bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract P6-05-02: Expression of ING1b-derived peptide inhibits viability of breast cancer cells and promotes apoptosis
Authors: Boyko Oleksandr , Riabowol Karl 
Published: May 2015

Abstract
The ING1b protein is a type II tumor suppressor and a stoichiometric member of HDAC-containing protein complexes. Primarily by altering chromatin structure, ING1b contributes to regulation of gene expression, senescence and apoptosis. Mislocalization and decreased levels of ING1b are commonly observed in human tumors and cancer cell lines. Multiple independent studies in varied cell types report that ING1b overexpression promotes apoptosis. Since the inactivation of apoptosis pathways is frequent in cancer cells, modulating ING1b expression in tumors may serve as a viable approach for cancer therapy. We have defined the minimal ING1b region that confers apoptotic function as estimated by the levels of PARP cleavage, FACS analysis and using an Annexin V binding assay. We have established that ING1b-derived peptides containing its third alpha helix (A3H) and NLS/NTS domains are able to induce apoptosis at levels comparable to those of full length ING1b. The A3H-NLS/NTS peptide exhibited strong nucleolar localization characteristic of full length ING1b. Cells overexpressing the full length ING1b and A3H-NLS/NTS peptide showed similar changes in cell morphology characteristic of apoptosis and exhibited increased levels of PARP cleavage. While the A3H region that includes the N-terminal part of the highly conserved Lamin Interacting Domain (LID) was necessary but not sufficient, the NLS/NTS domain that mediates nuclear and nucleolar localization of ING1b was required and partially sufficient for induction of apoptosis. Adenoviral-mediated expression of A3H-NLS/NTS peptide in cells of osteosarcoma, glioblastoma and breast cancer origins resulted in strong reduction of cell viability. Depending on the cell line, treating cells with 45 MOI of virus expressing A3H-NLS/NTS peptide resulted in a 60 - 85% decrease in cancer cell survival compared to cells treated with the control construct (Ad-GFP), and the highly transformed triple negative tumorigenic MDA-MB-468 breast cancer line was sensitive to the peptide when infected with 5 MOI of A3H-NLS/NTS adenovirus. These pro-apoptotic effects were found to be dose and time dependent. Furthermore, using p53 wild-type, p53 mutant and p53-null cancer cell lines we demonstrated that the effects of A3H-NLS/NTS expression on cell survival and apoptosis were independent of p53-status. The evaluation of the synergy between the A3H-NLS/NTS peptide and common chemotherapeutic agents is currently ongoing. Our long-term goal is to develop ING1b-based therapeutics that can be used as an adjuvant therapy in combination with the existing breast cancer treatments.
Citation Format: Oleksandr Boyko, Karl Riabowol. Expression of ING1b-derived peptide inhibits viability of breast cancer cells and promotes apoptosis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-05-02.
Abstract P6-07-03: An exhaustive algorithm for detecting copy number aberrations and large structural variants in whole-genome mate-pair sequencing data
Authors: Asmann Yan W , Wang Chen , Necela Brian M , Chen Xianfeng , Kocher Jean-Pierre A , Maurer Matthew J , Habermann Thomas M , Slager Susan L , Feldman Andrew L , Novak Anne J , Cerhan James R , Perez Edith A , Thompson E  Aubrey 
Published: May 2015

Abstract
Objectives and Rationale: Structural variants (SV) including large copy number aberrations (CNV), translocations, inversions, and large insertions and deletions (INDEL) play a critical role in tumorigenesis and progression. In fact, we now know that tumors can be categorized according to the size of mutations harbored. In several cancers, including ovarian and breast cancer, the large structural mutations, rather than single site mutations, play a dominate role in tumor etiology. Therefore, it's critical to implement reliable algorithm for the detection of structural variants in DNA sequencing data. Mate-pair sequencing is a protocol specifically implemented for detection of the whole-genome level structural variants. It requires less sequencing depth therefor is cost effective, and enables the detection of CNVs, translocations, and inversions simultaneously. However, so far there has been no reliable bioinformatics pipeline for the analyses of the mate-pair sequencing data.
