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The rapamycin-regulated gene expression signature determines prognosis for breast cancer
Argun Akcakanat, Li Zhang, Spiridon Tsavachidis, Funda Meric-Bernstam
Molecular Cancer , 2009, DOI: 10.1186/1476-4598-8-75
Abstract: Colony formation and sulforhodamine B (IC50 < 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In the Wang dataset, RMI predicted time to disease relapse (P = 0.009).Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment.Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth [1]. The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway in particular is deregulated in many cancers, including breast cancer. PI3K activates Akt, which regulates various cellular processes and promotes cell survival. mTOR is a downstream effector of the PI3K/Akt pathway and phosphorylates S6 kinase (S6K1) and 4E-binding protein-1 (4E-BP1), which control cell growth and proliferation and protein translation. Furthermore, PI3K is a mediator of oncogenesis in breast cancer cases. Mutations in the PI3K catalytic subunit p110α [2,3] and overexpression of growth factor receptors such as HER2/neu [4], epidermal growth factor receptor [5], insulin-like growth factor receptor [6], and integrins [7] may activate PI3K signaling. Additiona
CanDrA: Cancer-Specific Driver Missense Mutation Annotation with Optimized Features
Yong Mao, Han Chen, Han Liang, Funda Meric-Bernstam, Gordon B. Mills, Ken Chen
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0077945
Abstract: Driver mutations are somatic mutations that provide growth advantage to tumor cells, while passenger mutations are those not functionally related to oncogenesis. Distinguishing drivers from passengers is challenging because drivers occur much less frequently than passengers, they tend to have low prevalence, their functions are multifactorial and not intuitively obvious. Missense mutations are excellent candidates as drivers, as they occur more frequently and are potentially easier to identify than other types of mutations. Although several methods have been developed for predicting the functional impact of missense mutations, only a few have been specifically designed for identifying driver mutations. As more mutations are being discovered, more accurate predictive models can be developed using machine learning approaches that systematically characterize the commonality and peculiarity of missense mutations under the background of specific cancer types. Here, we present a cancer driver annotation (CanDrA) tool that predicts missense driver mutations based on a set of 95 structural and evolutionary features computed by over 10 functional prediction algorithms such as CHASM, SIFT, and MutationAssessor. Through feature optimization and supervised training, CanDrA outperforms existing tools in analyzing the glioblastoma multiforme and ovarian carcinoma data sets in The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia project.
Coordinated prophylactic surgical management for women with hereditary breast-ovarian cancer syndrome
Larissa I Batista, Karen H Lu, Elisabeth K Beahm, Banu K Arun, Diane C Bodurka, Funda Meric-Bernstam
BMC Cancer , 2008, DOI: 10.1186/1471-2407-8-101
Abstract: High risk women for breast and ovarian cancer who underwent coordinated PM and BSO were included in this study. Clinical characteristics and surgical and oncologic outcomes were retrospectively reviewed.Twelve patients underwent coordinated PM and BSO. Ten had history of previous breast cancer. Autologous breast reconstruction was performed in ten patients. The mean age at surgery was 43 (range 34–65). Mean operating time was 9.3 hours (range 3–16) with a mean postoperative hospitalization of 5.4 days (range 4–8). Intraoperatively, there were no major surgical complications. Postoperatively, one patient developed an abdominal wound dehiscence, another reoperation for flap congestion; one had umbilical superficial epidermolysis, and one patient developed aspiration pneumonia. At a mean follow-up of 84 months, 10 of patients were cancer-free. Although no patients developed a new primary cancer, two developed a distant recurrence.Coordinated PM and BSO is a feasible procedure with acceptable morbidity in selected high-risk patients that desire to undergo surgery at one operative setting.Women with BRCA1 or BRCA2 mutation have a substantially increased risk of breast and ovarian cancer compared with the general population [1]. Breast cancer due to a hereditary cause is about 5 to 10% of all malignant breast disease and 25 to 40% of breast cancers that occur in women younger than 35 years old. Cumulative lifetime risk (to 70 years of age) for invasive breast cancer in women with BRCA1 and BRCA2 mutation is 40 to 85% and for invasive epithelial ovarian cancer is 15 to 65% [1-4]. Women who are BRCA1/2 mutation carriers also have a 26–40% risk of contralateral breast cancer in 10 years [5,6].Currently, management strategies for high-risk women include intense clinical follow up (every 3–6 months clinical breast exams and annual breast magnetic resonance imaging starting at 25 years of age, as well as gynecologic cancer screening with twice-yearly transvaginal ultrasound and
Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer
Funda Meric-Bernstam, Huiqin Chen, Argun Akcakanat, Kim-Anh Do, Ana Lluch, Bryan T Hennessy, Gabriel N Hortobagyi, Gordon B Mills, Ana Gonzalez-Angulo
Breast Cancer Research , 2012, DOI: 10.1186/bcr3343
Abstract: Primary tumors were collected from 190 patients with Stage I to III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays. Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.High eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node positivity. Median follow-up for living patients was 96 months.High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR = 1.62, 95% CI = 1.13-2.31; P = 0.008). In addition to age, pS6 S235/236 (HR = 1.73, 95% CI = 1.03-2.90, P = 0.039), eEF2K (HR = 2.19, 95% CI = 1.35-3.56, P = 0.002) and pdcd4 (HR = 0.42, 95% CI = 0.25-0.70, P = 0.001) were associated with OS.Increased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets.Control of mRNA translation to protein is an important point of regulation for gene expression. Translation is deregulated in cancer through a variety of mechanisms [1]. The most recognized alteration in translation is the overexpression of eukaryotic initiation factor 4E (eIF4E), the mRNA 5'cap-binding protein. Cap-dependent mRNAs initiate translation through interaction with the cap-dependent initiation complex eIF4F, comprised of eIF4E, scaffold protein eIF4G, and ATP-dependent helicase eIF4A (Figure 1) [2]. eIF4E is the rate limiting step for cap-dependent translation [3]. eIF4E overexpression leads to selective translation of a subset of mRNA such as cyclin D1, Bcl-2, Bcl-xL, and vascular endothelial
Local-regional control according to surrogate markers of breast cancer subtypes and response to neoadjuvant chemotherapy in breast cancer patients undergoing breast conserving therapy
Abigail S Caudle, Tse-Kuan Yu, Susan L Tucker, Isabelle Bedrosian, Jennifer K Litton, Ana M Gonzalez-Angulo, Karen Hoffman, Funda Meric-Bernstam, Kelly K Hunt, Thomas A Buchholz, Elizabeth A Mittendorf
Breast Cancer Research , 2012, DOI: 10.1186/bcr3198
Abstract: Clinicopathologic data from 595 breast cancer patients who received neoadjuvant chemotherapy and BCT from 1997 to 2005 were identified. Estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry were used to construct the following subtypes: ER+ or PR+ and HER2- (hormone receptor (HR)+/HER2-; 52%), ER+ or PR+ and HER2+ (HR+/HER2+; 9%), ER- and PR- and HER2+ (HR-/HER2+; 7%) and ER- and PR- and HER2- (HR-/HER2-; 32%). Actuarial rates were calculated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used for multivariate analysis (MVA).After a median follow-up of 64 months, the five-year local-regional recurrence (LRR)-free survival rate for all patients was 93.8%. The five-year LRR-free survival rates varied by subtype: HR+/HER2- 97.0%, HR+/HER2+ 95.9%, HR-/HER2+ 86.5% and HR-/HER2- 89.5% (P = 0.001). In addition to subtype, clinical stage III disease (90% vs. 95% for I/II, P = 0.05), high nuclear grade (92% vs. 97% with low/intermediate grade, P = 0.03), presence of lymphovascular invasion (LVI) (89% vs. 95% in those without LVI, P = 0.02) and four or more positive lymph nodes on pathologic examination (87% vs. 95% with zero to three positive lymph nodes, P = 0.03) were associated with lower five-year LRR-free survival on univariate analysis. On MVA, HR-/HER2+ and HR-/HER2- subtypes and disease in four or more lymph nodes were associated with decreased LRR-free survival. A pathologic complete response (pCR) was associated with improved LRR-free survival.Patients with HR+/HER2- and HR+/HER2+ subtypes had excellent LRR-free survival regardless of tumor response to neoadjuvant chemotherapy. Patients with HR-/HER2+ and HR-/HER2- subtypes with poor response to neoadjuvant chemotherapy had worse LRR-free survival after BCT. Additional study is needed to determine the impact of trastuzumab on local-regional control in HER2+ tumors.
