bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2353: Novel inhibitors of PIM-1, PIM-2, and PIM-3 protein kinases: medicinal chemistry leading to AZD1208.
Authors: Lamb Michelle L. , Dakin Les A. , Block Michael H. , Chen Huawei , Code Erin , Dowling James E. , Feng Xiaomei , Ferguson Andrew D. , Green Isabelle , Hird Alexander W. , Howard Tina , Huszar Dennis , Keeton Erika K. , Lyne Paul D. , Pollard Hannah , Rooney Michael , Read Jon , Wu Allan J. , Zhang Tao , Zheng Xiaolan 
Published: August 2014

Abstract
The PIM serine/threonine kinase family, composed of three highly homologous members, PIM-1, PIM-2 and PIM-3, are upregulated in leukemias and lymphomas, including AML, NHL and CLL, highlighting the potential of these kinases as therapeutic targets in these indications. Over-expression of PIM-1 or PIM-3 has also been observed several solid tumors, in particular prostate, pancreatic, gastric, bladder and hepatocellular cancers. PIM kinases are downstream effectors of many cytokine and growth factor signaling pathways and are direct transcriptional targets of STAT transcription factors activated by these pathways, thereby mediating cell proliferation and survival. We have identified novel, potent and highly selective inhibitors of the PIM family kinases. The synthesis, X-ray crystallographic binding mode, and SAR of this benzylidene-1,3-thiazolidine-2,4-dione series are described. Examples from this series exhibit single digit nanomolar potency against all three PIMs, and have been shown to be selective across a panel of more than 440 kinases, with inhibition found for only approximately 3% of the panel, and at least 10-fold selectivity over kinases outside the PIM family. The compounds additionally are stable in rat microsomes, have high aqueous solubilities, and are not potent against the hERG ion channel. The series has antiproliferative activity in a panel of AML cells, has excellent pre-clinical pharmacokinetic properties, and lead compounds have shown strong tumor growth inhibition in vivo in mouse AML xenograft models. From this series, AZD1208 has recently entered Phase I clinical trials for AML and solid tumors.
Citation Format: Michelle L. Lamb, Les A. Dakin, Michael H. Block, Huawei Chen, Erin Code, James E. Dowling, Xiaomei Feng, Andrew D. Ferguson, Isabelle Green, Alexander W. Hird, Tina Howard, Dennis Huszar, Erika K. Keeton, Paul D. Lyne, Hannah Pollard, Michael Rooney, Jon Read, Allan J. Wu, Tao Zhang, Xiaolan Zheng. Novel inhibitors of PIM-1, PIM-2, and PIM-3 protein kinases: medicinal chemistry leading to AZD1208. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2013-2353
Abstract 2361: SNP (-617G&gt;A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma.
Authors: Okano Yasuko , Ichikawa Yasushi , Miyagi Yohei , Natsumeda Yutaka , Ishikawa Toshihisa 
Published: August 2014

Abstract
Purpose: Accumulating evidence suggests nuclear factor (erythroid-derived 2)-like 2 (NRF2) plays an important role as cellular defense, tumor suppression, and oncogenesis. However, little information is available as to the genetic polymorohisms of the NRF2 gene and their clinical relevance. We aimed to validate the NRF2 gene as a prognostic biomarker in lung cancer.
Experimental Design: We prepared genomic DNA from 392 Japanese patients with primary lung cancer and detected a SNP (c.-617C&gt;A) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We analyzed an association between the NRF2 gene and overall survival.
Results: We detected homozygous (A/A) and heterozygous (C/A) alleles with the SNP (c.-617C&gt;A) in 24 (6.2%) and 147 (38.0%) patients, respectively. The frequency of the homozygote (A/A) was four-fold higher in females than in males (11.0% versus 2.7%). Multivariate logistic regression models including standard lung cancer factors revealed that the homozygous alleles (c.-617A/A) were significantly related to gender. Interestingly, lung cancer patients carrying the homozygous alleles (c.-617A/A) exhibited remarkable survival over 1,700 days after surgical operation (log-rank p=0.021).
Conclusion: The homozygous allele (c.-617A/A) in the NRF2 gene is considered to be a prognostic biomarker for assessing both the gender-related risk of lung adenocarcinoma in the non-smoking sub-population and their overall survival.
Citation Format: Yasuko Okano, Yasushi Ichikawa, Yohei Miyagi, Yutaka Natsumeda, Toshihisa Ishikawa. SNP (-617G&gt;A) in ARE-like loci of the NRF2 gene: a new biomarker for prognosis of lung adenocarcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2361. doi:10.1158/1538-7445.AM2013-2361
Abstract 2375: Prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumors.
Authors: Miyanaga Akihiko , Honda Kazufumi , Tsuta Koji , Masuda Mari , Miyamoto Akitomo , Shinagawa Shingo , Tsuda Hitoshi , Asamura Hisao , Gemma Akihiko , Yamada Tesshi 
Published: August 2014

