bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4724: Adverse prognostic significance of TNFAIP8 protein expression in non small cell lung cancer
Authors: Kallakury Bhaskar V. , Kasid Usha N. , Voronel Olga , Sheehan Christopher B. , Sheehan Christine E. , Ross Jeffrey S. 
Published: May 2015

Abstract
Background: Tumor necrosis factor alpha induced protein 8 (TNFAIP8) is a transcription factor NF-kB inducible antiapoptotic and oncogenic molecule. Positive correlation between TNFAIP8 expression and cancer progression/poor prognosis has been described in a few human solid cancers including pancreatic and esophageal primaries. We were the first to publish the correlation of TNFAIP8 expression with high tumor grade and its independent predictor status for disease recurrence in prostatic adenocarcinomas. In this study, we evaluated the significance of this protein in non small cell lung cancer (NSCLC).
Design: A total of 144 formalin-fixed, paraffin-embedded NSCLCs were analyzed (122 primary tumor resections and 22 tissue microarray samples); including 47 squamous cell carcinomas (SCC), 59 adenocarcinomas (AC), and 38 bronchioloalveolar carcinomas (BAC), were immunostained by a manual method using a custom made anti-TNFAIP8 antibody as described earlier (Zhang et al., Int J Cancer,133: 31-42, 2013). The staining pattern was semiquantitatively assessed based on staining intensity and distribution and the results were correlated with morphologic and prognostic variables.
Results: Immunoreactivity for TNFAIP8 was predominantly cytoplasmic. TNFAIP8 protein overexpression was noted in 84/144 (58%) tumors and correlated with tumor type [45/59 (76)% AC vs 29/47 (62%) SCC vs 10/38 (26%) BAC, p&lt;0.0001], overall with advanced tumor stage [24/31 (77%) advanced vs 60/113 (53%) early, p=0.015] and lymph node positive status [31/41 (76%) LN+ vs 53/103 (52%) LN-, p=0.008]. Within the AC subgroup, there was a trend toward correlation with advanced tumor stage [13/14 (93%) advanced vs 32/45 (71%) early, p=0.095] and lymph node positive status [18/20 (90%) LN+ vs 27/39 (69%) LN-, p=0.076]. On multivariate analysis, LN+ status independently predicted shortened survival.
Conclusion: TNFAIP8 immunohistochemical expression portends poor prognosis in NSCLC and may constitute a novel therapeutic target in the management of aggressive NSCLC, warranting further study.
Citation Format: Bhaskar VS Kallakury, Usha N. Kasid, Olga Voronel, Christopher B. Sheehan, Christine E. Sheehan, Jeffrey S. Ross. Adverse prognostic significance of TNFAIP8 protein expression in non small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4724. doi:10.1158/1538-7445.AM2014-4724
Abstract 4727: Prognostic roles of DDB2 and XPC mRNA expressions in treatment responses and overall survivals of head and neck cancer patients
Authors: Lin Chang-Shen , Lee Ka-Wo , Huang Jau-Ling , Wang Yu-Chu , Tsai Yi-Shan 
Published: May 2015