Implications of constructed biologic subtype and its relationship to locoregional recurrence following mastectomy
Laura S Dominici, Elizabeth A Mittendorf, Xumei Wang, Jun Liu, Henry M Kuerer, Kelly K Hunt, Abenaa Brewster, Gildy V Babiera, Thomas A Buchholz, Funda Meric-Bernstam, Isabelle Bedrosian
Breast Cancer Research , 2012, DOI: 10.1186/bcr3197
Abstract: A total of 819 patients with invasive breast cancer underwent mastectomy from January 2000 through December 2005. No patient received preoperative chemotherapy. Estrogen receptor (ER) receptor, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status were used to construct the following 4 subtypes: i) ER+ or PR+ and HER2- (HR+/HER2-), ii) ER+ or PR+ and HER2+ (HR+/HER2+), iii) ER- and PR- and HER2+ (HR-/HER2+)and iv) ER- and PR- and HER2- (HR-/HER2-). LRR-free survival was estimated by the Kaplan-Meier method. Cox proportional hazard models were used to evaluate the association between time-to-event outcomes and patient prognostic factors.At a median follow-up of 58 months, five-year cumulative incidence of LRR for the entire cohort was 2.5%. Subtype specific LRR rates were 1% for HR+/HER2-, 6.5% in HR+/HER2+, 2% for HR-/HER2+ and 10.9% for HR-/HER2- (P < 0.01). In HER-2+ patients (irrespective of ER/PR status), trastuzumab therapy was not associated with LRR-free survival. On multivariate analysis, one to three positive lymph nodes (HR 4.75 (confidence interval (CI) 1.75 to 12.88, P < 0.01), ≥ 4 positive lymph nodes (HR23.4 (CI 4.64 to 117.94, P < 0.01), HR+/HER2+ (HR 4.26 (CI 1.05 to 17.33), P = 0.04), and HR-/HER2- phenotype (HR 13.87 (CI 4.96 to 38.80), P < 0.01) were associated with shorter LRR-free survival whereas age > 50 at diagnosis (HR 0.31 (CI 0.12 to 0.80), P = 0.02) was associated with improved LRR-free survival. Among the HR-/HER2- subtypes, five-year LRR incidence was 23.4% in patients with positive lymph nodes compared to 7.8% for lymph node negative patients (P = 0.01), although this association did not reach significance when the analysis was limited to HR-/HER2- women with only one to three positive lymph nodes (15.6% versus 7.8%, P = 0.11).Constructed subtype is a prognostic factor for LRR after mastectomy among low risk women not receiving adjuvant radiation therapy, although rates of LRR remain low across subtypes.