Abstract
Background: High-grade neuroendocrine tumours (HGNTs) of the lung manifest a wide spectrum of clinical behaviour, but no method of predicting their outcome has been established.
Materials and methods: We newly established a monoclonal antibody specifically recognizing the product of the alternatively spliced ACTN4 transcript (namely, variant actinin-4), and used it to examine the expression of variant actinin-4 immunohistochemically in a total of 609 surgical specimens of various histological subtypes of lung cancer.
Results: Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 0.8% (3/378) of non-neuroendocrine lung cancers. Expression of variant actinin-4 was significantly associated with unfavorable overall survival in HGNT patients (P = 0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards model showed that expression of variant actinin-4 was the most significant independent negative predictor of survival in HGNT patients (hazard ratio, 2.18; P = 0.000714) after the presence of lymph node metastasis (hazard ratio, 2.30; P = 0.00012).
Conclusions: Expression of variant actinin-4 is an independent prognostic factor for patients with HGNTs. This protein has high affinity for filamentous actin polymers and likely promotes aggressive behaviour of cancer cells. The present clinical findings clearly support this notion.
Citation Format: Akihiko Miyanaga, Kazufumi Honda, Koji Tsuta, Mari Masuda, Akitomo Miyamoto, Shingo Shinagawa, Hitoshi Tsuda, Hisao Asamura, Akihiko Gemma, Tesshi Yamada. Prognostic significance of the alternatively spliced ACTN4 variant in high-grade neuroendocrine pulmonary tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2375. doi:10.1158/1538-7445.AM2013-2375
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 2383: Clinical significance of intratumoral HER2 heterogeneity in gastric cancer.
Authors: Lee Hye Seung Seung , Lee Hee Eun , Park Kyoung Un , Nam Soo Kyung , Park Do Joong , Kim Hyung-Ho 
Published: August 2014

Abstract
Aim: To evaluate the clinical significance of intratumoral HER2 heterogeneity in gastric cancer (GC).
Methods: A total of 322 GC tissues were evaluated by HER2 immunohistochemistry (IHC), of which 73 with IHC 2+ or 3+ were subjected to fluorescence in situ hybridization (FISH). Also, 3-5 distinct spots in each case showing different HER2 staining intensity were evaluated individually for comparing IHC staining intensity with gene copy number (GCN). Minimum, average, and maximum FISH scores were generated for each case.
Results: Intratumoral heterogeneity of HER2 overexpression and gene amplification were 54 and 30 of 73 cases with IHC 2+ or 3+, respectively. These cases were characterised by diffuse or mixed Lauren type, HER2 IHC 2+, and low-level amplification. Kaplan-Meier survival analysis revealed that the heterogeneous overexpression was significantly associated with longer disease-free survival times than the homogeneous, and the high average GCN was most associated with poor outcome. Also, there was a strong correlation between the IHC and FISH results for each spot. Quantitative PCR analysis of the cancer tissues and the cell-free plasma showed that HER2 gene copy by quantitative PCR on tissue correlated well with those by FISH, but plasma HER2 level was not.Conclusions: Considering the high incidence of intratumoral HER2 heterogeneity in GC, accurate HER2 assessment would require larger tissues and more detailed guidelines. The guidelines should include the recommendation that FISH-scoring areas be selected with reference to a corresponding IHC slide. Also, the definition of HER2-positive tumours should be reassessed considering the intratumoral heterogeneity.
Citation Format: Hye Seung Seung Lee, Hee Eun Lee, Kyoung Un Park, Soo Kyung Nam, Do Joong Park, Hyung-Ho Kim. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2383. doi:10.1158/1538-7445.AM2013-2383
Abstract 2384: A new, highly sensitive IHC test for the detection of HER2 protein in breast cancer (BC) tissue.
Authors: Pedersen Hans Christian , Thomsen Anni , Jensen Kristian , Jakobsen Karen , Wellings Bob , Dalgliesh Gillian , Tosh Kerrie , Harbron Chris , Walker Jill 
Published: August 2014

