bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A11: Lower baseline levels of plasma hepatocyte growth factor, IL-6, and IL-8 are correlated with greater tumor shrinkage in renal cell carcinoma patients treated with pazopanib
Authors: Heymach John V. , Tran Hai T. , Fritsche Herbert A. , Gornet Terrie G. , Liu Yuan , Rajagopalan Dilip , Martin Anne-Marie , Baker Katherine L. , Downie Louise , Hutson Thomas E. , Figlin Robert A. ,   VEG102616 Team, Amado Rafael G. , Pandite Lini N. 
Published: June 2012

Abstract
Introduction: A Phase II RCC study (VEG102616) demonstrated activity with a response rate = 34.7% (CI 95%, 28.4 – 40.9) and disease control rate (CR + PR +SD) = 80% [ASCO 2008, #5046]. An analysis of plasma cytokines and angiogenic factors (CAFs) was undertaken with the objective of identifying patients who were the most likely to respond to pazopanib.
Methods: A subset (n=129/217) of available plasma samples were selected based on extremes of tumor shrinkage from baseline. CAF levels were correlated with dichotomized tumor shrinkage (DTS) by logistic regression, with continuous tumor shrinkage (CTS) by linear regression, and with progression-free survival (PFS) by Cox regression. ROC analysis was performed using a stratified random sample of 97 patients in a training set and 32 pts in a test set.
Results: Elevated levels of HGF, IL-8, and IL-6 were significantly correlated with less tumor shrinkage. Lower levels of E-Selectin and elevated IL-6 were associated with shorter PFS. ROC curve analysis for HGF resulted in an AUC of 0.668 with an optimal cutoff of 638.5 pg/ml. Using this cutoff, HGF-based predictions in the test set had an overall accuracy of 53%, positive predictive value of 67% and negative predictive value of 50%.
Conclusion: CAF profiling showed that lower baseline levels of plasma HGF, IL-6, and IL-8 are correlated with greater tumor shrinkage in renal cell carcinoma pts treated with pazopanib. Also, elevated levels of E-Selectin and lower levels of IL-6 were associated with longer PFS.
CAF1 p-value Fold Change2 Dichotomized HGF 0.006 Fold change: 1.3 Tumor Shrinkage IL-8 0.036 Fold change: 3.0 (Logistic regression) IL-6 0.039 Fold change: 1.5 TIMP1 0.047 Fold change: 1.2 Continuous HGF 0.029 Not Applicable - NA Tumor Shrinkage IL-8 0.048 NA (Linear Regression) IL-6 0.031 NA PFS (Cox Proportional E-Selectin 0.017 NA Hazards Model) IL-6 0.005 NA 1 The following CAF analysis were performed: Angio-10 (VEGF, VEGF-R2, ICAM-1, TIE-2, PLGF, TIMP-1, HGF, FGF basic, E-Selectin, and IL-8) and Cyto-8 (IL-1 beta, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, TNF alpha) BIOCHIPS (Biomarker Workstation, Decision Biomarkers, Inc). Only the significant results were displayed above. 2 Fold change = (median CAF level for group with less tumor shrinkage) / (median CAF level for group with greater tumor shrinkage).
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A11.
Abstract A64: Mechanistic insights into the misregulation of p27 in HER2-positive breast cancers
Authors: Faltermeier Claire M. , Eide Erik E. , Roberts James M. 
Published: June 2012