Methods: Our novel algorithm, the SnowShoes-SV, is an exhaustive search algorithm designed specifically for mate-pair DNA sequencing data analyses. It calls the SVs based on disconcordant read pairs. The false SVs are filtered according to the following criteria: (i) the number of the supporting read pairs; (ii) the lack of reads from control data that implicate SV at the same region; (iii) the mappability and uniqueness of the region based on data from the ENCODE project; (iv) consistencies of the mapping orientations of the supporting read pairs; (v) the similar sizes between sequencing library and the two end read clusters.
Results: Using a set of samples previously genotyped by aCGH, the SnowShoes-SV successfully detected all known CNVs and other SVs. It also identified copy number neutral translocations and inversions previously not identified by aCGH. In addition, the algorithm nominated novel SVs which are to be validated by PCR.
Conclusions: SnowShoes-SV is a highly sensitive and specific algorithm for SV detection from the mate-pair DNA sequencing data.
Citation Format: Yan W Asmann, Chen Wang, Brian M Necela, Xianfeng Chen, Jean-Pierre A Kocher, Matthew J Maurer, Thomas M Habermann, Susan L Slager, Andrew L Feldman, Anne J Novak, James R Cerhan, Edith A Perez, E Aubrey Thompson. An exhaustive algorithm for detecting copy number aberrations and large structural variants in whole-genome mate-pair sequencing data [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-07-03.
Abstract P6-08-31: Linking genotype to clinical outcome in breast cancer by combining NGS and gene chip data
Authors: Gyorffy Balazs , Pongor Lorinc , Kormos Mate 
Published: May 2015

Abstract
Introduction: Next generation sequencing (NGS) provides the possibility to measure mutational status for any part of any gene. However, because of scarce data available to date, linking these mutations to relevant clinical outcome in a large number of patients is not possible.
Aim: Our goal was to combine available genotype data generated by using NGS with gene expression data generated by gene chips to establish a framework to assess the effect of genotype on clinical outcome.
Methods: NGS data generated by the TCGA consortia and publicly available gene chip data obtained from the GEO and EGA repositories were utilized. NGS data was processed using MuTect, SNPeff, GRCh37 and R. RNA-seq data was normalized using DEseq. Gene chip data was MAS5 normalized. Generation of the transcriptomic fingerprint for mutation status was computed by ROC utilizing the RNA-seq data. In the gene chip data, the average expression of significant genes identified was designated as a metagene for the given genotype. Correlation to survival for this metagene was assessed by computing Cox regression and plotting Kaplan-Meier survival plots. Finally, we have set up an online interface to enable running the analysis for any selected gene.
Results: The database contains 332 NGS samples containing mutational status for 22,938 genes and RNA-seq data for 10,987 genes. The gene chip database contains 5,934 patients with 10,987 genes plus detailed clinical characteristics and survival data. We evaluated correlation to outcome for previously identified genes harboring the ten most common somatic mutations in breast cancer. Of these, TP53 (n of mutations out of 332=93, hazard rate=0.51, p&lt;1E-16), AKT1 (n=18, HR=1.6, p=1.6E-15), PIK3CA (n=119, HR=1.5, p=8.5E-12), MAP3K1 (n=20, HR=1.4, p=1.3E-08), CDH1 (n=34, HR=1.3, p=4.4E-07), and RB1 (n=21, HR=1.3, p=7E-06) reached statistical significance while PI3K, PTEN, CDKN1B and GATA3 were not significant or had insufficient number of mutated samples.
Discussion: By connecting genotype to gene expression signature and employing this signature for survival analysis we have set up a pipeline enabling the functional validation of a discovered mutation for any gene in a large breast cancer cohort.
Citation Format: Balazs Gyorffy, Lorinc Pongor, Mate Kormos. Linking genotype to clinical outcome in breast cancer by combining NGS and gene chip data [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-31.
Abstract P6-08-45: Predictive characteristics for extensive nodal involvement in patients with axillary lymph node metastases
Authors: Verheuvel Nicole C , Van den Hoven Ingrid , Ooms Hendrik WA , Tjan-Heijnen Vivianne CG , Roumen Rudi MH , Voogd Adri C 
Published: May 2015

Abstract
Background
Staging of axillary lymph nodes in invasive breast cancer is an important prognostic indicator. Various prediction models have been developed to predict the risk of not having additional axillary metastases in patients with a positive sentinel node, thereby disregarding patients with a positive ultrasound. However, it is important to identify all patients with extensive nodal involvement, defined as 3 or more positive axillary lymph nodes, in whom an axillary lymph node dissection cannot be omitted.