Abstract
HER2 protein over-expression occurs in 15-20% of invasive BC. Trastuzumab and other HER2-targeted agents have mainly been investigated in HER2 over-expressing BC (HercepTest™ 2+/3+). Analysis of clinical study NSABP-31 suggests patients with HER2 non-over-expressed BC (HercepTest™ 0, 1+, 2+ and/or HER2 FISH negative) may benefit from anti-HER2 therapy. Other novel agents are under investigation in HER2 non-over-expressed BC including AZD8931. No IHC assays are optimized for reliable detection of HER2 in the non-over-expressed range. We have therefore developed a highly sensitive, robust HER2 IHC test with a low limit of detection (HER2Low Test).
Methods and results:
The HER2Low Test uses a novel, high affinity anti-HER2 rabbit monoclonal antibody. Antibody specificity was demonstrated by western blotting using cell lysates expressing HER1, HER2, HER3 or HER4. Analytical sensitivity experiments on BC cell lines showed an ability to differentiate lower levels of HER2 than HercepTest™. Three HER2Low Test staining categories were defined: Low, Medium and High, reflecting differing levels of HER2 expression. A comparative study between HER2Low Test and HercepTest™ on 182 AZD8931 clinical trial BC samples with appropriate ethical approval and consent (Table) showed a redistribution of HercepTest™ scores 0, 1+ and 2+ into HER2Low Test categories Low, Medium and High, demonstrating increased analytical sensitivity of the HER2Low Test. HER2Low Test reproducibility and repeatability studies showed intra-run agreement of 97%, inter-run agreement of 96%, inter-instrument agreement of 87% and observer-to-observer agreement of 89%.
Conclusion:
Presented here is a novel, reproducible and highly sensitive HER2 IHC assay. This is the first study to demonstrate accurate differentiation across a wide range of HER2 expression levels in non-over-expressed BC. This assay may supplement existing HER2 testing methods for the accurate segmentation of HER2 non-over-expressing BC patients.
HER2Low Test score and conventional HercepTest™ (HcT) score in the tested samples from a phase II clinical trial (NCT00900627" locator-type="CLINTRIALGOV"&gt;NCT00900627) HER2Low Test Total Low Medium High HcT 0 11 34 12 57 (31.3%) 1+ 4 24 36 64 (35.2%) 2+ 0 11 50 61 (33.5%) 3+ (not included) 0 0 0 0 (0.0%) Total 15 (8.2%) 69 (37.9%) 98 (53.9%) 182
Citation Format: Hans Christian Pedersen, Anni Thomsen, Kristian Jensen, Karen Jakobsen, Bob Wellings, Gillian Dalgliesh, Kerrie Tosh, Chris Harbron, Jill Walker. A new, highly sensitive IHC test for the detection of HER2 protein in breast cancer (BC) tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2384. doi:10.1158/1538-7445.AM2013-2384
Abstract 241: Tumor initiating cells and FZD8 play a major role in drugresistance and tumor progression in triple negative breast cancer.
Authors: Reddy Kaladhar B. , Yin Shuping , Daniel R. Bonfil , Banerjee Sanjeev , Sarkar Fazlul , Sethi Seema 
Published: August 2014

