bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3426: Occult and clinical pancreatic cancers in elderly patients
Authors: Matsuda Yoko , Suzuki Akemi , Hamashima Yuri , Hamayasu Hideki , Yoshimura Hisashi , Ishiwata Toshiyuki , Arai Tomio 
Published: August 2015

Abstract
Objectives: This study aimed to investigate the clinicopathological features of pancreatic cancer at different stages using autopsy results. Methods: We retrospectively evaluated 8399 consecutive cases of autopsy performed between 1972 and 2013 at our geriatric hospital. Results: Macroscopic pancreatic lesions were detected in 6.13% of cases. Primary and secondary pancreatic tumors were observed in 2.88% and 2.10% of cases, respectively. Most primary tumors were invasive ductal adenocarcinomas (193 cases, 2.31%, mean patient age: 78.09 years) with a peak incidence at 50-59 years. Occult invasive ductal adenocarcinoma was discovered incidentally in 15 cases (Table), with distant metastasis present in 26.67% of those. Microscopically, occult and advanced tumors exhibited similar characteristics such as hyalinized fibrous stroma; necrosis; and invasion into vessels, peripancreatic fat tissues, and extrapancreatic nerve plexus. Mucin 1 and 2 immunohistochemical expression levels were also similar. Occult cancer incidence increased with age. Patients aged ≥85 years had shorter survival, a small tumor size, and a low incidence of lymph node metastasis. Approximately 8% of pancreatic invasive ductal adenocarcinomas progressed asymptomatically and were discovered incidentally at autopsy. Conclusions: Pancreatic cancers in elderly patients tend to progress asymptomatically, but once symptoms develop, they are more often fatal than those in younger patients.
Comparison of clinical and occult invasive ductal adenocarcinoma cancer cases (193 cases)Clinical cancer casesOccult cancer casesP valueAge, years (mean ± S.D.)77.67 ± 8.6583.13 ± 8.130.02*Size, cm (mean ± S.D.)5.88 ± 2.683.03 ± 1.91&lt;0.01*MUC1 score2.00 ± 0.871.90 ± 0.830.75MUC2 score0.05 ± 0.180.28 ± 0.530.09Number of cases17815SexMale7780.45Female1017Main locationPancreatic head1076&lt;0.01*Pancreatic body502Pancreatic tail177No data40PathologyWell43100.01*Moderately773Poorly391Adenosquamous carcinoma110Anaplastic carcinoma81Lymph node metastasisNegative239&lt;0.01*Positive1556Stage (UICC)I07&lt;0.01*II234III10IV1544
Citation Format: Yoko Matsuda, Akemi Suzuki, Yuri Hamashima, Hideki Hamayasu, Hisashi Yoshimura, Toshiyuki Ishiwata, Tomio Arai. Occult and clinical pancreatic cancers in elderly patients. [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 3426. doi:10.1158/1538-7445.AM2015-3426
Abstract 3441: Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer
Authors: Skinner Heath D. , Giri Uma , Yordy John S. , Story Michael D. , Wang Jing , Byers Lauren A. , Williams Michelle D. , El-Naggar Adel K. , Woo Sang H. , Yang Liang P. , Fan You , Pickering Curtis R. , Myers Jeffrey N. , Heymach John V. 
Published: August 2015

