bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: Circulating tumor cells in lung cancer: Biomarkers, biology, and mouse models to study drug resistance
Authors: Dive Caroline , Morrow Chris , Brady Ged , Blackhall Fiona 
Published: May 2015

Abstract
SCLC patients (∼75%) respond well initially to standard chemotherapy (platinum/etoposide) but drug resistant disease relapse ensues rapidly. Most Small Cell Lung Cancer (SCLC) patients present with metastases, consequently tumor resection is rare and tumor biopsy is rarely obtained at disease relapse to explore drug resistance mechanisms. Targeted therapies have yet to impact SCLC patient outcomes, new drug targets and biomarkers measured in minimally invasive samples are required. Using EpCam dependent CellSearch technology, we showed that CTCs are prevalent in SCLC and CTC number is an independent prognosticator. SCLC CTC number is pharamcodynamic and CTCs are amenable to biomarker assay development (protein expression, omic profiling, FISH etc.) to be applied in clinical trials. We also developed unique patient CTC derived mouse models (CDX) to study SCLC biology, search for new drug targets, develop biomarkers and explore drug resistance mechanisms. Successful CDX engraftment has been observed so far in ∼45% cases. The molecular landscape of CDX can be compared to that of single, isolated CTCs from the same patient. CDX are readily passaged and their response to cisplatin/etoposide closely mimics the donor patient. CDX offer unparalleled opportunity to interrogate drug resistance mechanisms as paired models can be generated at presentation (chemosensitive) and again at relapse (drug resistance). Our data demonstrate that serial blood sampling with CDX and CTC molecular analysis could facilitate delivery of precision medicine to improve outcomes in SCLC. A program of evaluation of novel therapeutics in CDX models, the development of orthotopic CDX SCLC and NSCLC CDX are underway.
Citation Format: Caroline Dive, Chris Morrow, Ged Brady, Fiona Blackhall. Circulating tumor cells in lung cancer: Biomarkers, biology, and mouse models to study drug resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA05.
Abstract IA15: Strategies to overcome acquired resistance to kinase inhibitors
Authors: Bollag Gideon 
Published: May 2015

Abstract
Current therapies for oncogenic kinase-driven cancers often involve kinase inhibitors. While the efficacy of these therapies is often striking, eventual relapse due to acquired resistance is common.
For example, first-generation BRAF inhibitors are making a major impact on the disease-course in BRAF-mutant cancers and metastatic melanoma in particular. Nonetheless, many patients relapse and relapsed tumors generally display BRAF pathway re-activation. In order to improve the durability and tolerability of therapy, Plexxikon has been pursuing multiple strategies. Since the well-documented RAF inhibitor paradox is implicated as a contributor to drug resistance as well as unwanted side effects, we have designed a series of compounds that exhibit potent anti-BRAF efficacy without causing paradoxical pathway activation in RAS mutant cells. These compounds, dubbed Paradox Breakers, are also active against certain BRAF isoforms that are resistant to inhibition by first-generation compounds. Furthermore, we believe that macrophages in the tumor microenvironment are likely to enable resistance to BRAF inhibition. Therefore, we are pursuing studies to co-target BRAF in tumors and macrophages in the tumor microenvironment.
Furthermore, inhibiting oncogenic KIT mutations is a validated therapeutic approach to treat gastrointestinal stromal tumors (GIST). The use of clinically approved kinase inhibitors such as imatinib frequently reveals secondary or acquired mutations that render these first-generation KIT inhibitors ineffective. Some of the acquired mutations reside in exon 17, coding for amino acids in the activation loop of the folded protein. This set of mutations has been shown to constitutively activate the receptor. Using a scaffold-based drug discovery approach, we have successfully identified a novel KIT exon 17 mutant-targeted inhibitor that shows minimal cross-reactivity in a kinome wide screen. This inhibitor shows robust efficacy in a patient-derived, imatinib-resistant GIST xenograft (Molecular Response).
Plans to develop these approaches into clinical projects will be discussed.
Citation Format: Gideon Bollag (on behalf of the Plexxikon team). Strategies to overcome acquired resistance to kinase inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA15.
RAI2: Linking Retinoic Acid Signaling with Metastasis Suppression
Authors: Esposito Mark , Kang Yibin 
Published: May 2015