Abstract
Background:
DNA repair genes function in the maintenance of genome integrity and prevent tumorigenesis. On another hand, DNA repair genes modulate cancer cell responses to DNA-damaging therapeutics. We hypothesize that altered expression of DNA repair genes are correlated with therapeutic outcomes of head and neck cancer patients.
Patients and methods:
Messenger RNA (mRNA) expressions of DDB2 and XPC were examined in specimens of 95 head and neck cancer patients using real-time quantitative RT-PCR. Patients were dichotomized by ROC curve analysis based on their DDB2 and XPC mRNA levels. Overall survival (OS) rates were measured using Kaplan-Meier estimates and the log-rank tests. The adjusted hazard rate ratios (HRRs) were computed by multivariate Cox regressions.
Results:
The levels of DDB2 and XPC mRNA expression in tumor tissues were reduced (tumor/normal &lt; 0.9) in 84 and 80 cases, respectively, when compared with those in adjacent normal parts. Lower DDB2 (tumor/normal &lt; 0.24) and XPC (tumor/normal &lt; 0.36) mRNA expressions were correlated with larger tumor, positive lymph node invasion, advanced stage, and poor 5-yr OS rates (26.7% vs. 54.3%, and 28.1% vs. 53.0%, respectively). Multivariate Cox model showed that, in addition to T and N stages, lower XPC mRNA level (&lt; 0.36) was an independent risk factor for patient's survival (HRR = 2.68, 95% CI 1.12-6.40). Concurrent chemotherapy and radiotherapy (CCRT) did not improve OS of patients with lower XPC mRNA (&lt; 0.36) and showed even worse outcomes within 5 years for patients with lower DDB2 expression (&lt; 0.24). However, patients with higher DDB2 (&gt; 0.24) and XPC (&gt; 0.36) mRNA levels had improved 5-yr OS rates if they received CCRT (64.4% vs. 41.8% and 73.3% vs. 39.2%).
Conclusion:
mRNA expressions of XPC and DDB2 might be useful biomarkers for prognosis and efficacy of CCRT medication in head and neck cancer patients.
Citation Format: Chang-Shen Lin, Ka-Wo Lee, Jau-Ling Huang, Yu-Chu Wang, Yi-Shan Tsai. Prognostic roles of DDB2 and XPC mRNA expressions in treatment responses and overall survivals of head and neck cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4727. doi:10.1158/1538-7445.AM2014-4727
Abstract 4728: FGFR1 gene amplification in small cell lung cancer
Authors: Park Ji Soo , Lee Jae-Seok , Shim Hyo Sup , Kim Hye Ryun , Lim Sun Min , Kim Joo Hang , Cho Byoung Chul 
Published: May 2015

Abstract
Background: Fibroblast growth factor receptor 1 (FGFR1) received special attention from many clinicians according to finding that FGFR1 played a critical role in many human cancers. Some clinical trials using FGFR1 targeting agents are in progress especially in breast cancer and squamous non-small cell lung cancer. Recently, FGFR1 amplifications were also found in about 5.6-6% of small cell lung cancer (SCLC) by gene copy number analysis and FISH.
Methods: Tumor tissues from 113 patients diagnosed with SCLC from October 2009 to February 2013 in YUHS, Korea were collected. FGFR1 FISH assay was performed on the tissue microarray using FISH probe that hybridized to the band 8p12-8p11.23 (FISH probes were provided by Abbott Molecular, Abbott Park, IL).
Results: Thirty-two patients with limited-stage disease (LD) and eighty-one patients with extensive-stage disease (ED) were enrolled. Fourteen patients were female. Among 113 tumor samples, 5 samples (4.4%) showed FGFR1 amplification. All 5 samples were obtained from the patients with ED. The patients with FGFR1 amplification more frequently had pleural metastasis at the time of diagnosis (80% vs. 26%, P=0.022). In ED, the patients with FGFR1 amplification represented shorter disease free survival from first line chemotherapy (Hazard ratio [HR], 4.469; 95% confidence interval [CI], 1.600-12.483; P=0.004) and second line chemotherapy (HR, 6.533; 95% CI, 1.700-25.108; P=0.006) than the patients without FGFR1 amplification in multivariate analysis. Median overall survival time was 8.2 months in the patients with FGFR1 amplification and 10.2 months in the patients without FGFR1 amplifications (P=0.296).
Conclusion: FGFR1 amplification is a poor potential predictive biomarker of standard chemotherapy, necessitating further research in a large cohort of SCLC. The validity of targeting FGFR1 in SCLC should be confirmed in a clinical trial.
Citation Format: Ji Soo Park, Jae-Seok Lee, Hyo Sup Shim, Hye Ryun Kim, Sun Min Lim, Joo Hang Kim, Byoung Chul Cho. FGFR1 gene amplification in small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2014-4728
Abstract 4735: Stem cells like phenotype of inflammatory breast cancer and locally advanced breast cancer: increased expression of sox2 and oct3/4 contributes to poor response to treatment and reduced survival rates
Authors: Zekri Abdel-Rahman N. , Bahnassy Abeer , El-Bastawisy Ahmed E. , Nassar Hanan R. , Elhady Neveen M. , Effat John 
Published: May 2015

