bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2708: New approaches to overcome tyrosine kinase inhibitor resistances in chronic myeloid leukemia
Authors: Halbach Sebastian , Wöhrle Franziska U. , Braun Sandra , Brummer Tilman 
Published: August 2015

Abstract
Chronic myeloid leukemia (CML) is driven by the hyperactive fusion kinase Bcr-Abl, generated by a chromosomal translocation between chromosome 9 and 22. This oncogenic tyrosine kinase builds up its own signaling network with various proteins such as the docking protein Gab2 or the Src kinase Lyn. As a result, the cells become addicted to the constant signals derived from this fusion kinase. This is the reason why selective Bcr Abl tyrosine kinase inhibitors (TKIs), such as Imatinib mesylate or dasatinib, became so successful in the therapy of CML. Despite the great success of these TKIs in CML treatment, TKI resistance remains a serious clinical problem. These resistances can be caused by mutations in the Bcr-Abl oncogene, like the clinical relevant T315I mutation or by aberrant activity of components of the Bcr-Abl signaling network. In that regard, we could show that the overexpression of Gab2 or the expression of a hyperactive mutant of Lyn can confer TKI resistance.
Using different CML cell lines and models we aimed to identify new approaches to overcome TKI resistances caused by Bcr-Abl mutations or aberrant downstream signaling. Therefore, we screened inhibitors for their ability to overcome Gab2 mediated resistance or to inhibit the activity of T315I mutated Bcr-Abl. We identified the multikinase inhibitors sorafenib and axitinib, both clinical approved as second line drugs in renal cell or hepatocellular carcinoma, as compounds reducing the viability of Bcr-AblT315I transformed cells. Interestingly, these inhibitors were highly active against TKI resistant Bcr-Abl positive cells in contrast to non-transformed cells. These results invite for the further evaluation of sorafenib and axitinib in the treatment of TKI-resistant CML.
Citation Format: Sebastian Halbach, Franziska U. Wöhrle, Sandra Braun, Tilman Brummer. New approaches to overcome tyrosine kinase inhibitor resistances in chronic myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2708. doi:10.1158/1538-7445.AM2015-2708
Abstract 272: Checkpoint inhibitor combinations in a human mixed leukocyte reaction
Authors: Sult Erin , Hay Carl , Huang Qihui , Fuhrmann Stacy , Hollingsworth Robert , Sachsenmeier Kris F. 
Published: August 2015

Abstract
In an effort to identify effective target combinations, molecules specific for several immuno-oncology targets were combined in vitro using a mixed leukocyte reaction (MLR) assay. Briefly, 20 different healthy human peripheral blood mononuclear cell donor pairs were tested for proliferation and cytokine release in the presence of each molecule alone and in combination. The collection of agents targeted CTLA-4, PD-1, PD-L1, and CD73. Examples of significant (p&lt;0.05) synergy as well as antagonism and additivity were observed. In addition the phenotype and genotype of the MLR donor PBMCs were characterized. The results from this study are significant for at least two reasons: 1) In contrast to murine syngeneic models they represent aspects of multiple different human donor “immune responses” and 2) In contrast to purified T-cell assays they represent an assay system in which both the lymphoid and myeloid/innate immune compartments play a crucial role, and so better recapitulate a physiological T-cell response. Furthermore, these results provide information at the human population level, offering a glimpse of “responder” and “non-responder” population profiles. This information is impossible to obtain from the currently available collection of syngeneic mouse models.
Citation Format: Erin Sult, Carl Hay, Qihui Huang, Stacy Fuhrmann, Robert Hollingsworth, Kris F. Sachsenmeier. Checkpoint inhibitor combinations in a human mixed leukocyte reaction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 272. doi:10.1158/1538-7445.AM2015-272
Abstract 2725: Progesterone promotes estrogen induced mammary tumorigenesis through the activation of nodal and notch signaling
Authors: Pedroza Diego A. , Arumugam Arunkumar , Nandy Sushmita , Subramani Ramadevi , Boopalan Thiyagarajan , Lakshmanaswamy Rajkumar 
Published: August 2015