Abstract
Summary: Considerable evidence points to the importance of disseminated tumor cells, which are commonly detected in the bone marrow and display features of cellular plasticity, in predicting the clinical outcome of breast cancer. In this issue of Cancer Discovery, Werner and colleagues report on the discovery of retinoic acid–induced 2 (RAI2) as a differentiation factor that suppresses early metastatic spread of estrogen receptor–positive breast cancer. Cancer Discov; 5(5); 466–8. ©2015 AACR.
See related article by Werner et al., p. 506
CHD5 downregulation associated with poor prognosis in epithelial ovarian cancer in Hong Kong Chinese women
Authors: Wong Raymond R. , Chan Loucia K.Y. , Tsang Teresa B.T. , Lee Coral W.S. , Cheung T.H. , Yim S.F. , Siu Nelson S.S. , Lee Sophia N.C. , Chim Stephen S.C. , Wong Y.F. , Chung Tony K.H. 
Published: May 2015

Abstract
Background: CHD5 gene located on 1p36, encodes a non-histone chromosomal protein, chromodomain helicase DNA binding protein 5. Recently, CHD5 has been shown to be a tumor suppressor gene candidate. This study was to investigate the involvement of CHD5 in epithelial ovarian cancer and its clinico-pathological significance.
Methods: CHD5 expression in ovarian cancer and its normal counterpart was determined by quantitative RT-PCR. The methylation of CHD5 promoter was evaluated by methylation specific PCR. The correlation of CHD5 expression to patient age, tumor histological type and grade, clinical stage and status, recurrence and patient survival time was analyzed statistically.
Results: CHD5 expression was down at least two-fold in 32 of 72 (41%) invasive epithelial ovarian carcinomas when compared to 12 normal controls in Hong Kong Chinese women. Hypermethylation in two promoter regions of CHD5 was not detected in any of the 20 tumor samples available to be analyzed. CHD5 down-regulation was correlated to clinical status (P&lt;0.05), but not to patient age, tumor type and grade, recurrence and clinical stage (P&gt;0.05). Kaplan-Meier survival analysis showed that patients with CHD5 down-regulation in their tumors were associated with shorter disease-free and total survival times compared to those without CHD5 down-regulation (P&lt;0.05). Cox proportional hazard regression analysis indicated that down-regulation of CHD5 is an independent adverse prognostic factor in ovarian cancer.
Conclusion: This preliminary study shows that CHD5 s down-regulated in a certain part of ovarian cancers and appears to be an adverse predictor candidate of ovarian cancer disease-free and total survival in Hong Kong Chinese women. If this role of CHD5 dysregulation can be confirmed in more prospective studies with a large number of patients, it is also worthwhile to further evaluate if CHD5 can be as an individualized molecular therapeutic target for epithelial ovarian cancer.
Identification of radiosensitivity predictive genes in gastric cancer cell line using gene expression profiling
Authors: Kim Han Sang , Rha Sun Young , Kim Sun Jeong , Park Chan Hee , Roh Jae Kyung , Chung Hyun Cheol , Ahn Joong Bae , Jeung Hei-Cheul , Shin Sang Joon , Kim Yong Bae 
Published: May 2015