Abstract
Although it is often stated that low amounts of the cell cycle inhibitory protein p27 are predictive of a poor outcome in breast cancers, this is an oversimplifcation of the data. Typically, tumor cells exhibit decreased expression of p27 in the nucleus, while preserving or even increasing the pool of p27 in the cytoplasm. Whereas nuclear p27 is tumor suppressive by inhibiting cell proliferation, newer evidence suggests that cytoplasmic p27 has an oncogenic action: it interacts with the GTPase RhoA to promote cellular migration and motility. Thus, cytoplasmic p27 may be an indicator of tumor cell invasiveness and metastatic potential. Understanding the mechanism of p27 mislocalization in breast cancers may offer insight into pathways of oncogenic transformation, and provide new markers for predicting clinical responses to specific therapies. Toward this goal, we developed antibodies that reliably detect cytoplasmic p27, and also identified a subset of breast cancers positive for the growth factor receptor HER2 that exhibited increased amounts of cytoplasmic p27. In parallel experiments we discovered an E3 ubiquitin ligase, Trim62 that regulates p27 stability, and found that it is overexpressed in HER2+ breast cancers. siRNA knock down of Trim62 in HER2+ breast cancer cell lines not only induced cell cycle arrest but also caused p27 to relocate entirely to the nucleus. We compared knock down of Trim62 to that of the well-characterized p27 regulator, the F box protein Skp2. Unlike Trim62, Skp2 inhibition had no detectable effect on p27 in these cells. As pharmacological inhibition of HER2 has also been shown to increase nuclear p27 protein levels, we investigated the role of Trim62 in modulating the response of breast cancer cells to anti-HER2 therapeutics. Like Trim62 siRNA, the HER2/EGFR inhibitor, Lapatinib increased p27 amounts, and this increase in p27 was located exclusively in the nucleus. Furthermore, we showed that knockdown of Trim62 increased cellular sensitivity to Lapatinib. Overexpression of Trim62 had the opposite effect. Collectively, our results suggest Trim62 underlies the misregulation of p27 in HER2+ breast cancer cell lines. By modulating p27 expression and cellular localization, Trim62 may mediate the antiproliferative effect of HER2 antagonists in breast cancer cells. Moreover, Trim62 could be a potential biomarker to predict biological response of breast cancer cells to anti-HER2 therapeutics such as Lapatinib.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A64.
Abstract C60: In vitro efficacy of the dual PI3-kinase/mTOR inhibitor NVP-BEZ235 in hepatocellular carcinoma
Authors: Buchbinder Elizabeth I. , Cohen Matthew B. , Jung Dorothy E. , Panka David J. , Atkins Michael B. , Mier James W. , Cho Dan C. 
Published: June 2012

Abstract
Background: The PI3-Kinase/Akt/mTOR pathway has been shown to be involved in the development of hepatocellular carcinoma (HCC). Allosteric inhibitors of mTORC1, such as everolimus (RAD001), have shown preliminary activity in patients with advanced HCC. The PI3-K pathway affects cell growth and survival through the activation of numerous other kinases besides mTOR. Therefore, disruption of this pathway upstream of mTOR may be more effective therapeutically than inhibition of mTOR alone. To investigate this hypothesis, the effects of NVP-BEZ235, a dual inhibitor of PI3-K and mTOR, were compared to rapamycin in HCC cell lines in vitro.
Methods: Four HCC cell lines (PLC, HepG2, SKHep1, and Hep3B) were exposed to NVP-BEZ235 at increasing concentrations (50nM-250nM) for 4 hours. Based upon results of western blots and MTS proliferation assays, a dose of 100nM was chosen for further in vitro studies. The same HCC cell lines were treated with DMSO, Rapamycin (100nM) or NVP-BEZ235 (100nM) and either lysed after 24hours for western blot analysis or assayed for proliferation by MTS after 48 hours. Expression of substrates of interest such as phospho-Akt, phospho-S6, phospho-4EBP, and survivin were determined by western blot.
Results: NVP-BEZ235 effectively suppressed tumor cell proliferation and inhibited its biologic targets, as determined by phosphorylation of S6 and Akt [Ser473], at low nanomolar concentrations. No significant apoptosis was detected at any concentration as determined by propidium iodide staining. In addition, NVP-BEZ235 was more effective than either rapamycin or DMSO in reducing proliferation in HCC cell lines. Both rapamycin and NVP-BEZ235 inhibited S6 phosphorylation; however only NVP-BEZ235 diminished Akt or PRAS40 (proline-rich Akt substrate) phosphorylation. NVP-BEZ235 was also significantly more effective than rapamycin in suppressing the phosphorylation of 4EBP, a well recognized substrate of TORC1. In keeping with this, NVP-BEZ235 was more effective than rapamycin in suppressing the expression of proteins such as survivin, suggesting a more profound inhibition of cap-dependent translation.
Conclusions: Dual inhibition of PI3-K/mTOR induced greater arrest of tumor cell proliferation compared to inhibition of mTORC1 alone in HCC. The ability to more effectively suppress cap-dependent translation may be central to the efficacy of drugs such as NVP-BEZ235 in HCC. Xenograft studies are underway to confirm these effects in vivo. Inhibition of PI3-K/mTOR may be a promising therapeutic strategy for patients with advanced HCC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C60.
Abstract 2215: Use of peptide nucleic acid(PNA)-mediated PCR clamping method for detection EGFR mutation in patients with non-small cell lung cancer
Authors: Kim Hee Joung , Kim Young-Chul , Kim Kyu-Sik , Lee Sung Yong , Jang Tae Won , Lee Min Ki , Shin Kyeong-Cheol , Lee Gwan Ho , Kim Hye Ryun , Lee Jae Chol , Lee Jeong Eun , Kim Sun Young , Lee Kye Young ,   Korean Molecular Lung Cancer Group
Published: June 2012