Abstract
Nodal and Notch are considered to be important embryonic morphogens, regulating cell - cell communication, determining left - right asymmetry and in formation of the mesoderm. Cellular processes in embryogenesis can be compared to processes occurring during tumorigenesis. Nodal has been shown to re emerge in aggressive triple negative breast carcinomas, and Notch is known to promote breast cancer. The role of Nodal and Notch in breast carcinomas is being studied; however hormonal regulation of theses two cancer-promoting genes is unknown. Ovarian hormones Estrogen (E) and Progesterone (P) play a vital role in the normal development and function of breast tissue, while extensive exposure to these hormones increases the risk of breast cancer. Studies conducted by the Women's Health Initiative (WHI) have demonstrated that combined Hormone Replacement Therapy (HRT) increases breast cancer risk. The objective of this study is to determine whether P promotes E induced mammary tumorigenesis through the activation of Nodal and Notch signaling. To study the molecular mechanism, MCF-7 cells were cultured and treated with hormones: E, P, E+P and E+Mifepristone (MP - a progesterone antagonist). MTS assay for cellular proliferation, PCR array for gene expression, and western blot for protein expression, were performed. MTS assay showed increased cell proliferation of MFC-7 hormone treatment E+P when compared to control. PCR array analysis showed significant alteration of genes associated with Nodal signaling, specifically Lefty in E+MP treatment, protein expression analysis showed activation of Notch and up - regulation of its downstream targets HES1 and HEY1 with E and P individual and combination treatments while it was down regulated in E+MP treatment. Based on our findings, we suggest that P mediates E induced mammary tumorigenesis through the activation of Nodal and Notch signaling, proposing a possible crosstalk between both pathways in the development and progression of breast cancer.
Citation Format: Diego A. Pedroza, Arunkumar Arumugam, Sushmita Nandy, Ramadevi Subramani, Thiyagarajan Boopalan, Rajkumar Lakshmanaswamy. Progesterone promotes estrogen induced mammary tumorigenesis through the activation of nodal and notch signaling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2725. doi:10.1158/1538-7445.AM2015-2725
Abstract 2734: Ethanol potentiates tobacco smoke carcinogens-induced MAPK activation
Authors: Pandey Manoj K. , Mukherjee Jagat J. , Desai Dhimant H. , Amin Shantu G. , Kumar Subodh 
Published: August 2015

Abstract
Alcohol consumption along with smoking is a well-known health hazard to human. How alcohol consumption potentiates the smoking mediated hazard is not clear. Previously we reported that DNA damage caused by tobacco smoke carcinogen (+/-) anti-benzo[a]pyrene-7, 8-diol-9,10-epoxide [BPDE] is responded by cells through induction of cell growth inhibition in different cell lines. Here we observed that ethanol (EtOH) treatment at physiologically relevant concentration (60mM) increases the DNA synthesis in DNA damaging carcinogen (BPDE) treated cells. BPDE treatment of cells elicits G1-S cell cycle arrest, but EtOH does not have any significant modulating effect of G1-S arrest, indicating increased DNA synthesis by EtOH is due to modulation of some other signaling event(s). We observed that EtOH co-treatment/ pretreatment potentiates BPDE induced phosphorylation and activation of extracellular regulated kinase 1/2 (ERK1/2). Interestingly, treatment of cells with MEK1 inhibitor (PD09059) significantly reduced EtOH's ability to increase DNA synthesis in BPDE treated cells. All together, these findings suggest that the ability of EtOH to potentiate BPDE-induced ERK activation may potentiates PAH-induced tumorigenesis. [Supported by NIH grant # R03 ES021779].
Citation Format: Manoj K. Pandey, Jagat J. Mukherjee, Dhimant H. Desai, Shantu G. Amin, Subodh Kumar. Ethanol potentiates tobacco smoke carcinogens-induced MAPK activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2734. doi:10.1158/1538-7445.AM2015-2734
Abstract 2736: Analysis of ROS concentration in serous ovarian carcinoma
Authors: Cohen Shakeria L. , Mehbari Sharifeh , Partridge Edward E. , Aikhionbare Felix 
Published: August 2015

Abstract
Serous ovarian cancer is the most malignant form of cancer affecting the female reproductive tract. Early detection is associated with 90% five year survival however, current screening tools are not sensitive enough to detect ovarian cancer at early stages. Thus, there remains a critical need for advanced diagnositic tools for early detection and improved prognosis. An accumulation of ROS compounds coupled with increased oxidative stress over time can be deleterious and has been implicated in many human diseases including serous ovarian cancer. Evalution of the ROS concentration in different stages of serous ovarian cancer could be helpful in understanding of the different signaling pathways that may be involved in the transformations of ovarian tumor tissue phenotype. In this study the production of ROS compounds were evaluated in the mitochondria as a caustic of oxidative stress that involve in the transformations of serous ovarian carcinoma. Through the use of a fluorogenic probe, dichlorodihydrofluorescin (DCFH-DiOxyQ) that reacts with the free radicals in a sample, cumulative level of ROS concentrations among stages of serous ovarian carcinoma were detected. Results revealed an increase of 25% ROS fluorescence in the malignant stages compared to normal/surrounding tissues samples. Additionally there was a notably higher ROS concentration in the malignant stages compared to the borderline tissue samples. Results from this study indicate an exponential increase in the levels of ROS from the benign to malignant stages of the disease, suggesting that cumulative ROS levels from early to late of stages may be involved in the progressive stages of the serous ovarian disease type.
Citation Format: Shakeria L. Cohen, Sharifeh Mehbari, Edward E. Partridge, Felix Aikhionbare. Analysis of ROS concentration in serous ovarian carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2736. doi:10.1158/1538-7445.AM2015-2736
Abstract 2737: Dynamics of Epstein-Barr virus loss in the live epithelial cells
Authors: Zhou Yuan , Tsao George 
Published: August 2015