Abstract
Background: In the post-genome era, the development of a radiation sensitivity predictive assay is significant as it could lead to better patient and dose selection in radiotherapy.
Methods: To identify radiosensitivity predictive genes in gastric cancer cells, 12 gastric and 4 colorectal cancer cell lines were used. Oligonucleotide microarray was performed using a human oligo chip containing 22,740 oligonucleotide probes of 70 bases with a reference design before radiation. Clonogenic survival assays with 2Gy of radiation were performed and survival fraction at 2 Gy (SF2) was measured. Differentially expressed genes were identified through Significant analysis of microarrays (SAM) between radiosensitive and radioresistant cell lines and functional study through Ingenuity pathway analysis was conducted.
Results: According to SF2, SNU-638 (0.127±0.038), MKN-1 (0.143±0.032), and HCT-116 (0.313±0.034) were classified as radiosensitive cells, whereas YCC-2 (0.609±0.046), YCC-16 (0.62±0.091), HT29 (0.641±0.070), and YCC-7 (0.667±0.192) were determined as radioresistant cells. Eighty-two up-regulated and one hundred and forty-two down-regulated genes were identified in radiosensitive cell lines compared to radioresistant cell lines. Cell death (43 genes), cellular growth and proliferation (36 genes), cell-to-cell signaling (16 genes), cell cycle (13 genes), and DNA repair (6 genes) were related with identified gene set. Genetic network via TGFB1 and TP53 showed important role in radiosensitivity.
Conclusions: Our results suggest that identified genes are candidates for radiosensitivity biomarker discovery and in vitro clonogenic assay with expression analysis may assist to predict responsiveness to radiotherapy.
EGFR mutations in African American NSCLC patients occurs at a similar frequency to Caucasians but demonstrates an extreme bias to exon 19 mutations
Authors: Atikukke Govindaraja , Cote Michele L. , Schwartz Ann G. , Shirish Gadgeel , Soubani Ayman O. , Ethier Stephen P. , Lonardo Fulvio , Haddad Ramsi , Edwards David J. 
Published: May 2015

Abstract
Oncogenomic mutations found in NSCLC are potential therapeutic targets, as seen in the dramatic responses individuals with EGFR mutations have to tyrosine kinase inhibitors. We selected 149 patients with NSCLC from previous population-based studies of lung cancer which included 80 (54%) Caucasian samples and 69 African American (46%) samples. Tumor DNA was extracted from formalin fixed paraffin embedded tissue. We examined 238 mutations in 19 oncogenes using the OncoCarta Assay v1.0 (Sequenom). We identified a total of 52 mutations in tumors from 47 individuals; the remaining 102 tumors did not have mutations in the oncogenes we assayed. Mutations were identified in EGFR (n=20), KRAS (n=19), PIK3CA (n=6), PDGFRA (n=2), AKT2 (n=1), FLT3 (n=1) and CDK1 (n=1). Consistent with previous studies, EGFR mutation was more likely to occur in non-smokers (p=3.3E-08 Fisher's test) and the significance of this effect was more pronounced when analyzed against the number of pack years smoked (p=7.3E-08, Kruskal-Wallis test). Previously published reports have suggested that African American patients are less likely to exhibit EGFR mutations compared to Caucasian NSCLC patients and are therefore less likely to respond to tyrosine kinase inhibitors. We found no difference in the proportion of EGFR mutations in African American patients (n=8, 11.6%) compared to Caucasian (n=12, 15.0%, p-value=0.54). Furthermore, EGFR mutations in African American patients were exclusively in exon 19 (n=8, 100%), whereas Caucasian patients had mutations in exon 21 (n=3, 25%) and exon 18 (n=1, 8.3%) in addition to those in exon 19 (n=8, 66.7%). Interestingly, several reports have suggested a higher rate of response of NSCLC to erlotinib, an EGFR tyrosine kinase inhibitor, associated with exon 19 deletions relative to the exon 21 L858R mutation. Thus, our oncogenomic data demonstrates that African American NSCLC patients not only harbor a similar frequency of EGFR mutation as Caucasians, but that the specific nature of the mutation may result in a higher frequency of response to EGFR targeted therapeutics.
Diagnosis of prostate cancer using differentially expressed genes in stroma
Authors: Jia Zhenyu , Wang Yipeng , Sawyers Anne , Yao Huazhen , Rahmatpanah Farahnaz , Xia Xiao-Qin , Xu Qiang , Pio Rebecca , Turan Tolga , Koziol James A. , Goodison Steve , Carpenter Philip , Wang-Rodriguez Jessica , Simoneau Anne , Meyskens Frank , Sutton Manuel , Lernhardt Waldemar , Beach Thomas , McClelland Michael , Mercola Dan 
Published: May 2015

