tumor microenvironment may directly influence tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 510. doi:10.1158/1538-7445.AM2011-510