Abstract
Epstein-Barr virus (EBV) infection is highly associated with not only lymphoma but also some solid tumour such as nasopharyngeal carcinoma (NPC) and gastric adenocarcinoma. Previous study found that EBV genomes were present in all of NPC cells in vivo, however they lost rapidly during in vitro cell culture. Previously, because it was difficult to label the EBV DNA with fluorescence protein in the nuclear, the mechanism for EBV loss has not been well studied. In present study, we confirmed in the immortalized nasopharyngeal epithelial cells that the percentage of EBV positive cells decreased rapidly after infection. In addition, we infected epithelial cells with recombinant EBV particles that could be visualized as fluorescent signals after entering host nuclear. We further monitored the dynamics of EBV in host nucleus at single cell level by live cell imaging. We found that inefficient replication and uneven partition may contribute to the EBV loss in epithelial cells. In conclusion, our data provides quantitative information about the dynamics of EBV plasmids in epithelial cells at single cell level. This information will shed light to uncover the mechanism for EBV loss after infection in epithelial cells. This work is supported in part by grants from GRF, HKU 779713M and HKU779312M.
Citation Format: Yuan Zhou, George Tsao. Dynamics of Epstein-Barr virus loss in the live epithelial cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2737. doi:10.1158/1538-7445.AM2015-2737
Abstract 2743: Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries
Authors: Kharazmi Elham , Hemminki Kari , Pukkala Eero , Sundquist Kristina , Tryggvadottir Laufey , Tretli Steinar , Olsen Jørgen H. , Fallah Mahdi 
Published: August 2015

Abstract
Background: None of population-based epidemiological studies to date had a large enough sample size to show familial risk of testicular cancer (TC) by patients’ and their relatives’ age at diagnosis and also by rare histological subtypes.
Objective: We aimed to estimate absolute and relative risk of TC in relatives of TC patients by age at diagnosis in patients and their relatives and histology subtypes.
Design: A joint population-based cohort study.
Setting and Participants: A cohort of 97,402 first-degree relatives of 21,254 TC patients who were diagnosed between1955 and 2010 in five European countries was followed for cancer incidence.
Outcome Measurements and Statistical Analysis: Standardized incidence ratios (SIRs) were estimated using histology-, age-, period-, and country-specific incidence rates as the reference. The lifetime cumulative risks also were calculated.
Results and Limitations: The lifetime cumulative risk of TC in brothers of a patient with TC was 2.3%, which represents 4-fold increased risk (SIR = 4.1, 95%CI = 3.6-4.6) over the general population risk. TC in a father increased the risk up to 2-fold in his son (95%CI = 1.7-2.4; lifetime risk 1.2%) and vice versa. When there were ≥2 TC patients diagnosed in a family, lifetime TC risk for relatives was 10-11%. Depending on age at diagnosis, twins had 9-74% lifetime risk of TC. Family history of most of the histological subtypes of TC increased the risk for concordant and most of the discordant subtypes. There was a tendency toward concordant age at diagnosis of TC among relatives.
Conclusions: This study provides clinically relevant age-specific cancer risk estimates for family members of TC patients. Familial TC cases tended to develop TC at an age close to age at diagnosis of TC among their relatives, which is the novel finding of this study.
Citation Format: Elham Kharazmi, Kari Hemminki, Eero Pukkala, Kristina Sundquist, Laufey Tryggvadottir, Steinar Tretli, Jørgen H. Olsen, Mahdi Fallah. Cancer risk in relatives of testicular cancer patients by histology type and age at diagnosis: a joint study from five Nordic countries. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2743. doi:10.1158/1538-7445.AM2015-2743
Abstract 2746: Significant evidence for linkage for lethal prostate cancer on chromosome arm 4q in Utah high-risk pedigrees
Authors: Cannon-Albright Lisa A. , TEERLINK craig C. , Stephenson Robert A. , Agarwal Neeraj 
Published: August 2015

