bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3916: A “moneyball” approach to predicting clinical trial toxicity events
Authors: Gayvert Kaitlyn , Madukhar Neel , Elemento Olivier 
Published: July 2016

Abstract
Over the past decade, significant strides have been made in the management and treatment of various diseases. Despite this progress, clinical attrition rates have continued to substantially rise. Clinical trials can fail for a variety of reasons, ranging from design issues to drug efficacy and safety problems. Drug-likeness approaches, as first proposed by Lipinski almost two decades ago, have become a key tool for the pre-selection of compounds that are likely to have manageable toxicity in clinical studies. However all these methods consider molecular properties of the drug itself alone. In general, these approaches struggle to simultaneously well-characterize the properties of both FDA approved drugs (which we term the sensitivity) and drugs that fail clinical trials (specificity).
We introduce an approach that integrates chemical properties of a compound, along with that of its targets, to provide a new quantitative measure that helps predict whether drugs in clinical trials will fail for toxicity reasons. When trained on failed clinical trials and FDA approved drugs, this method performs at a high accuracy, specificity and sensitivity (∼0.75), as well as high area under the ROC curve (&gt;0.80). In comparison, none of the drug-likeness approaches were able to successfully maintain both high sensitivity and specificity. A feature analysis of the model indicates that it is critical to consider both structural properties and properties of the drug target, with the target's network connectivity and liver toxicity as two important features. The approach was further evaluated by testing the predictions of the trained model on an established independent dataset. We found that our method was able to significantly distinguish a representative set of bioavailable drugs from a representative set of toxic drugs (D = 0.2133, p&lt;2.2e-16, Kolmogorov-Smirnov test). Additionally, we found that the measure is strongly correlated with severe toxicity events, such as pleural effusion (ρ = −0.9792) and neutropenia (ρ = −0.9613). Altogether, our method provides a novel, broadly applicable strategy that is able to identify drugs likely to possess manageable toxicity in clinical trials.
Citation Format: Kaitlyn Gayvert, Neel Madukhar, Olivier Elemento. A “moneyball” approach to predicting clinical trial toxicity events. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3916.
Abstract 3921: A screen of breast and colon cancers with HER2 antibody clone UMAB36 does not exhibit the cross-reactivity of clone 4B5 with HER4 protein
Authors: Zhou Lixin , Yuan Kehu , Ren Fangfang , Ki Lili , Zhou Min , Fu Wei , Huang Xiaozheng , Gonzalez Rachel M. , Shu Youmin , Shen Yi , Wang Guangli , Ma Donghui , He Wei-Wu , Chen Jian 
Published: July 2016

Abstract
Increased sensitivity and specificity of immunohistochemical (IHC) detection of HER2 expression is crucial as the role of Trastuzumab have expanded in the treatment of HER2 positive non-breast cancer patients such as gastric cancer patients. Non-specific nuclear and cytoplasmic staining of the HER2 antibody clone 4B5 has been reported by other labs. In this study, we evaluated the specificity of HER2 clone 4B5 and a new HER2 antibody clone UMAB36 using a suite of methods including protein lysate arrays, western blots, FISH and IHC correlation screens on 129 breast and 158 colon cancer cases for HER2 expression. The protein lysate array and western results revealed that clone 4B5 recognizes three proteins: HER2, HER4, and ZSCAN18, a nuclear transcription protein. In comparison, clone UMAB36 recognized only HER2 protein in the same protein lysate array and western screen as clone 4B5. False negative results, based on correlation of IHC with FISH HER2 positives, were generated using clone 4B5 in 1 breast and 5 gastric of the total 287 cancer cases screened. Comparatively, no false negative results were observed using clone UMAB36 in which there was a 100% correlation between IHC and FISH screen. In this study, areas of normal gastric tissue often stained positive by HER2 clone 4B5, so we performed further analysis of 470 normal gastric cases using Ventana's BenchMark instrument. The results show that 278 normal gastric cases had positive stain with clone 4B5 compared to 3 cases with clone UMAB36. The high background by clone 4B5 may be due HER4 being upregulated in adjacent normal gastric tissue. Our results indicate clone UMAB36 has higher specificity and sensitivity than clone 4B5 in screening gastric tumors.
Citation Format: Lixin Zhou, Kehu Yuan, Fangfang Ren, Lili Ki, Min Zhou, Wei Fu, Xiaozheng Huang, Rachel M. Gonzalez, Youmin Shu, Yi Shen, Guangli Wang, Donghui Ma, Wei-Wu He, Jian Chen. A screen of breast and colon cancers with HER2 antibody clone UMAB36 does not exhibit the cross-reactivity of clone 4B5 with HER4 protein. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3921.
Abstract 3924: AIRE is expressed and associated with good prognosis in breast cancer
Authors: Bianchi Francesca , De Cecco Loris , Triulzi Tiziana , Romero-Cordoba Sandra , Sommariva Michele , Storti Chiara , Aiello Piera , Tagliabue Elda , Balsari Andrea , Sfondrini Lucia 
Published: July 2016