Aim
This study aims to identify factors predicting extensive nodal involvement in the axilla, with the emphasis on the method of axillary staging; ultrasound guided lymph node biopsy versus sentinel node procedure.
Methods
All patients diagnosed with invasive breast cancer in the period between January 2006 and December 2011 at the breast center of the Máxima Medical Center were studied. Univariate and multivariate regression analyses were performed. Variables with a p-value of ≤0.10 in univariate analyses were entered in the multivariate model where a p-value of ≤0.05 was considered statistically significant.
Results
We included 307 cases, representing 306 node positive patients, of whom 178 cases had 1 or 2 positive lymph nodes and 129 cases had 3 or more positive lymph nodes. Multivariate analyses showed that factors as a positive axillary ultrasound (OR=4.513; 95%CI=2.30-8.86), palpability of axillary lymph nodes (OR=2.143; 95%CI=1.04-4.42) and lymphovascular invasion (OR=3.622; 95%CI=1.63-7.81) are significantly associated with extensive nodal involvement in patients with invasive breast cancer.
Conclusion
This study has identified clinically important factors predicting extensive nodal involvement in patients with a positive lymph node biopsy by either a sentinel lymph node procedure or an ultrasound guided lymph node biopsy. Hence, the role of axillary staging by ultrasound should be redefined since it might play an important role in selecting patients with extensive nodal involvement who, in our opinion, may still benefit from axillary treatment.
Citation Format: Nicole C Verheuvel, Ingrid Van den Hoven, Hendrik WA Ooms, Vivianne CG Tjan-Heijnen, Rudi MH Roumen, Adri C Voogd. Predictive characteristics for extensive nodal involvement in patients with axillary lymph node metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-45.
Abstract P6-09-08: Can proton therapy for localized mediastinal Hodgkin's lymphoma reduce second breast cancer incidence?
Authors: Horn Samy R , Pernin Victor , Fournier-Bidoz Nathalie , Kirova Youlia 
Published: May 2015

Abstract
Introduction
Secondary breast cancer (SBC) is a recognized late complication of radiation therapy, after treatment for Hodgkin lymphoma (HL), with reported relative risks as high as 50 with older techniques (Mantle Field). Within the past, it has been estimated that reduction in dose and volume will reduce the incidence of late complications such as secondary neoplasms and cardiovascular disease. We evaluate the impact of mediastinal proton therapy on potential limitation of SBC risk.
Material & methods
For 14 young female patients with early-stage, mediastinal HL, treated with chemotherapy and involved-field raditation therapy (IFRT), we simulated similar treatment plans with conformal radiotherapy (CRT), helical tomotherapy (HT) and proton therapy at the dose of 30 Gy. We report the respective doses to the breasts. Treatment plans were not specifically designed for breast sparing.
Results
Proton therapy significantly lowered the dose to the breasts, with mean doses of 2,76/1,53 Gy to the left and right breast respectively with proton therapy (vs. 4,95/3,88 Gy with HT and vs. 5,56/3,58 Gy with CRT). Proton therapy best limited lower doses (V4Gy and V10Gy) compared to CRT, while HT could limit the higher doses (V20Gy) at the expense of larger volume irradiated at low doses (V4Gy).
Conclusion
Relative reduction in mean doses to the left and right breasts was of 50 and 57% respectively with proton therapy compared to CRT. Relation between radiation dose and SBC seems to be linear, and reduction in SBC should be in such proportion with proton therapy. Proton therapy seems highly interesting for breast sparing after curative treatment for HL, but these results need to be confirmed by individualized risk estimations and prospective trials.
Citation Format: Samy R Horn, Victor Pernin, Nathalie Fournier-Bidoz, Youlia Kirova. Can proton therapy for localized mediastinal Hodgkin's lymphoma reduce second breast cancer incidence? [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-08.