Abstract
Introduction : Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in patients with nonsmall cell lung cancer (NSCLC). Direct sequencing is known to be the standard for detecting EGFR mutations; however, it has limited sensitivity. Peptide nucleic acids (PNA)-mediated Real-Time PCR clamping method is a newly introduced method for analyzing EGFR mutations with increased sensitivity and stability.
Methods : Clinical specimens from 240 NSCLC patients were analyzed for EGFR mutations in exons 18, 19, 20 and 21. All clinical data and tumor specimens were obtained from 8 centers of Korean Molecular Lung Cancer Group (KMLCG). After genomic DNA extracted from paraffin-embedded tissue specimens, both PNA-mediated Real-Time PCR clamping and direct sequencing were performed. The results and clinical response to EGFR-TKIs were compared.
Results : Sequencing revealed a total of 63(26.3%) mutations and PNA-mediated RT PCR clamping detected EGFR kinase mutation in 83(34.6%) samples. 61 mutations were consistent by both of direct sequencing and PNA-mediated RT PCR, however PNA-mediated RT PCR detected additional 22 mutations; 10 in exon 19, 9 in exon 21 and 3 in both of them. Furthermore, patients whose tumors expressed EGFR mutations exhibited an excellent response to EGFR-TKIs by more than 88%.
Conclusion : PNA-mediated Real-Time PCR clamping is a simple and rapid, as well as a more sensitive method for screening of genomic alterations in EGFR gene compared to direct sequencing. This data suggests that PNA-mediated Real-Time PCR clamping should be implemented as a useful screening tool for detection of EGFR mutations in clinical setting.
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 2215. doi:10.1158/1538-7445.AM2011-2215
Abstract 268: Differential regulation of MMP promoters by E2F transcription factors: Potential role of c-MYC and Id1
Authors: Johnson Jackie , Pillai Smitha , Chellappan Srikumar 
Published: June 2012

Abstract
The retinoblastoma tumor suppressor, Rb, is the major negative regulator of E2F-1 transcription factor, and the Rb-E2F pathway is altered in most cancers. Further, many oncogenic mutations initiate tumors by targeting the Rb-E2F pathway. E2Fs regulate genes involved in a variety of biological processes, including angiogenesis, apoptosis, and differentiation, but it is unclear whether these molecules contribute to cancer cell invasion and metastasis. To investigate the role of E2F in metastasis, we analyzed the promoters of matrix metalloproteinase genes (MMPs), which are major contributors to the invasion and migration programs. We find that many MMP genes had potential E2F binding sites; we focused on MMP2, MMP9, MMP14, and MMP15 promoter, which have multiple E2F binding sites. Chip assays showed Rb, and E2Fs 1-5 could bind to the each MMP promoter. Transient transfection experiments with MMP promoter-luciferase constructs showed thatMMP9, MMP14, and MMP15-luc promoters were induced by E2Fs, whereas the MMP2 promoter was repressed by E2F1-5 in A549, and H1650 NSCLC cell lines. QRT-PCR showed that MMP2 was upregulated in A549 cells transfected with an siRNA targeting E2F1 and E2F3, whereas other MMPs were downregulated. To determine if MMP2 was repressed in an Rb-dependent manner, A549 cells stably expressing shRNA targeting Rb or a non-targeting control were transiently transfected with MMP2-luc construct and E2F1. In both cases, the MMP2-luc promoter was repressed by E2F1, suggesting that the repression is Rb-independent. Further, cells transfected with MMP2-luc promoter and E2F1 had less luciferase activity than cells transfected with MMP2 alone, independent of BRG-1, YY1, HDAC1, prohibitin-1, mSIN3a, or SUV39h1. Further, depletion of these co-repressors did not enhance MMP2 mRNA levels when compared to cells depleted of E2F1 alone. To determine if this repression is through binding site competition, we examined the effect of depleting transcription factors that have potential binding sites in the MMP2 promoter and were in close proximity to the E2F binding sites. We found that depletion of c-Myc and ID1 significantly enhanced MMP2 luciferase activity, and there was less repression from E2F1 in transient transfection experiments. These data suggest that E2F family members can repress the MMP2 promoter through mechanisms that may involve c-MYC and ID1.
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 268. doi:10.1158/1538-7445.AM2011-268
Abstract 621: Targeting phosphatidylserine to improve androgen deprivation therapy of prostate cancer
Authors: Yin Yi , Thorpe Philip E. 
Published: June 2012