Abstract
The transcription factor Autoimmune Regulator (AIRE) gene plays a fundamental role in tolerance process by promoting the ectopic expression of thousands of genes encoding for tissue-specific antigens (TSAs) in medullary thymic epithelial cells (mTECs). Beside the high expression of AIRE in mTECs, there are few evidences of AIRE expression in other lymphoid organs and very recently, AIRE was described to be expressed in human and mouse keratinocytes and in tumors originating in stratified and pseudostratified epithelia. Therefore, we evaluated the hypothesis that AIRE could be expressed by epithelial tumors and we focused on breast cancer, for which large public datasets are available.
Our analysis on the TCGA, the largest public breast cancer RNA-seq dataset, revealed that AIRE is expressed in 33% of the cases, and Aire protein expression was confirmed in 26% of 115 human primary breast cancer specimens by immunohistochemistry analysis. AIRE expression was revealed associated to a better relapse-free survival in the TCGA patients and also in two public gene expression microarray-based dataset developed on Agilent and Illumina platform (NKI-295 and KM-plotter). In all the datasets analyzed, AIRE expression resulted an independent strong prognostic factor for relapse-free survival, particularly in ER-positive tumors. Ingenuity Pathway Analysis (IPA) showed that AIRE-expressing tumors were enriched in translation-related pathways, accordingly with AIRE's described function in mTECs. Moreover, in breast cancer luminal cell lines MCF-7 and MDA-MB-361 transfected with AIRE-expressing vector, a significant increase of cell in G1 phase and activation of caspases cascade were observed, supporting the hypothesis that genotoxic stress, induced by AIRE-mediated proteins over-translation, leads to cycle arrest and apoptosis.
These data highlight for the first time AIRE expression in breast cancer and an association with a better prognosis was revealed. Imbalance of cellular homeostasis, caused by AIRE transcriptional function, is a new unusual mechanisms to trigger apoptosis in breast cancer cells.
Citation Format: Francesca Bianchi, Loris De Cecco, Tiziana Triulzi, Sandra Romero-Cordoba, Michele Sommariva, Chiara Storti, Piera Aiello, Elda Tagliabue, Andrea Balsari, Lucia Sfondrini. AIRE is expressed and associated with good prognosis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3924.
Abstract 3937: Nestin expression is associated with a basal-like phenotype and poor prognosis in breast cancer
Authors: Krüger Kristi , Wik Elisabeth , Klingen Tor Audun , Chen Ying , Aas Turid , Akslen Lars A. 
Published: July 2016