Abstract
One of the primary treatments for head and neck squamous cell carcinoma (HNSCC) is radiotherapy. Despite decades of study, few if any targetable biomarkers for resistance to this modality. To systematically evaluate resistance to radiotherapy in HNSCC, we evaluated 50 HNSCC cell lines using reverse phase protein array (RPPA). Utilizing this method we identified 11 protein markers with altered expression in radioresistant HNSCC cell lines (FDR 1%), including PTK2/FAK. Both PTK2/Fak gene expression and copy number were highly correlated to PTK2/Fak protein expression and both were associated with radioresistance in these cell lines. Additionally, in clinical samples from the TCGA, PTK2/Fak copy number was highly associated with gene expression, with high expression levels in HNSCC tumors. To validate the association between PTK2/Fak and clinical radioresistance in HNSCC, we examined PTK2/FAK copy number in two separate cohorts of HNSCC patients treated uniformly with radiotherapy (n = 39 and n = 44). In both cohorts, PTK2/Fak amplification was associated with treatment failure following radiotherapy (p = 0.04 and p = 0.03 respectively and p = 0.004 for the combined population). Additionally, in a separate cohort of HNSCC patients treated with radiotherapy, high levels of PTK2/Fak gene expression were associated with failure following radiotherapy (p = 0.02). Additionally, in vitro pharmacologic inhibition of PTK2/FAK function led to radiosensitization in multiple HNSCC cell lines, primarily via induction of G2/M arrest, with minimal apoptosis observed. Taken together, these data identify a validated, targetable biomarker of radioresistance in HNSCC.
Citation Format: Heath D. Skinner, Uma Giri, John S. Yordy, Michael D. Story, Jing Wang, Lauren A. Byers, Michelle D. Williams, Adel K. El-Naggar, Sang H. Woo, Liang P. Yang, You Fan, Curtis R. Pickering, Jeffrey N. Myers,, John V. Heymach. Proteomic profiling identifies PTK2/FAK as a targetable marker of radioresistance in head and neck cancer. [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 3441. doi:10.1158/1538-7445.AM2015-3441
Abstract 3442: Ganetespib sensitizes colorectal cancer in vitro and in vivo to a clinically relevant regimen of radiation and chemotherapy
Authors: Nagaraju Ganji Purnachandra , Patel Kirtesh , Wen Jing , Diaz Roberto , Bassel El-Rayes F. 
Published: August 2015

Abstract
Purpose: We describe the efficacy of the second generation HSP90 inhibitor ganetespib in combination with radiation and chemotherapy against colorectal adenocarcinoma in vitro and in vivo.
Methods and Materials: Ganetespib's effects on colorectal adenocarcinoma proliferation and ability to sensitize to radiation and/or chemotherapy were analyzed in the colorectal cell lines HCT-116 and HT-29. Ganetespib's ability to modulate apoptosis when combined with radiation and chemotherapy was characterized, and its effects on the AKT, ERK and PI3K pathways were investigated. Tumor growth delay of colorectal adenocarcinoma with ganetespib alone and in combination with radiation and chemotherapy was analyzed in xenografts. Lastly, immunohistochemical analyses of HSP90 and p-AKT levels where performed in paired normal and tumor colorectal tissue samples from 10 patients.
Results: At the clinically achievable dose of 50 nM, ganetespib inhibited colorectal cancer cells proliferation (p&lt;0.014), potentiated 5-FU chemotherapy and 2Gy of ionizing radiation (p&lt;0.0001), increased pro-apoptotic signaling proteins, and decreased levels of p-AKT, PI3K, and p-ERK in vitro. Combinations of ganetespib, 5-FU, and radiation therapy exhibited synergistic efficacy in human xenograft models in vivo (p&lt;0.0001). Finally, HSP90 and p-AKT were both co-overexpressed in human colorectal cancer tissue samples relative to normal colon tissue. Conclusion: Altogether, these data show the clinically relevant combination of ganetespib with chemotherapy and radiation is effective in colorectal adenocarcinoma in vitro and in vivo. We are currently evaluating ganetespib's safety with chemotherapy and radiation therapy in a phase I study of patients with localized colorectal adenocarcinoma.
Citation Format: Ganji Purnachandra Nagaraju, Kirtesh Patel, Jing Wen, Roberto Diaz, El-Rayes F. Bassel. Ganetespib sensitizes colorectal cancer in vitro and in vivo to a clinically relevant regimen of radiation and chemotherapy. [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 3442. doi:10.1158/1538-7445.AM2015-3442
Abstract 3448: Overexpression of the steroid inactivating UGT2B28 enzyme is associated with high circulating androgens, tumor aggressiveness and adverse prostate cancer outcome
Authors: Belledant Anaïs , Hovington Hélène , Brisson Hervé , Têtu Bernard , Fradet Yves , Lacombe Louis , Caron Patrick , Guillemette Chantal , Lévesque Eric 
Published: August 2015