FBXW7 Mutations in Patients with Advanced Cancers: Clinical and Molecular Characteristics and Outcomes with mTOR Inhibitors
Denis L. Jardim, Jennifer J. Wheler, Kenneth Hess, Apostolia M. Tsimberidou, Ralph Zinner, Filip Janku, Vivek Subbiah, Aung Naing, Sarina A. Piha-Paul, Shannon N. Westin, Sinchita Roy-Chowdhuri, Funda Meric-Bernstam, David S. Hong
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0089388
Abstract: Purpose FBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. Preclinical data suggest that FBXW7 mutations sensitize cells to mTOR inhibitors. Clinicopathologic characteristics of cancer patients with FBXW7 mutations and their responses to mTOR inhibitors remain unknown. Methods Using multiplex gene panels we evaluated how the FBXW7 mutation affected the cancer phenotype of patients referred to a phase I clinic starting January 2012. Whenever possible patients positive for FBXW7 mutation were treated with regimens containing an mTOR inhibitors and their outcomes were reviewed. Results FBXW7 mutations were detected in 17 of 418 patients (4.0%). Among tumor types with more than 10 patients tested, FBXW7 mutations occurred in colorectal cancer (7/49; 14.3%), squamous cell cancer of head and neck (2/18; 11.1%), liver (1/13; 7.7%), and ovarian cancers (1/40; 2.5%). No one clinical, pathological or demographic feature was characteristic of the FBXW7-mutated patient population. The mutation occurred in isolation in only 2/17 (12%) patients, and KRAS was frequently found as a concomitant mutation, especially in patients with colorectal cancer (6/7; 86%). Ten patients were treated on a protocol containing an mTOR inhibitor, with a median time to treatment failure of 2.8 months (range, 1.3–6.8). One patient with liver cancer (fibrolamellar subtype) continues to have a prolonged stable disease for 6.8+ months. Conclusion In patients with advanced cancers, somatic mutations in FBXW7 usually occur with other simultaneous molecular aberrations, which can contribute to limited therapeutic efficacy of mTOR inhibitors.
Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer
Ana M Gonzalez-Angulo, Bryan T Hennessy, Funda Meric-Bernstam, Aysegul Sahin, Wenbin Liu, Zhenlin Ju, Mark S Carey, Simen Myhre, Corey Speers, Lei Deng, Russell Broaddus, Ana Lluch, Sam Aparicio, Powel Brown, Lajos Pusztai, W Symmans, Jan Alsner, Jens Overgaard, Anne-Lise Borresen-Dale, Gabriel N Hortobagyi, Kevin R Coombes, Gordon B Mills
Clinical Proteomics , 2011, DOI: 10.1186/1559-0275-8-11
Abstract: Reverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.Six breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).We developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.To inform decisions about therapy, it is necessary to have a better understanding of the molecular mechanisms underlying the heterogeneity of breast cancer. Transcriptional profiling revealed that breast cancer represents at least six molecular subtypes associated with different clinical features [1-3]. However, comprehensive analysis of breast cancer transcriptomes does not capture all levels of biological complexity; important additional information may reside in the proteome [4-7].Proteins are the direct effectors of cellular function. Protein levels and function depend on translation
Optimum Arrival Routes for Flight Efficiency  [PDF]
Ozlem Sahin Meric
Journal of Power and Energy Engineering (JPEE) , 2015, DOI: 10.4236/jpee.2015.34061

With the development of aircraft equipment, conventional navigation is the shift from performance based navigation (PBN). As is known, conventional navigation is based on ground-based navigation aids; however, PBN is based on aircraft avionics and performance. In this paper, a new method called Point Merge System (PMS) considered as one of PBN procedures will be introduced. PMS has many benefits related to fuel savings and emission reductions by implementing Continuous Descent Approaches (CDAs). A new PMS standard arrival route (STAR) model will be designed in radar simulation and it will be suggested.

The Application of Ultra High Voltage in the World  [PDF]
Metin Candas, Ozlem Sahin Meric
Journal of Power and Energy Engineering (JPEE) , 2015, DOI: 10.4236/jpee.2015.34062

With rapidly growth in industrial sectors, in order to meet the demand, the usage of Ultra High Voltage (UHV) is needed. High voltage (HV) is between the range of 52 kV and 300 kV. In case of voltage above 800 kV, it can be defined as UHV. With the development of technologies in the world, it could be seen that Japan, Russia, Italy, Brazil, America (U.S), and Canada began to improve UHV in the 1960s and 1970s. In addition, China, a leader developing country for UHV technologies in the world, started UHV technologies in transmission, in 1980s. Nowadays, seven transmission lines are in operation in China. In this study, the concept of HV and UHV will be introduced. Especially, UHV transmission in the worldwide will be researched. Then, the historical development and current situation of UHV will be analyzed and the assessment for Turkey will be done.

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