Abstract
Background:
Nestin, neuroepitheilal stem cell protein, is an intermediate filament protein first described in neural stem or progenitor cells, and its expression has been seen in several tissues, including different types of cancer.
In breast cancer, Nestin expression has been linked to the triple negative and basal-like phenotypes. We here evaluated Nestin and its association with clinico-pathologic markers and survival in two prospective Norwegian breast cancer cohorts.
Materials and methods:
Series I includes 546 women (50-69 years) diagnosed with primary invasive breast cancer (403 screen-detected and 143 interval cancers) as part of the prospective and population-based Norwegian Breast Cancer Screening Program (NBCSP) during 1996-2003 (Hordaland county).
Series II includes 282 women (50-69 years) with invasive cancers (199 screen-detected and 83 interval cancers) diagnosed as part of the NBCSP during 2004-2009 (Vestfold County).
Immunohistochemical staining of Nestin was done on tissue microarrays (TMAs). Expression in tumor cells was graded by a Staining Index (SI) (values 0-9).
Results:
Nestin positivity, observed in 9% and 13% of the breast cancer cases in Series I and II, was associated with higher histological grade (OR, odds ratio 14.3 and 8.1), high tumor cell proliferation by Ki-67 (OR 11.4 and 9.1), larger tumor diameter (OR 1.8 and 2.4), but not with lymph node status or HER2 status. Further, Nestin positivity was associated with negativity for estrogen (OR 14.9 and 11.9) and progesterone receptor (8.5 and 3.4), the triple negative phenotype (OR 29.1 and 17.4) and basal-like differentiation by positivity for Cytokeratin 5 (OR 9.1 and 8.7) or P-cadherin (OR 7.0 and 8.5).
By univariate survival analysis, Nestin positivity was associated with reduced breast cancer specific (p = 0.002 and p = 0.076) and overall survival (p = 0.005 and p = 0.039). When including the standard variables tumor size, histologic grade and lymph node status in a multivariate analysis, Nestin was still significantly associated with reduced breast cancer specific survival in the largest cohort (Series I).
Conclusion:
We found that Nestin expression in breast cancer is associated with aggressive features, the triple negative phenotype, basal-like differentiation, and reduced breast cancer specific survival.
Citation Format: Kristi Krüger, Elisabeth Wik, Tor Audun Klingen, Ying Chen, Turid Aas, Lars A. Akslen. Nestin expression is associated with a basal-like phenotype and poor prognosis in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3937.
Abstract 3947: Atypical chemokine receptor ACKR3 expression is associated with aggressive behavior and poor prognosis in gastric cancer
Authors: Kim Nayoung , Baek Seung-Woo , Ryu Hyewon , Choi Yoon Seok , Song Ik Chan , Yun Hwan Jung , Jo Deog Yeon , Kim Samyong , Lee Hyo Jin 
Published: July 2016

Abstract
Chemokine and their receptors are key mediators of normal physiology and a large number of pathologic conditions such as cancer, and this family of receptors is the emerging therapeutic target in the field of cancer treatment. ACKR3 is an atypical chemokine receptor first cloned from a dog cDNA library as the orphan receptor and was initially named Receptor Dog cDNA 1 (RDC1). Shortly after demonstrating that RDC1 binds with its ligand, stromal cell-derived factor-1α (SDF-1α) and interferon-inducible T-cell α chemoattractant (I-TAC), RDC1 was officially deorphanized. Accumulating evidence of recent studies have suggested that expression of ACKR3 is augmented in most of tumor cells as compared to their normal counterparts and is involved in cell proliferation, survival, migration, invasion during the initiation and progression of cancer. However, there is little information regarding their expression and clinical relevance in gastric cancer. The expression status of ACKR3 was investigated in 221 specimens of primary gastric cancer using immunohistochemistry. The correlation of ACKR3 expression with the clinicopathological features and survival outcomes was analyzed as well. Immunohistochemical staining of gastric cancer tissue sections revealed diverse cytoplasmic and membrane staining patterns for ACKR3. One hundred-fourteen cases (51.6%) showed low ACKR3 expression according to an arbitrary scoring system (grade 0-1; grade 0, n = 26; grade 1, n = 88), and one hundred-seven cases (48.4%) showed high expression (grade 2-3; grade 2, n = 58; grade 3, n = 49). There were no significant differences in age, gender, histology, tumor location, lymphatic and venous invasion among the two groups. However, high CXCR7 expression in cancer cells tended to be associated with proportion of tumor size greater than 5 cm (P = 0.055) and was significantly correlated with depth of tumor invasion (P &lt; 0.001), lymph node metastasis (P = 0.042), and higher stage (P = 0.002). Furthermore, patients with high ACKR3 expression showed worse overall survival rate of 47% compared to 56% in patients with low ACKR3 expression. In conclusion, ACKR3 is differentially expressed in gastric cancer cells, and high expression of ACKR3 is associated with aggressive tumor behavior and poor survival in patients with gastric cancer, suggesting that ACKR3 plays an important role during gastric cancer progression.
Citation Format: Nayoung Kim, Seung-Woo Baek, Hyewon Ryu, Yoon Seok Choi, Ik Chan Song, Hwan Jung Yun, Deog Yeon Jo, Samyong Kim, Hyo Jin Lee. Atypical chemokine receptor ACKR3 expression is associated with aggressive behavior and poor prognosis in gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3947.
Abstract 397: Brain natriuretic peptide (BNP) as molecular marker for bladder, ovarian, and glioblastoma cancers
Authors: Lee Cynthia , Yeh William , Lee Dongwoon , Dixon Samuel , Trieu Vuong 
Published: July 2016