Abstract
Background: Inflammatory breast cancer (IBC) is an aggressive form of locally advanced breast cancer (LABC) with poor response to treatment or metastasis in one-third of patients at presentation. The aggressive behavior of IBC was attributed to the cancer stem cell (CSC) component in these tumors. We assessed the correlation between CSC markers in IBC, LABC and the aggressive behavior of these tumors compared to invasive duct carcinoma (IDC-NOS).
Methods: CD44, CD90, CD133, nestin, SOX2 and OCT4 RNA and proteins expression were assessed in 30 cases of IDC-NOS, IBC and LABC (each) using quantitative real time PCR (qPCR) and immunohistochemistry (IHC). Markers expression was correlated to patients' characteristics, response to treatment, 4 years- overall and progression free survival (OS& PFS) .
Results: The expression levels in IBC and LABC was as follows: (CD44; 70%& 26.3%, p=0.003), (CD90; 49.2%& 28.1%, p=0.06), (CD133; 66.7%& 26.3%, p=0.006), (OCT4; 70%& 26.6%, p=0.004), (SOX2: 63.3%& 30%, p=0.02) and (Nestin; 53.3%& 31%, p=0.08). The difference in the expression levels of all studied markers between IDC-NOS and the other two groups was statistically significant (p.value: &lt;0.05- &lt;0.001). A significant relation was reported between the expression levels of SOX2, OCT-4 and the clinical response in IBC and LABC (p&lt;0.01). PFS significantly correlated with SOX2 and OCT4 expression (p=0.045) in IBC, whereas OS correlated with OCT4 in IBC and LABC (0.034& 0.04)
Conclusions: The aggressive phenotype of IBC and LABC could be attributed, at least partially, to the presence of CSC populations in these tumors. Therefore, CSC markers represent Interesting candidates for targeted therapy for this resistant type of breast tumors.
Citation Format: Abdel-Rahman N. Zekri, Abeer Bahnassy, Ahmed E. El-Bastawisy, Hanan R. Nassar, Neveen M. Elhady, John Effat. Stem cells like phenotype of inflammatory breast cancer and locally advanced breast cancer: increased expression of sox2 and oct3/4 contributes to poor response to treatment and reduced survival rates. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4735. doi:10.1158/1538-7445.AM2014-4735
Abstract 4737: Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX and glucose transporter-1 in cervical cancer
Authors: Iwasaki Keita , Yabushita Hiromitsu , Ueno Taiki , Wakatsuki Akihiko 
Published: May 2015

Abstract
Objectives: Hypoxia can drive the tumor toward a more aggressive malignant phenotype through genomic and proteomic changes. Hypoxia-inducible factor-1α (HIF-1α) transactivates genes whose proteins allow metabolic adaptation to hypoxia, including carbonic anhydrase-IX (CA-IX) and glucose transporter-1 (Glut-1). This study aimed to determine whether the HIF-1α, CA-IX and Glut-1 were associated with clinico-pathological characteristics and progression-free survival in patients with cervical carcinoma.
Methods: Under the written informed consent, tumor tissue samples were obtained from 54 patients with cervical carcinoma performed radical hysterectomy. The expressions of HIF-1α, CA-IX and Glut-1 were detected by immunohistochemical staining using paraffin-embedded sections.
Results: CA-IX and Glut-1 expressions were found in cell membrane and cytoplasm, and HIF-1α expression was observed in cell nuclear. In 54 cases, the positive expression was observed in 28 cases for HIF-1α, 35 for CA-IX and 40 for Glut-1. The HIF-1α expression was related with clinical stage and histology, CA-IX expression was related with clinical stage, tumor size, lymph-node metastasis and lymph-vascular space involvement, and the Glut-1 expression was related with clinical stage and lymph-vascular space involvement. The multivariate regression analysis revealed that the CA-IX expression and lymph-vascular space involvement were the independent variable associated with lymph-node metastasis in patients with cervical cancer. Progression-free survival was shorter in patient with positive CA-IX expression compared to negative CA-IX expression.
Conclusion: In cervical cancer patients, CA-IX expression is possible to be a risk factor for lymph-node metastasis and disease recurrence, it was suggested that pH regulation induced by CA-IX under hypoxic condition may be associated with lymph node metastasis.
Citation Format: Keita Iwasaki, Hiromitsu Yabushita, Taiki Ueno, Akihiko Wakatsuki. Role of hypoxia-inducible factor-1α, carbonic anhydrase-IX and glucose transporter-1 in cervical cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4737. doi:10.1158/1538-7445.AM2014-4737
Abstract 4738: Clinicopathological roles of adiponectin receptor and leptin receptor in endometrial carcinoma
Authors: Yabushita Hiromitsu , Iwasaki Keita , Ueno Taiki , Wakatsuki Akihiko 
Published: May 2015