Abstract
Androgen inactivation occurs mainly through the glucuronidation conjugative reaction mediated by uridine diphospho-glucuronosyltransferase enzymes, namely UGT2B28. This metabolic pathway controls systemic and local androgen bioavailability along with other biotransformation and transport pathways. In this study, we examined the relationship between UGT2B28 protein expression, circulating steroid levels and prostate cancer phenotype. To study distribution of the UGT2B28 protein in prostatic tissues, we used a specific antipeptide antibody displaying no cross-reactivity against highly identical UGT2B family members. Findings revealed that UGT2B28 cytoplasmic staining of secretory cells was distinctive of early stage tumorigenesis (i.e. prostatic intraepithelial neoplasia) and cancer cells with a variable nuclear staining, whereas normal prostate presented only nuclear enzyme expression. Using tissue microarray analysis, we analyzed 239 localized prostate cancer cases that underwent radical prostatectomy. Compared to patients with prostate tumors displaying absent or weak UGT2B28 staining, those with tumors presenting strong UGT2B28 nuclear expression had significantly lower PSA levels at diagnosis (20%; p = 0.043). UGT2B28 expression in the cytoplasm was also correlated with Gleason scores (p≤0.03) and nodal invasion status (p = 0.024). After adjustments for known prognostic markers including PSA, Gleason score, margin and nodal status, tumor size, smoking and germline UGT2B28 deletion status, overexpression of the UGT2B28 protein was an adverse and independent prognostic factor associated with disease recurrence and/or death (HR = 2.82; 95%CI, 1.09-7.36; p = 0.033). Remarkably, prostatic overexpression of UGT2B28 concurs with 30% higher circulating levels of testosterone (p = 0.004) and dihydrotestosterone (p = 0.002), measured by mass spectrometry. Our observations demonstrate that an increased expression of the UGT2B28 enzyme is associated with circulating steroid hormone levels, disease aggressiveness and risk of cancer progression.
Citation Format: Anaïs Belledant, Hélène Hovington, Hervé Brisson, Bernard Têtu, Yves Fradet, Louis Lacombe, Patrick Caron, Chantal Guillemette, Eric Lévesque. Overexpression of the steroid inactivating UGT2B28 enzyme is associated with high circulating androgens, tumor aggressiveness and adverse prostate cancer outcome. [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 3448. doi:10.1158/1538-7445.AM2015-3448
Abstract 3452: Conversion of abiraterone to D4A drives antitumor activity in castration-resistant prostate cancer
Authors: Li Zhenfei , Sharifi Nima 
Published: August 2015

Abstract
Castration resistant prostate cancer (CRPC) still relies on androgens for progression. Abiraterone, an FDA approved CYP17A inhibitor, blocks androgen synthesis and prolongs survival. Abiraterone metabolites are generally thought to be inactive. We have identified a novel abiraterone metabolite, D4A, which inhibits three steroidogenic enzymes and androgen receptor (AR) itself. After abiraterone acetate administration, plasma from mice and patients were analyzed with liquid chromatography-mass spectrometry (LC-MS). The LC-MS results indicate that abiraterone is converted to D4A at detectable concentrations in both mice and patients. To test the function of D4A, the androgen synthesis pathway was analyzed in cell lines and xenografts. After incubation with [3H] labeled androgens, metabolites from cell lines and xenografts were analyzed by HPLC. We found that D4A inhibits activity of the steroidogenic enzymes CYP17A, 3β-hydroxysteroid dehydrogenase (3[[Unsupported Character - Symbol Font ]]HSD) and 5α-reductase. Furthermore D4A competes with the AR agonist R1881 and binds to AR directly. D4A inhibits DHT-induced AR occupancy on the PSA enhancer as detected by chromatin immunoprecipitation and reduces PSA expression. Our findings suggest that D4A is an abiraterone metabolite and a potent inhibitor of the androgen pathway.
Citation Format: Zhenfei Li, Nima Sharifi. Conversion of abiraterone to D4A drives antitumor activity in castration-resistant prostate cancer. [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 3452. doi:10.1158/1538-7445.AM2015-3452
Abstract 3466: Regulation of iodine uptake by SENP2 in thyroid cancer
Authors: Lee Eun Kyung , Park Min Ji , Lee You Jin 
Published: August 2015