Abstract
Over 1 million prostate biopsies are performed in the U.S. every year. A failure to find cancer is not definitive in a significant percentage of patients due to the presence of equivocal structures or continuing clinical suspicion. We have identified gene expression changes in stroma that can detect tumor nearby. We compared gene expression profiles of 13 biopsies containing stroma near tumor and 15 biopsies from volunteers without prostate cancer. More than a thousand significant expression changes were found and thereafter filtered using large numbers of other expression profiles to eliminate possible age-related genes and genes expressed at detectable levels in tumor cells. A stroma-specific classifier was constructed based on 114 candidate genes and tested on 364 independent samples, including 243 tumor-bearing samples and 121 non-tumor samples (normal biopsies, normal autopsies, remote stroma, as well as stroma within a few millimeters of tumor). The classifier predicted the tumor status of patients using tumor-free samples with an average accuracy of 97.2% (sensitivity = 97.9% and specificity = 88.0%) whereas classifiers trained with sets of 100 randomly generated genes had no diagnostic value. These results indicate that the prostate cancer microenvironment exhibits reproducible changes useful for categorizing the presence of tumor in patients when a prostate sample is derived from near the tumor but does not contain any recognizable tumor.
Four-protein signature accurately predicts lymph node metastasis and survival in oral squamous cell carcinoma
Authors: Zanaruddin Sharifah NurAin Syed , Saleh Amyza , Yi-Hsin Yang , Hamid Sharifah , Mustafa Wan Mahadzir Wan , AAN Khairul Bariah , Teo Soo-Hwang , Zain Rosnah Binti , Lau Shin Hin , Cheong Sok Ching 
Published: May 2015

Abstract
The presence of lymph node metastasis significantly affects the survival of oral squamous cell carcinoma patients and successful detection and removal of positive lymph nodes is crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the lymph nodes, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis—positive LNs in the neck. We aimed to develop a molecular signature in the primary tumor that could predict lymph node (LN) metastasis in oral squamous cell carcinoma. The expression levels of 11 proteins was evaluated using immunohistochemical analysis in a tissue microarray (TMA) consisting of 110 specimens from 32 individuals. We used receiver operating characteristic (ROC) curve to identify proteins that could significantly differentiate patients with LN metastasis from those that did not. Unsupervised hierarchical clustering analysis was used to verify the ability of chosen biomarkers in segregating LN positive patients from those with no LN involvement. Kaplan-Meier survival curve and log rank test was utilized to determine the association between LN metastasis and biomarker expression with disease-specific survival. Of the 11 biomarkers, EGFR, HER-2/neu, LAMC2 and RHOC were found to be significantly associated with LN metastasis. Unsupervised hierarchical clustering demonstrated that expression patterns of these 4 proteins could be used to differentiate the positive LN metastasis specimens from specimens that are negative. Collectively, EGFR, HER-2/neu, LAMC2 and RHOC have a specificity of 87.5% and sensitivity of 70% with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated the LN signature could independently predict disease-specific survival (p = 0.023). In summary, we developed a 4-protein LN signature that could reliably distinguish patients with lymph node metastasis from those who were metastasis free. In addition, this LN signature is also associated with disease-specific survival indicating that would be a useful prognostic tool for the management of oral cancer patients.
SCV-07 treatment leads to alterations in VEGF, MIF, IL-1alpha, and MIP-1beta levels in patients with head and neck cancer
Authors: Tuthill Cynthia W. , Rios Israel , Modelska Katharina , Sonis Stephen T. , Fey Edward , Alterovitz Gil , Epstein Joel B. 
Published: May 2015