Abstract
Objectives:
To clarify the roles of adiponectin receptor (AdipoR) and leptin receptor (ObR) in endometrial carcinoma, expressions of AdipoR-1 and -2 and ObR in endometrial cancer were examined immunohistochemically and relationships to clinicopathological implications were also analyzed.
Methods: Under the written informed consent, paraffin-embedded tissues were obtained from 77 patients with endometrial carcinoma and were stained immunohistochemically using antibodies against AdipoR-1, AdipoR-2 and ObR.
Results: AdipoR-1, AdipoR-2 and ObR were localized predominantly in the cell membrane and cytoplasm of tumor cells and normal endometrial cells. In 77 cases of endometrial cancer, positive expression was observed in 46 cases (59.7%) for AdipoR-1, 47 cases (61.0%) for AdipoR-2 and 33 cases (42.9%) for ObR. Expression of AdipoR-1 was observed more in stage I cases, G1 tumours, tumors with shallow myometrial invasion, tumors negative for lymphovascular space involvement, cases negative for adnexal invasion, and cases with no lymph node metastasis. However, expressions of AdipoR-2 and ObR showed no relationship to any clinicopathological factors. Kaplan-Meier analyses revealed that progression-free and overall survivals were longer in cases with positive AdipoR-1 expression compared with negative AdipoR-1 expression.
Conclusion: Poor expression of AdipoR-1 thus appears to be associated with tumour grade, myometrial invasion, adnexal invasion, lymph-vascular space involvement and lymph-node metastasis, as well as poor prognosis in endometrial cancer.
Citation Format: Hiromitsu Yabushita, Keita Iwasaki, Taiki Ueno, Akihiko Wakatsuki. Clinicopathological roles of adiponectin receptor and leptin receptor in endometrial carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4738. doi:10.1158/1538-7445.AM2014-4738
Abstract 4739: Nutrient depletion caused by PKR induces phosphorylation of AMPK in lung cancer
Authors: Pataer Apar , Guo Chengcheng , Shao Ruping , Correa Arlene M. , Behrens Carmen , Fang Bingliang , Roth Jack A. , Wistuba Ignacio I. , Swisher Stephen G. 
Published: May 2015

Abstract
We have demonstrated that RNA-dependent protein kinase (PKR) and its downstream protein p-eIF2α are independent prognostic markers for survival in lung cancer. In the current study, we aimed to elucidate PKR's specific role in lung cancer. We examined PKR and p-PKR protein expression in 60 frozen primary lung tumor tissues by Western blot analysis and analyzed the association between PKR/p-PKR expression and expression of 139 proteins examined previously by reverse phase protein array in tissue samples from the same 60 patients. We demonstrated several biomarkers that were either positively (p-AMPK) or negatively (IRS1, p-IGF1R, MRE11, ATRIP, telomerase, CHK1, and cyclin E1) correlated with PKR and p-PKR. We confirmed that induction of PKR or p-PKR with expression vectors in lung cancer cells caused phospholation of the AMP-activated protein kinase (AMPK) protein; phospholation was independent of the LKB1, CaMKKβ, and TAK1 pathways. We observed that AMPK phosphorylation was caused by the elevated levels of AMP and decreased levels of ATP resulting from PKR-mediated nutrient depletion. Inhibition of AMPK expression by compound C or siRNA enhanced PKR-mediated cell death. We next investigated the combination of PKR and p-AMPK expression in non-small cell lung cancer patients; we observed that high expression of p-AMPK predicted worse prognosis in patients with high PKR expression but better prognosis in patients with low PKR expression. The p-AMPK may be required for cancer cell survival in patients with high PKR expression and may inhibit cancer cell growth in patients with low PKR expression. In summary, our data indicate that PKR-mediated nutrient depletion induces phosphorylation of AMPK, which is required for lung cancer cell survival.
Citation Format: Apar Pataer, Chengcheng Guo, Ruping Shao, Arlene M. Correa, Carmen Behrens, Bingliang Fang, Jack A. Roth, Ignacio I. Wistuba, Stephen G. Swisher. Nutrient depletion caused by PKR induces phosphorylation of AMPK in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4739. doi:10.1158/1538-7445.AM2014-4739
Abstract 4744: Structure-based development of covalent inhibitors of the activating and T790M gatekeeper mutant forms of the epidermal growth factor receptor (EGFR) leading to the discovery of AZD9291
Authors: Ward Richard A. , Ashton Susan , Anderton Mark , Ballard Pete G. , Bradbury Rob H. , Butterworth Sam , Colclough Nicola , Cross Darren A E , Finlay M Ray V. , McFarland Heather L. , Mellor Martine , Waring Mike J. 
Published: May 2015