Abstract
Background: About 10∼20% of thyroid cancer patients does not respond to radioactive iodine(RAI) therapy, since the expression or membrane trafficking of sodium iodine symporter(NIS) was ameliorated. We investigated whether iodine uptake and expression of NIS were regulated by the balance of SUMOylation in thyroid cancer.
Methods: We analyzed the expression of NIS mRNA using fresh frozen tissues of papillary thyroid cancer. After overexpression of desumoylating enzyme SENP2 in human anaplastic thyroid cancer cell line (FRO) and silencing SENP2 in human NIS-overexpressed HeLa cell line (HeLa-hNIS), we evaluated the expression of NIS mRNA and iodine uptake. We selected 30 patients of different expression level of SENP2 (low and normal SENP2) and constructed tissue microarray for immunohistochemistry stain. And the patients’ clinico-pathologic features were reviewed using medical records.
Results: Twenty six percent of papillary thyroid cancer tissue showed reduced expression of SENP2 and NIS mRNA. Silencing SENP2 in HeLa-hNIS, NIS mRNA and iodine uptake was reduced. By co-immunoprecipitation, the interaction between SUMO2/3 and C/EBPβ was detected. After overexpression of SENP2, NIS mRNA and iodine uptake was restored. By comparison of response of RAI among two groups, reduction of serum thyroglobulin level after RAI was blunted in the group of low SENP2, compared to that in the group of normal SENP2.
Conclusion: Overexpression of SENP2 can induce NIS expression and iodine uptake. This may be a novel therapeutic target for RAI-refractory thyroid cancer patients.
Citation Format: Eun Kyung Lee, Min Ji Park, You Jin Lee. Regulation of iodine uptake by SENP2 in thyroid cancer. [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 3466. doi:10.1158/1538-7445.AM2015-3466
Abstract 3478: A multi-orthogonal strategy for targeting EGFRvIII expressing glioblastomas
Authors: Shen Ying , Li Jie , Furnari Frank B , Desai Arshad , Chen Hong-Zhuan , Chen Clark 
Published: August 2015

Abstract
Epidermal Growth Factor Receptor variant III (EGFRvIII) is a recurrent oncogenic EGFR isoform found in 25-64% of glioblastomas, the most common form of primary brain cancer. While EGFRvIII expressing glioblastomas are initially sensitive to EGFR inhibition, emergence of resistance clones is universal. We previously demonstrated that EGFRvIII expressing glioblastoma can be ablated through inhibition of compensatory mechanisms that allow cancer cells to adapt to EGFRvIII induced oncogenic stress. Here we propose that this strategy can be combined with direct inhibition of EGFR signaling.
A synthetic lethal RNAi screen revealed synthetic lethality between Polo-Like Kinase 1 (PLK1) inhibition and EGFRvIII expression in glioblastoma cells. PLK1 mediated glioblastoma adaptation to excessive DNA damage associated with EGFRvIII expression through activation of Rad51, a protein essential for homologous recombination (HR). PLK1 inhibition (by BI2536) enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ), a DNA alkylating agent and the standard-of-care chemotherapy for glioblastoma. This TMZ-sensitizing effect is 3-5 fold more pronounced in a formed Ink4a/Arf(-/-) EGFRvIII GEMM (genetically engineerd murine model)-derived glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β GEMM-derived glioblastoma model and correlated to the endogenous level of DNA damage accumulation in these models.
Importantly, the tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, Gefitinib and Erlotinib, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, complete ablation was not achieved until TMZ was added. Such synergistic effect was not observed in the Ink4a/Arf(-/-) PDGF-β model.
Our study revealed a novel synthetic lethal interaction between PLK1 inhibition and EGFRvIII expression. Our results suggest that optimal therapeutic effect against EGFRvIII expressing glioblastomas requires “multi-orthogonal” integration of oncogenic inhibition, oncogenic stress, and conventional chemotherapy, tailored to the molecular physiology associated with the target cancer genome.
Citation Format: Ying Shen, Jie Li, Frank B Furnari, Arshad Desai, Hong-Zhuan Chen, Clark Chen. A multi-orthogonal strategy for targeting EGFRvIII expressing glioblastomas. [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 3478. doi:10.1158/1538-7445.AM2015-3478
Abstract 3498: Synergistic cytotoxicity of everolimus in combination with crizotinib in ALK-positive anaplastic large cell lymphoma cells
Authors: Kim Ji-Won , Xu Wendan , Yoon Sung-Soo 
Published: August 2015