Abstract P6-09-09: Body mass index and prognosis after breast cancer diagnosis in Japanese women
Authors: Yamashita Toshinari , Aruga Tomoyuki , Miyamoto Hiromi , Horiguchi Kazumi , Honda Yayoi , Idera Nami , Goto Risa , Kuroi Katsumasa 
Published: May 2015

Abstract
Background: Studies conducted mainly in Western countries have reported a relationship between body mass index (BMI) and prognosis among women with breast cancer. Only a few studies have been conducted in Japan so far because the percentage of high BMI is low. In the present retrospective study, we investigated the associations between BMI and the clinical characteristics and prognosis among breast cancer patients.
Methods: We analyzed 1,744 breast cancer patients who started treatment between 2004 and 2012 at a single hospital in Japan. All patients with ductal carcinoma in situ, male breast cancer as well as metachronous and synchronous bilateral breast cancer were excluded. Median age was 57 years (range 23–91). The number of patients less than 50 years old was 496. World Health Organization BMI classifications were used: Underweight, less than18.5 kg/m2, n=157; Normal, 18.5–24.9 kg/m2, n=1181; Overweight, 25–29.9 kg/m2, n=316; and Obese, more than or equal to 30kg/m2, n=90. The Cox proportional hazards model was used to estimate hazard ratios for recurrence free survival (RFS) in relation to BMI classifications.
Results: Median follow up interval was 4.2 years. During the follow-up period, 126 breast cancer recurrences were observed. BMI classification correlated with clinical tumor size (cT) significantly and BMI classification tended to correlate with lymph node metastases and estrogen receptor (ER) status.
Among patients less than 50 years old, the RFS of those with BMI ≥25.0 kg/m2 was compared to that of patients with BMI &lt;25.0 kg/m2. In multivariate analyses, BMI classification was one of the significant factors (p=0.02) along with lymph node metastases (p=0.0001) and ER status (p=0.04).
However in patients aged 50 years or over BMI category was not a significant factor (p=0.12).
Conclusions: It has been reported that higher BMI is a risk factor for breast cancer recurrence among postmenopausal patients. Our results suggest that higher BMI is also associated with an increased risk of breast cancer recurrence among premenopausal patients. It raises the possibility that maintaining an appropriate body weight improves the prognosis in premenopausal patients after they have been diagnosed.
Citation Format: Toshinari Yamashita, Tomoyuki Aruga, Hiromi Miyamoto, Kazumi Horiguchi, Yayoi Honda, Nami Idera, Risa Goto, Katsumasa Kuroi. Body mass index and prognosis after breast cancer diagnosis in Japanese women [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-09-09.
Abstract P6-12-08: The effects of the BKM120 in combination with herceptin on HER2+ BC cells and BCSCs
Authors: Zhang Jin , Yu Feng , Liu Jingjing , Zhang Xiaobei , Hu Yunhui 
Published: May 2015

Abstract
Introduction: Breast cancer stem cells (BCSCs) are suspected to be responsible for tumour recurrence, metastasis as well as chemo-resistance. Dysregulated PI3K/Akt signaling is implicated in the pathogenesis of a number of breast cancers, including the HER2+ breast cancer. This study evaluated the efficacy of BKM120 monotherapy and BKM120 plus Herceptin in treatment of normal cells and the BCSCs of the HER2+ breast cancer .
Methods:The BCSCs of SK-BR-3 cells were isolated by Serum free cells suspension culture. The impacts of BKM120 monotherapy and BKM120 combined with Herceptin on normal breast cancer cells and BCSCs were assayed by MTT assay, wound-healing assay and plate clone formation assay. The mammosphere-forming efficiency (MFE) of breast cancer cells treated with BKM120 and BKM120 plus Herceptin were also calculated. The nature of the drug interaction of BKM120 and Herceptin was evaluated by using the combination index (CI) according to the method of Chou and Talalay. The impacts of BKM120 monotherapy and BKM120 combined with Herceptin in PI3K/AKT pathway on the normal cancer cells and BCSCs of SK-BR-3 were assayed by Western bloting.