Abstract
Background: BNP has been reported as molecular marker for ovarian cancer. This study evaluated BNP as a molecular marker for bladder, ovarian, glioblastoma, and pancreatic cancers. Methods: Serum samples collected at the time of diagnosis were tested using rapid and quantitative point-of-care (POC) devices for BNP blood biomarkers and the data was evaluated using JMP® 11.2.1 statistical analysis software. Samples were collected from bladder cancer patients (48 transitional cell carcinoma of the bladder), glioblastoma patients (51), pancreatic cancer patients (39 adenocarcinoma, 1 mucinous adenocarcinoma), ovarian cancer patients (24 serous adenocarcinoma, 20 serous papillary adenocarcinoma, 7 endometrioid adenocarcinoma, 3 clear cell carcinoma, 1 endometrial adenocarcinoma, 1 endometrioid papillary carcinoma, 1 serous papillary carcinoma), and normal subjects (n = 60). Results: Compared to normal subjects, bladder patients are more likely to be smokers (p = 0.0064). All four patient groups were more likely to be hypertensive (bladder, p = 0.0165; glioblastoma, p&lt;0.0001, ovarian, p = 0.0002; pancreatic, p &lt; 0.0001). No significant differences among the groups versus normal for weight were observed. Significant differences between the groups versus normal for BMI (ovarian, p = 0.0061), age (bladder, p = 0.0006; pancreatic = 0.0085), BNP (ovarian, p = 0.0012; glioblastoma, p = 0.0016; bladder, p = 0.0112) were noted. There was positive correlation between age and BNP level among all four cancer groups (bladder, p = 0.0133; glioblastoma, p = 0.0629; ovarian, p = 0.0304; pancreatic, p = 0.0172); whereas there was a negative correlation between age and BNP level among normal controls (p = 0.0109). Age-adjusted BNP level was highly significant different versus normal (bladder, p &lt;0.0001; ovarian, p = 0.0013; glioblastoma, p = 0.0047). Neither BNP nor age-adjusted BNP level was significantly different from normal for pancreatic cancer patients. Hypertensive condition had no impact on BNP or age-adjusted BNP. Conclusions: Bladder, ovarian, and glioblastoma cancers are associated with significant reduction in BNP and age-adjusted BNP blood levels. Pancreatic cancer was an exception. BNP level could be useful in the monitoring of treatment efficacy in which the BNP POC device described here would be highly appropriate due to its ease in deployment at the patient's home or doctor's office.
Citation Format: Cynthia Lee, William Yeh, Dongwoon Lee, Samuel Dixon, Vuong Trieu. Brain natriuretic peptide (BNP) as molecular marker for bladder, ovarian, and glioblastoma cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 397.
Abstract 3970: Impact of endoscopic stent insertion on detection of viable circulating tumor cells for obstructing colon cancer
Authors: Yamashita Shinya 
Published: July 2016