Abstract
Small molecule inhibitors of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations such as T790M, (mutation of the gatekeeper residue), is recognized as a clinical issue. This presentation will describe the discovery and evolution of one of our novel chemical series, leading ultimately to the identification of AZD9291, an orally bioavailable, covalent EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 &lt;0.025 uM) and activating mutations (PC9, cell phosphorylation IC50&lt;0.025 uM) that spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50&gt;0.5 uM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhea) for these first generation therapies in the clinic. New data will be presented for the first time including a broader description of the medicinal chemistry program that led to the identification of AZD9291. We shall also present previously undisclosed work on the identification of additional distinct chemical series and an update of recent data from ongoing AZD9291 Phase I clinical studies in NSCLC patients.
L858R/T790M Double Mutant (resistance) cell IC50 uMEGFRm+ Single Mutant (activating) cell IC50 uMEGFR Wild Type cell IC50 uMAqueous solubility, (salt) (pH=6.8, ug/mL)L858R/T790M Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days)&lt;0.025&lt;0.025&gt;0.5&gt;490119
Citation Format: Richard A. Ward, Susan Ashton, Mark Anderton, Pete G. Ballard, Rob H. Bradbury, Sam Butterworth, Nicola Colclough, Darren A E Cross, M Ray V. Finlay, Heather L. McFarland, Martine Mellor, Mike J. Waring. Structure-based development of covalent inhibitors of the activating and T790M gatekeeper mutant forms of the epidermal growth factor receptor (EGFR) leading to the discovery of AZD9291. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4744. doi:10.1158/1538-7445.AM2014-4744
Abstract 475: GATA3 mutations in breast cancer
Authors: Takaku Motoki , Adomas Aleksandra , Grimm Sara A. , Takashi Shimbo , Wade Paul A. 
Published: May 2015

Abstract
Breast cancer is one of the most common cancers in women worldwide, resulting in over 400,000 deaths per year. Approximately 90% of breast cancers occur in women who have no family history of breast cancer, indicating that most breast cancers occur following spontaneous mutations resulting from the aging process or the action of environmental agents. Breast cancers can be divided into several subtypes base on gene expression profiles. Luminal breast cancer, the most common subtype, is characterized by expression of estrogen receptor alpha (ER-alpha). The zinc finger transcription factor GATA3, which is known as a regulator of mammary gland development, is frequently expressed in luminal breast cancer cells, and its expression is highly correlated with ER-alpha. In breast cancers, the expression levels of GATA3 directly correlate with favorable prognosis, and its ectopic expression leads to the suppression of tumor metastasis. Comprehensive genomic analysis of breast tumors has revealed frequent somatic mutations of GATA3 in luminal breast cancers. However it is unclear how these GATA3 mutations affect the biological properties of breast cancer. These mutations are located at exclusively in exons 5 and 6 that encode the carboxyl terminus of the protein. Exon 5 contains the second of two zinc finger domains (ZnF2), which is important for the DNA binding activity of GATA3. Exon 6 has no previously described biochemical function.
In this study, we focus on two mutations found in cancer patients - a frame shift at tyrosine 345 (Y345fs) and a frame shift at arginine 330 (R330fs). These two mutants are of particular interest as they produce truncated proteins, and both mutants lack exon 6. Y345fs preserves ZnF2, while R330fs interrupts ZnF2. These two mutants permit dissection of the molecular outcomes flowing from loss of exon 6 (Y345fs) versus the combination of loss of ZnF2 and exon 6 (R330fs). To assess the impact of these mutations, we established breast cancer cells expressing Y345fs and R330fs respectively, and analyzed their phenotype at the cellular and molecular levels. These studies begin to address the biochemical and functional outcomes of commonly occurring mutations in breast cancer.
Citation Format: Motoki Takaku, Aleksandra Adomas, Sara A. Grimm, Shimbo Takashi, Paul A. Wade. GATA3 mutations in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 475. doi:10.1158/1538-7445.AM2014-475