Abstract
Introduction: Serum was collected before and after chemoradiation therapy from head and neck cancer (HNC) patients enrolled in a phase 2, randomized, double-blind, dose-ranging, placebo-controlled trial designed to test the safety, tolerability and efficacy of an immunomodulatory peptide, gamma-D-glutamyl-L-tryptophan (SCV-07) as an intervention for oral mucositis (OM). Results of the trial demonstrated that the high dose of SCV-07 (0.1 mg/kg daily on days of radiation) was safe and effective in attenuating the course of OM. The objective of this study was to determine if the administration of high dose SCV-07 affected detectable levels of peripheral blood cytokines that may be involved in the host response to chemoradiation therapy for HNC.
Experimental Procedures: Samples were analyzed via multiplex (Affymetrix Procarta cytokine assay), evaluating 35 proteins expected to be affected by SCV-07, which has been shown to stimulate a Th1 cytokine profile and to inhibit IL-6 dependent STAT3 signaling. For each of the 35 proteins, the null hypothesis “average subject protein value in high-dose regimen subjects equals average subject protein value in placebo regimen subjects” was tested against the alternative hypothesis “average subject protein value in high-dose regimen subjects does not equal average subject protein value in placebo regimen subjects.” A two tail test (=0.05) was used as there was no a priori knowledge of a relationship between protein levels and treatment regimen. Unequal population variances were assumed as the samples were not assumed to be random draws from the same population. The dataset analyzed 26 subjects given the high dose SCV-07 regimen and 23 subjects given placebo.
Summary of Results: MIF, MIP-1beta, and VEGF were found to be significantly higher (p &lt; 0.049, p &lt; 0.049, p &lt; 0.015 respectively) in high dose SCV-07 treated individuals compared to placebo, whereas IL-1alpha was found to be significantly lower (p &lt; 0.045) in high dose SCV-07 treated individuals compared to placebo.
Conclusions: SCV-07 treatment leads to increases in circulation of some immune-related cytokines (MIF, MIP-1beta, and VEGF) and leads to a decrease in another (IL-1alpha). These results can be used to better understand SCV-07's mechanism of action, and to follow biomarkers during future clinical trials evaluating SCV-07.
Basic Research, Epigenetics, Immunology, Noncoding RNAs, Tumor Microenvironment, Metastasis, Target Identification, Validation, Lead Discovery, and Optimization
Using biomedical informatics to see the forest AND the trees for molecular diagnostics in cancer therapeutic development
Authors: Buetow Kenneth H. 
Published: May 2015

Abstract
Cancer research in general—and molecular diagnostic development in particular—are leveraging the diverse collection of publicly-accessible molecular information that underpins disease. The ability to access and integrate this information will be crucial to the development of molecular diagnostics. Use of this data requires overcoming the silos and data disconnects common throughout biomedicine and new models for interpreting this massive amount of information. The National Cancer Institute has developed the caBIG® initiative (Cancer Biomedical Informatics Grid) to integrate the diverse multidimensional data. An active area of research is developing biologic process models for integrating and interpreting this massive volume of data.
The Cancer Genome Atlas (TCGA) is an example of the challenges faced in transforming data to information. Large volumes of diverse, multidimensional data including various genomic characterizations and clinical information must be synthesized. Through the caBIG® generated Cancer Molecular Analysis portal (http://cma.nci.nih.gov), it is possible to see integrated views of the TCGA data from different research perspectives including genomic and clinical views. Tools leveraging this data can be used to display and analyze the data in biologic networks. As more TCGA data and additional molecular data are shared through the portal it will become increasingly possible to obtain a comprehensive view of the molecular basis of cancer and drive development of molecular diagnostics.
Tissue issues: Clinical and research implications of diagnostic biopsy practices
Authors: Bethel Kelly J. 
Published: May 2015

Abstract
Tissue Issues for Researchers: Why the pathologist does NOT want to give you human tumor tissue...and how to get it anyway. Or: Why you should befriend a pathologist.
Overview: More research should be done using human tumor tissue.This is very hard for many logistical, organizational, and sociological reasons.Befriend a pathologist. Involve them early during the design phase. Fund their time.So you want some human tumor tissue...Tissue banks exist, with well-annotated tumor samples, sometimes with clinical follow up information.This tissue is either frozen or paraffin embedded.Tissue arrays are available, which are very efficient and allow for good QC because one can cut a section and actually see what cells are there, and then punch out a corresponding core of tissue from the block to use for experiment.Expensive, not necessarily tailored to your experiment, and not fresh tissue. Fresh tissue: No, we don't want to give you any...Pathologists control tissue in a hospital setting, where most cancer surgeries take place.Biopsies are hard won tiny fragments of people — we have to bully the other doctors into getting us enough in the first place.Resections usually provide lots of tissue but it takes a bunch of extra time and judgment to collect them fresh and carefully annotate them for you, and place them in special media and make sure they get picked up and handled promptly. How do we get the tissue to make the diagnosis? From whom do we get it? Diagnostic adequacy rate of sampling procedures is related to type of biopsy.Research samples are considered second priority after adequate diagnostic material is obtained. Suggestions for optimizing your chances of getting some.