Results: BKM120 showed significant antiproliferative activity in the BCSCs, as well as in normal SK-BR-3 cells. After treated with BKM120, invasion abilities of SK-BR-3 cells was significantly weakened(P&lt;0.01).The colony forming efficiency and the MFE was also decreased compared with the control (P&lt;0.01). Additionally, the pAKT and pS6 expression levels were inhibited. The effects of BKM120 in combination with Herceptin were investigated, which was called Combination Index, showed synergism between the two agents in BCSCs as well as in the normal cells. Furthermore, BKM120 plus Herceptin showed more significantly suppression on following aspects in BCSCs and normal cancer cells : proliferation, invasion ability, colony forming as well as MFE. In addition, the levels of pAKT,pS6 in the BKM120 plus Herceptin group were decreased more obviously than those in control and monotherapy group respectively(p&lt;0.05).
Conclusions:BKM120 can inhibit the growth of normal cancer cells and BCSCs of SK-BR-3, by inhibiting cell proliferation, impairing the invasion abilities and the MFE, and reducing the expression of pAKT(Thr308,S473)and pS6(Thr389).Moreover, these results suggest that the combination of PI3K Inhibitor BKM120 with Herception may provide a novel therapy strategy for HER2+ BC.
Citation Format: Jin Zhang, Feng Yu, Jingjing Liu, Xiaobei Zhang, Yunhui Hu. The effects of the BKM120 in combination with herceptin on HER2+ BC cells and BCSCs [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-12-08.
Abstract P6-16-12: Graded prognostic assessment for triple negative breast cancer brain metastases
Authors: Chi Ming , Alva Venur Vyshak , Abraham Jame , Budd Thomas G , Elson Paul , Ahluwalia Manmeet S 
Published: May 2015

Abstract
Background:
Brain metastases is a serious complication of triple negative breast cancer (TBCBM). We evaluated prognostic factors for overall survival (OS) in contemporary cohort of TBCBM patients treated at a tertiary care institution.
Methods:
With IRB approval, Cleveland Clinic’s database was used to identify BCBM patients treated between 2000 and 2013. OS from the diagnosis of TBCBM was the primary end point. Cox proportional hazards models with stepwise variable selection were used for data analysis.
Results:
One hundred forty three female patients were included for this analysis. Karnofsky performance scale (KPS) was 90-100 in 52 patients (39%), 70-80 in 50 (38%) and &lt;70 in 30 (23%) patients. Sixty eight (49%) patients were treated with whole brain radiation therapy (WBRT), 26 (19%) with stereotactic radiosurgery (SRS), 18 (13%) with WBRT and SRS, 13 (9%) underwent surgery and WBRT, 5 (4%) underwent surgery and SRS. Seventy nine percent (113/143) of patients are reported to have died. Overall survival was 8.3 months (95% C.I. 5.5-10.6). Disease specific graded prognostic assessment (GPA) for breast cancer brain metastases is based on KPS, age at diagnosis, and subtype. By definition triple negative patients fall into the lowest two GPA score groups. GPA was prognostic for survival (p=.05), however separation between groups was variable. Starting de-novo, KPS (but different coding than in the GPA), leptomeningeal disease, and the number of extracranial sites of disease at the time of diagnosis of TBCBM were found to be independently prognostic for survival (proportional hazards model, stratified by when brain metastases were diagnosed, and a stepwise selection algorithm). A new GPA was formulated by assigning "points" (weights) to the levels within each of these three factors that are proportional to the regression coefficient estimates in the final model and then adding the total number of points present.
Prognostic Factors Impacting Survival of TBCBMFactorNumber of pointsHazard RatiopKPS0.31 (0.21-0.48)&lt;.000180-1003 &lt;/= 700 No. Extra-Cranial Mets0.42 (0.28-0.64)&lt;.00010 or 12 &gt;/= 20 Leptomeningeal Disease0.43 (0.26-0.71)0.001No2 Yes0
The new GPA consists of three groups: unfavorable, intermediate and favorable with OS of 2.7, 9.1 and 13.6 months respectively.
New GPAGPANumber of pointsNumberMedian OS ( months)PFavorable736 (27%)13.6 Intermediate4-559 (45%)9.1 Unfavorable&lt;/= 336 (27%)2.7 &lt;0.0001
Conclusions:
A novel GPA for TBCBM is proposed.
Citation Format: Ming Chi, Vyshak Alva Venur, Jame Abraham, Thomas G Budd, Paul Elson, Manmeet S Ahluwalia. Graded prognostic assessment for triple negative breast cancer brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-12.