Abstract
Triple-negative breast cancer (TNBC) is usually associated with poor outcome in part due to lack of benefit from targeted therapy. Previous studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women with TNBC; in contrast, the majority who had a residual tumor after treatment had a relatively poor outcome. In order to identify the mechanism by which residual cancer cells survive chemotherapy, we performed gene expression profile using CRL2335 TNBC cell line before and after treatment with cisplatin plus TRAIL. We found a significant increase in the expression of FZD8, one of the Wnt receptors, and its downstream targets LEF1 and TCF in residual tumor cells after treatment with cisplatin plus TRAIL compared with untreated controls. Inhibition of FZD8 by siRNA in the presence of cisplatin plus TRAIL reduced β-catenin and survivin levels, and increased apoptosis compared to scrambled siRNA-treated cells. In vivo, data demonstrate that cisplatin plus TRAIL treatment, significantly reduces tumor volume in nod/SCID mice. However, we found that cisplatin plus TRAIL treatment predominantly eliminated non-tumor initiating cells (non-TICs), as demonstrated by whole-body fluorescent imaging of mice injected with mammosphere-forming cells stably transfected with DsRed. This led to TIC enrichment in residual tumors, as confirmed by immunostaining for TIC markers. Moreover, an increase in FZD8 expression was observed in residual tumors treated with cisplatin and TRAIL. Taken together, our findings suggest that FZD8-mediated Wnt-signaling may play a major role in mediating resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBC.
Citation Format: Kaladhar B. Reddy, Shuping Yin, R. Bonfil Daniel, Sanjeev Banerjee, Fazlul Sarkar, Seema Sethi. Tumor initiating cells and FZD8 play a major role in drugresistance and tumor progression in triple negative breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 241. doi:10.1158/1538-7445.AM2013-241
Abstract 2429: Airway necrosis after salvage esophagectomy.
Authors: Tanaka Norimitsu , Hokamura Nobukazu , Tachimori Yuji 
Published: August 2014

Abstract
Background: Recently definitive chemoradiotherapy (CRT) without surgery has been accepted as an alternative treatment for esophageal cancer. However, unfortunately, the tumors of 5-33% patients were resistant to CRT and persistent disease was detected soon after treatment, and 16-54% patients initially showed a response but locoregional disease was discovered later. Salvage esophagectomy is the sole curative intent treatment for patients with persistent or recurrent locoregional disease after definitive CRT for esophageal carcinoma. However, salvage esophagectomy is a very high-risk operation, and airway necrosis is a fatal complication.
Methods: Between 1997 and 2007, 49 patients with thoracic esophageal squamous cell carcinoma underwent salvage esophagectomy after definitive CRT. All patients received more than 50 Gy of radiation plus concurrent chemotherapy for curative intent. We retrospectively compared patients with and without airway necrosis. Additionally, airway necrosis was categorized primary necrosis and secondary necrosis according to the cause of necrosis, and operative procedures related to airway necrosis were investigated.
Result: Overall 23of 49 patients had at least one complication (morbidity: 46.9%), and 5 died during their hospitalization (mortality: 10.2%). Airway necrosis occurred in five patients (10.2%), of four patients (80%) died during their hospitalization. Airway necrosis seemed to be closely related to operative procedures, such as resection of bronchial artery (BA), cervical and subcarinal lymph node dissection (LND) and reconstruction route. Primary necrosis occurred in 3 patients with resection of BA, cervical LND, or subcarinal LND. And bronchogastric fistula following necrosis of gastric conduit occured in 2 patients reconstructed through posterior mediastinal route.
Conclusions: Airway necrosis is a highly lethal complication after salvage esophagectomy. It is important in salvage esophagectomy to take airway blood supply into consideration sufficiently and to reconstruct through retrosternal route to prevent bronchogastric fistula.
Citation Format: Norimitsu Tanaka, Nobukazu Hokamura, Yuji Tachimori. Airway necrosis after salvage esophagectomy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2429. doi:10.1158/1538-7445.AM2013-2429
Abstract 2477: Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance.
Authors: Gangjee Aleem , Mohan Rishabh , Hamel Ernest , Bai Ruoli 
Published: August 2014