Abstract
The obstructive colorectal cancer(CRC) was reported to be 7-20% of CRC. For the patients (pts) with obstructive colorectal cancer, self-expanding metallic stents (SEMS) have been useful as a palliative treatment. Insertion of SEMS for obstructive colorectal cancer is used as a bridge to surgery approach. But suspicion have been raised about whether shear forces that act on the tumor during expansion of the stent may result in a release of cancer cells into the circulation (i.e., CTCs). This study was conducted to clarify whether insertion of colonic stents results in increased levels of viable CTCs (v-CTCs). For detecting viable CTCs(v-CTCs) of CRC, we employed a novel method, TelomeScan F35 detection system. The system was constructed with a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication. 7.5 ml of peripheral blood samples were obtained before and after stent insertion and after operation. GFP-positive and CD45-negative cells were counted as v- CTCs. This study was a single institution trial, approved by the Kure Medical Center IRB. Surgical operation was scheduled within 1 month after stenting. Between October 2013 and June 2015,10 pts aged 58-89 years (5 males and 5 females) were enrolled. The surgical operation (R0) was performed in 9 cases. CEA was reduced to &lt;50% of baseline value in 6 of 9 measurable pts after resection. 6 pts had no v-CTCs before stenting. Among them, 3 pts had increasing number of 1-3 v-CTCs after stenting and 1 of them developed multiple liver metastasis 12 month after resection. While, 4 pts had v-CTCs (1-19 cells) before stenting and 3 of these 4 patients had significant increase of number of v-CTCs (1-21 cells) after stent insertion. 2 of them had 12 and 14 v-CTCs, respectively after operation, despite the normalized value of CEA. The present study suggested that endoscopic stent insertion may result in tumor cell dissemination into the peripheral circulation and may induce early distant metastasis. In conclusion, v-CTCs may become useful for prognosis assessment, especially when SEMS insertion is considered.
Citation Format: Shinya Yamashita. Impact of endoscopic stent insertion on detection of viable circulating tumor cells for obstructing colon cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3970.
Abstract 3980: Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma
Authors: Peng Yu-Hui , Xu Yi-Wei , Li En-Min , Xu Li-Yan 
Published: July 2016

Abstract
Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf-1 (DKK1) in combination of DKK1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK1 and DKK1 autoantibodies were measured by enzyme-linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristics (ROC) was applied to calculate diagnostic accuracy. The serum levels of DKK1 and DKK1 autoantibody were significantly higher in ESCC patients than in controls, respectively (P&lt;0.0001). Measurement of serum DKK1 demonstrated an area under curve (AUC) of 0.709 [95% confidence interval (CI), 0.647-0.771], 37.3% sensitivity, and 90.7% specificity in the training set and an AUC of 0.697 (95% CI, 0.613-0.780), 41.3% sensitivity, and 84.9% specificity in the validation set. Testing of DKK1 and DKK1 autoantibodies together effectively improved the diagnostic accuracy for ESCC versus normal controls compared with either test alone (AUC 0.769, 95% CI 0.715-0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI 0.675-0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK1 and DKK1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699-0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626-0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK1 or DKK1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P&lt;0.05). Our results suggest that measurement of DKK1 combined with DKK1 autoantibodies is a potentially valuable tool for the early detection of ESCC.
Citation Format: Yu-Hui Peng, Yi-Wei Xu, En-Min Li, Li-Yan Xu. Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3980.
Abstract 3985: First case of B LAL with MLL - MAML2 rearrangement
Authors: Usseglio Fabrice , Beaufils Nathalie , Costello Régis , Gabert Jean 
Published: July 2016

Abstract
Over 70 MLL partner genes have been reported so far. MLL gene (or 11q23) translocation is occurring in 7-10% of B acute lymphoblastic leukemias and AF4 being the most frequent partner gene. The prognostic is usually bad, specially for AF4 partner. A rare partner gene, mastermind like 2 (MAML2) gene has been reported in 4 cases of myeloid neoplasms after chemotherapy so far: 2 AML and 2 MDS. Here we report a case with MLL - MAML2 discovered by NGS analysis in front of an inv11 (q21q23) present in a 47 years old female previously treated for a sarcoma in 2014. It is, to our knowledge, the first case of B acute lymphoblastic leukemia (CD79a, CD22, CD19, CD45, CD10-) with this fusion gene. At the molecular level, the rearrangement consists in the fusion of exons 7 and 2 of the MLL and MAML2 genes respectively. We will discuss the biological, clinical, physiological and therapeutic consequences of this rare event. Its prognostic impact is unknown as the reported cases are too rare.
Citation Format: Fabrice Usseglio, Nathalie Beaufils, Régis Costello, Jean Gabert. First case of B LAL with MLL - MAML2 rearrangement. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3985.