Abstract
Androgen deprivation therapy (ADT) is effective against androgen-dependent prostate cancer, but patients usually relapse from the outgrowth of androgen-independent disease. Here, we tested the hypothesis that relapse can be prevented by combining ADT with treatment with a monoclonal antibody that binds exposed phosphatidylserine (PS). The rationale behind this hypothesis is that ADT will create hypoxia which induces PS exposure on the tumor vascular endothelial cells, leading to immune cell attack on tumor vasculature, collapse of the vessels and death of hormone-resistant and hormone-sensitive tumor cells through deprivation of oxygen and nutrients. In addition, the antibody should block the immunosuppressive effects of PS and induce reactivation of T-cell immunity. To test this hypothesis, we used ADT and anti-PS antibodies (2aG4 or murine chimeric 1N11) to treat mice bearing hormone-sensitive prostate tumors. The tumor models were: i) immunocompromised mice bearing human LNCaP prostate tumors; ii) transgenic (TRAMP) mice which spontaneously develop adenocarcinoma of the mouse prostate. Castration induced exposure of PS on blood vessels and tumor cells in both models. Vascular PS exposure corresponded with hypoxia, as judged by pimonidazole staining. In the LNCaP model, castration alone delayed tumor growth but all animals relapsed with hormone-independent disease, whereas mice treated with castration plus anti-PS antibody did not relapse. In TRAMP mice castrated at 15-weeks of age, only 54% (7/13) of mice treated with castration alone survived beyond 40-weeks of age, as compared with 92% (12/13) of mice treated with castration and 1N11. No toxicity to the mice was caused by the antibody treatment. Tumor blood flow and perfusion were markedly reduced in mice treated with castration and anti-PS antibody. Histological studies revealed extensive disruption of tumor vasculature and abundant infiltration of immune cells, principally M1 macrophages. These results demonstrate that PS becomes exposed on prostate cancer tumor vasculature and tumor cells in response to hypoxia caused by ADT in the tumor microenvironment. The exposed PS could serve as a target to enhance the efficacy of ADT against prostate cancer.
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 621. doi:10.1158/1538-7445.AM2011-621
Abstract 884: Pleiotropic effects on lung cancer of genetic susceptibility variants identified for other malignancies: The multiethnic cohort
Authors: Cheng Iona C. , Caberto Christian , Wilkens Lynne R. , Schumacher Fredrick R. , Kolonel Laurence N. , Henderson Brian E. , Stram Daniel O. , Haiman Christopher A. , Marchand Loic Le ,   The PAGE Consortium
Published: June 2012

Abstract
Genome-wide association studies of cancer have succeeded in identifying over 100 susceptibility loci, including some, such as those found at chromosome 8q24 and CPTM1L-TERT that influence the risk of several malignancies. As part of the Population Architecture using Genomics and Epidemiology (PAGE) Study, we evaluated whether established risk variants for 19 different cancer sites, excluding the lung, impact the risk of lung cancer. A total of 148 risk variants for these 19 malignancies were selected from genome-wide association studies published through May, 2009. These SNPs were genotyped in a lung cancer case-control study (cases, n=696; controls, n=3,225) nested within the Multiethnic Cohort Study, a large prospective study conducted among African Americans, Latinos, Japanese Americans, Native Hawaiians and whites. Unconditional logistic regression was performed to evaluate the association between SNPs and lung cancer risk, adjusting for age, sex, race/ethnicity, smoking status (current, never, former), and pack-years of cigarette smoking. Eleven of the 148 SNPs were associated with lung cancer risk (P&lt;0.05): two acute lymphocytic leukemia SNPs, two breast cancer SNPs, one glioma/testicular cancer SNP, one neuroblastoma SNP, four prostate cancer SNPs, and one thyroid cancer SNP. By chance, seven associations would be expected for the 148 tests (148 × 0.05=7), suggesting robust significant associations among the 11 associated SNPs. The top associations (P&lt;0.01) were observed with three prostate cancer SNPs (rs10090154 at 8q24-region 1, P=0.0008; rs7837688 at 8q24-region 1, P=0.0009; rs4962416 at CTBP2, P=0.003) and one breast cancer SNP (rs2981578 at FGFR2, P=0.0074). Future analyses will include approximately 4,400 additional lung cancer cases and controls from the Women's Health Initiative (WHI), Arthrosclerosis Risk In Communities (ARIC) study, and the Cardiovascular Health Study (CHS) as part of the PAGE initiative. If these genetic risk factors are replicated, they may clarify shared pathways involved in the carcinogenic process.
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 884. doi:10.1158/1538-7445.AM2011-884
Evaluation of Known Oncoantibodies, HER2, p53, and Cyclin B1, in Prediagnostic Breast Cancer Sera
Authors: Lu Hailing , Ladd Jon , Feng Ziding , Wu Mei , Goodell Vivian , Pitteri Sharon J. , Li Christopher I. , Prentice Ross , Hanash Samir M. , Disis Mary L. 
Published: June 2012