Abstract
Everolimus, an mTOR inhibitor, has shown promising anti-tumor activity in a variety of lymphomas, although its clinical efficacy was not satisfactory, due possibly to activation of several pro-surviving signaling pathways. The combined effect of everolimus and crizotinib, an ALK inhibitor, has not yet been investigated in ALK-positive anaplastic large cell lymphoma (ALCL). We treated ALK-positive ALCL cell lines, K-299 and SU-DHL-1, with various concentrations of everolimus and crizotinib at a fixed ratio of 1:40 (0.5 nM, 1.0 nM, and 2.0 nM for everolimus, and 20 nM, 40 nM, and 80 nM for crizotinib, respectively). After 72 hours, the combination index (CI) values were less than 1 (0.596, 0.583, and 0.763 in K-299 cells, and 0.326, 0.616, and 0.271 in SU-DHL-1 cells, respectively) in all tested combinations, suggesting synergistic cytotoxicity of everolimus and crizotinib. Western blot analysis demonstrated that everolimus up-regulated phosphorylation of ERK Thr202/Tyr204 and AKT Thr308 and Ser473. However, this aberrant activation of ERK and AKT was attenuated by the addition of crizotinib. In addition, while everolimus selectively inhibited mTOR Ser2448 phosphorylation, a marker for mTORC1 activity, the combination treatment more potently inhibited mTOR Ser2448 phosphorylation and decreased mTOR Ser2481 phosphorylation, a marker for mTORC2, as well. Cell-cycle analysis showed that the combination treatment induced G1 arrest. PARP cleavage was also increased after the combination treatment. To test the hypothesis that our findings could be applyed to other ALK-positive malignancies, we treated NCI-H2228, a lung adenocarcinoma cell line that harbors an EML4-ALK fusion gene, with everolimus and crizotinib for 72 hours. The CI values were less than 1 in all tested combinations: 0.228 in 1 nM everolimus plus 80 nM crizotinib, 0.216 in 2 nM everolimus plus 160 nM crizotinib, and 0.349 in 4 nM everolimus and 320 nM crizotinib. In summary, everolimus in combination with crizotinib synergistically inhibited the growth of ALK-positive ALCL cells. Crizotinib abrogated aberrant ERK and AKT activation induced by everolimus and more potently inhibited both mTORC1 and mTORC2 activity when combined with everolimus, resulting in increased G1 cell-cycle arrest and apoptosis. Our findings may provide an evidence for future research using everolimus and crizotinib combination in ALK-positive ALCL and could be used to improve the therapeutic outcome in patients with ALK-positive ALCL.
Citation Format: Ji-Won Kim, Wendan Xu, Sung-Soo Yoon. Synergistic cytotoxicity of everolimus in combination with crizotinib in ALK-positive anaplastic large cell lymphoma 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 3498. doi:10.1158/1538-7445.AM2015-3498
Abstract 3512: Measuring intracellular target engagement and drug residence time with nanoBRET
Authors: Robers Matthew B. , Dart Melanie , Zimprich Chad , Kirkland Thomas , Levin Sergiy , Machleidt Thomas , Hartnett Jim , Zimmerman Kris , Ohana Rachel , Daniels Danette , Cong Mei , Fan Frank , Wood Keith 
Published: August 2015

Abstract
We present a biophysical method to directly measure target engagement within intact mammalian cells using bioluminescence energy transfer (BRET). Compound interactions with intracellular targets can be detected with complete specificity by their ability to compete with energy transfer complexes introduced into the cells. These complexes can be detected at physiologically relevant levels by exploiting an extraordinarily bright luciferase (NanoLuc), together with fluorescent tracers optimized for cell-permeability and spectral resolution from the luciferase. We demonstrate applications of the technology for target engagement among key drug target classes, including; kinases, histone deacetylases (HDACs), bromodomains, and the methyltransferase EZH2. Intracellular selectivity and affinity profiles of various reference compounds and approved drugs will be presented. For a panel of HDAC inhibitors, affinity profiles for specific HDAC isozymes strongly correlate with phenotypic potencies (e.g. cell viability). Furthermore, the luminescent output of the energy transfer complex enables a technique to monitor ligand occupancy in real-time. Association and dissociation rates can be derived from the kinetic measurements, providing a means to quantify drug residence time on select targets within intact cell populations. This novel application of intracellular BRET should significantly advance target engagement work flows, and allow for intracellular target affinities to be coupled to phenotypic outcomes.
Citation Format: Matthew B. Robers, Melanie Dart, Chad Zimprich, Thomas Kirkland, Sergiy Levin, Thomas Machleidt, Jim Hartnett, Kris Zimmerman, Rachel Ohana, Danette Daniels, Mei Cong, Frank Fan, Keith Wood. Measuring intracellular target engagement and drug residence time with nanoBRET. [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 3512. doi:10.1158/1538-7445.AM2015-3512