Abstract
Background: Using the unique Utah genealogical resource that links 12 generations of genealogy data to a statewide cancer registry from 1966 and statewide death certificates from 1904 we have identified a set of high-risk lethal prostate cancer pedigrees with a significant excess of prostate cancer cases having died from prostate cancer.
Methods: Clusters of prostate cancer cases descended from a common ancestor, among whose descendants is observed a statistical excess of prostate cancer (high-risk prostate cancer pedigrees) were recruited and sampled over the past 25 years. Pedigrees including 4 or more cases who have subsequently been reported to have died from prostate cancer (as evidenced by inclusion as a cause of death on a Utah death certificate) were genotyped with 720k high-density SNPs across the genome. Linkage analysis with markers not in linkage disequilibrium was performed to identify regions hypothesized to contain a lethal prostate cancer predisposition gene.
Results: A single extended Utah high-risk prostate cancer pedigree (p&lt;0.05 for significant excess of deceased prostate cancer cases) including 6 distantly related sampled prostate cancer cases who went on to die as a result of their prostate cancer showed significant evidence for linkage at chromosome arm 4q24 (LOD score = +3.28), with 5 of the 6 cases having inherited the same region of chromosome 4 from a common ancestor.
Conclusions: The inability of association studies to identify prostate cancer predisposition genes has returned focus to linkage studies of highly informative high-risk pedigrees, which provide power for identifying and localizing regions of interest for predisposition genes. A focus on only those prostate cancer cases who are members of high-risk lethal prostate cancer pedigrees, who also went on to die as a result of their prostate cancer, has resulted in the identification of evidence for a prostate cancer predisposition gene on chromosome arm 4q24, confirming a previous GWAS that reported association with prostate-cancer-specific-survival (Pomerantz MM et al., 2011) in this region harboring TET2 (a tumor suppressor gene involved in pathogenesis of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms), and PP2A (implicated in androgen receptor regulation in prostate cancer cell lines).
Citation Format: Lisa A. Cannon-Albright, craig C. TEERLINK, Robert A. Stephenson, Neeraj Agarwal. Significant evidence for linkage for lethal prostate cancer on chromosome arm 4q in Utah high-risk pedigrees. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2746. doi:10.1158/1538-7445.AM2015-2746
Abstract 2751: Identification of predisposition genes involved in thyroid and breast carcinomas in patients with family history of these tumors by whole exome sequencing
Authors: Pinheiro Maisa , Marchi Fabio , Drigo Sandra , Reis Patricia , Coutinho Luiz Lehmann , Andrade Sonia , Kowaslki Luis Paulo , Achatz Maria Isabel , Rogatto Silvia 
Published: August 2015

Abstract
A significant number of patients with family history of breast (BC) and papillary thyroid carcinomas (PTC) have been detected at Oncogenetics Dept of AC Camargo Cancer Center, SP, Brazil. The aim of this study was to identify genetic alterations in patients with family cancer history of BC and TC by using whole exome sequencing (WES) analysis. All patients included in this study fulfilled the inclusion criteria as follows: proband with non-medullary TC and/or BC with family cancer history of these tumors AND at least two 1st- or 2nd- degree relatives with one of these tumors either diagnosed &lt;45 years old OR one 1st- relative with one of these tumors and proband diagnosed &lt;40 years old AND history of other tumors. Exclusion criteria comprised female patients with BC treated by radiotherapy before TC diagnosis and probands affected with common mutations in major hereditary predisposition genes. Twenty-four blood samples and four tumor samples were included in WES analysis. Libraries were prepared by using Nextera Exome Enrichment kit following manufacturer's instructions and were sequenced in HiSeq2000 sequencer (Illumina). An average depth of 95x was obtained. The analysis focusing in single nucleotide polymophisms (SNPs) in high penetrance genes detected 12 SNPs in six genes. Particularly, two potential pathogenic SNPs mapped at BRCA1 gene, previously associated with PTC and BC, were detected in at least 25% of samples. The evaluation of rare pathogenic alterations shared by all cases revealed two single nucleotide variations (SNVs) mapped at HYDIN gene. Alternative variants of HYDIN gene were previously detected in serum of patients diagnosed with colorectal, lung, breast and thyroid tumors [Laske K et al, Cancer Immunol Res 1: 190, 2013]. Further analyses are needed to confirm these alterations as potential predisposition candidates associated with breast and thyroid hereditary carcinomas. Furthermore, the data generated in this study could be incorporated into the general knowledge of cancer genetics, allowing the development of prevention strategies, screening and genetic counseling in these families.
Financial Support: FAPESP (2013/01867-8 and 2014/03983-8) and CNPq (481132/2012-0)
Citation Format: Maisa Pinheiro, Fabio Marchi, Sandra Drigo, Patricia Reis, Luiz Lehmann Coutinho, Sonia Andrade, Luis Paulo Kowaslki, Maria Isabel Achatz, Silvia Rogatto. Identification of predisposition genes involved in thyroid and breast carcinomas in patients with family history of these tumors by whole exome sequencing. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2751. doi:10.1158/1538-7445.AM2015-2751