Abstract
Serum autoantibodies, directed against oncogenic proteins, have been frequently detected in the sera of patients with breast cancer. It is unknown whether serum antibodies that are identified in patients with established disease could also be detected in patients with newly diagnosed disease or even predate the diagnosis of breast cancer. Using sera collected at the time of treatment, at the time of diagnosis, or before the time of diagnosis, the current study aimed to address the temporal relationship between breast cancer development and serum antibody response. Starting from serum antibodies to eight known breast cancer antigens, we first identified four serum antibodies, HER2/neu, p53, carcinoembryonic antigen (CEA), and cyclin B1, which are significantly increased in the sera collected from patients with breast cancer at the time of treatment. These antibodies were also elevated in breast cancer sera collected at the time of diagnosis. Finally, comparison of antibody responses in prediagnostic samples from women before the development of breast cancer and in controls showed that antibodies to the HER2/neu and p53 can be detected in sera that were collected on average more than 150 days before a breast cancer diagnosis. These results showed that serum autoantibodies commonly reported in sera from patients with established disease can also be detected in prediagnostic sera and may be useful for the early detection of breast cancer. Cancer Prev Res; 5(8); 1036–43. ©2012 AACR.
Changes in the Cerebrospinal Fluid Ceramide Profile After Subarachnoid Hemorrhage
Authors: Testai Fernando D. , Hillmann Maureen , Amin-Hanjani Sepideh , Gorshkova Irina , Berdyshev Evgeny , Gorelick Philip B. , Dawson Glyn 
Published: June 2012

Background and Purpose—
The purpose of this study was to investigate changes in the cerebrospinal fluid sphingolipid profile in patients with subarachnoid hemorrhage in relation to the occurrence of symptomatic vasospasm and outcome at hospital discharge.

Methods—
The ceramide profile in the cerebrospinal fluid was determined by mass spectrometry in control subjects and patients with Fisher 3 grade subarachnoid hemorrhage within 48 hours of the bleed. Patients were prospectively followed and subcategorized based on the occurrence of symptomatic vasospasm and modified Rankin Scale at discharge.

Results—

Compared to control subjects, patients with subarachnoid hemorrhage had higher cerebrospinal fluid levels of total ceramide (12.4±8.8 versus 54.6±49.3 pmol/mL;
P
<0.001). In the subgroup analysis, total ceramide levels in individuals with symptomatic vasospasm (104.2±57.0 pmol/mL) were higher than in those with asymptomatic vasospasm (32.4±25.7 pmol/mL;
P
=0.006) and no vasospasm (30.9±15.7 pmol/mL;
P
=0.003). In addition, compared to patients with a good outcome (modified Rankin Scale ≤3), individuals with poor outcome (modified Rankin Scale ≥4) had higher cerebrospinal fluid levels of total ceramide (79±25 versus 23±6 pmol/mL;
P
=0.008). When the relative contributions of the different ceramide species were calculated, a higher relative concentration of C
18:0
ceramide was observed in individuals with symptomatic vasospasm (
P
=0.018) and poor outcome (
P
=0.028).

Conclusions—

Ceramide profile changes occur in subarachnoid hemorrhage. In this small case-based series elevation of levels of this sphingolipid, particularly C
18:0
, was associated with the occurrence of symptomatic vasospasm and poor neurological outcome after subarachnoid hemorrhage.