Abstract
Tubulin binding agents are the most effective drugs in p53 resistant cancer cell lines. Although microtubule disrupting agents like paclitaxel are highly successful, they have major limitations against multidrug resistance (MDR) tumors. Overexpression of P-glycoprotein (Pgp) and/or βIII-tubulin can severely limit their clinical utility as cancer chemotherapeutic agents. Antitubulin agents like paclitaxel and other taxoids also have poor water solubility, and this hampers their administration to patients since these compounds must be formulated with polyethoxylated castor oil. This medium can cause hypersensitivity reactions and requires prolonged administration times. Recently, we reported analogs with the pyrrolo[3,2-d]pyrimidine scaffold that circumvent these drawbacks. To explore the structure-activity relationships of these compounds, including simplification of the pyrrolo[3,2-d]pyrimidine scaffold, we designed conformationally flexible substituted monocyclic N-methyl-4-methoxyanilino pyrimidines 1-6 from the corresponding 4-chloro analogs by treatment with N-methyl-4-methoxyaniline followed by N6-alkylation for 2-6 . Compounds 1-6 inhibited tubulin assembly (4, IC50 = 1.5 ± 0.2 μM) and binding of colchicine to tubulin (4, 75% inhibition at 1 μM, 95% at 5 μM with 5 μM [3H]colchicine). Four of these compounds inhibited the growth of human cancer cells in culture with nanomolar IC50’s from 15 to 62 nM. These compounds are also active in paclitaxel resistant tumor cells overexpressing either βIII-tubulin or Pgp, thus apparently overcoming two important mechanisms associated with clinical resistance to paclitaxel. Thus, we have identified simplified substituted monocyclic pyrimidines containing a novel structural scaffold for inhibition of tubulin assembly and colchicine binding and which have potent cytotoxic activity against human cancer cells in culture.
Citation Format: Aleem Gangjee, Rishabh Mohan, Ernest Hamel, Ruoli Bai. Design, synthesis and biological evaluation of substituted monocyclic pyrimidines as potent microtubule targeting antitumor agents that circumvent Pgp and βIII-tubulin-mediated resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2477. doi:10.1158/1538-7445.AM2013-2477
Abstract 2481: Synthesis and characterization of PEGylated chlorin e6 sensitizers for the photodynamic killing of human ovarian cancer cells.
Authors: Ghogare Ashwini , Ghosh Goutam , Kimani Stanley , Bartusik Dorota , Rudshteyn Benjamin , Hasan Tayyaba , Greer Alexander 
Published: August 2014

Abstract
Pegylated chlorin e6 photosensitizers have been synthesized with triethylene glycol attached at the ester bond(s) for a 1:1 conjugate, a 2:1 conjugate, and a 3:1 conjugate. These chlorin sensitizers were studied for hydrolytic stability and solubility. Our studies included an analysis of ovarian OVCAR-5 cancer cell uptake, localization, and phototoxicity. Because of our interest in fiber-based photosensitizer and singlet oxygen delivery methods, desirable aspects of the 3:1 chlorin e6 conjugate make it a potential sensitizer for incorporation into a fiber optic device, particularly in the area of ovarian cancer photodynamic therapy.
Citation Format: Ashwini Ghogare, Goutam Ghosh, Stanley Kimani, Dorota Bartusik, Benjamin Rudshteyn, Tayyaba Hasan, Alexander Greer. Synthesis and characterization of PEGylated chlorin e6 sensitizers for the photodynamic killing of human ovarian cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2481. doi:10.1158/1538-7445.AM2013-2481