bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gene expression signature associated with structural differentiation of prostate acini predicts postoperative recurrence of prostate cancer
Authors: Su Jimmy J.-M. , Li Chi-Rong , Lee Michael T.-L. , Chu Patrick Y. W. , Weaver Valerie M. , Tsai Kelvin K.-C. 
Published: May 2015

Abstract
Glandular malignancies such as prostate carcinoma display a considerable heterogeneity in the degree of structural organization while the prognostic role of the associated molecular changes awaits further exploration. Using a three-dimensional (3-D) tissue organization culture model that permits the structural differentiation of prostate glandular epithelium we profiled the transcriptomes of multicellular organoids formed by untransformed prostate epithelial cells (PECs) or prostate carcinoma cells as well as those cultured as cell monolayers. Interrogation into the multiple (n = 6) sets of differentially expressed genes (DEGs) identified that those altered significantly during the structural differentiation process of polarized PEC acini strongly associated with the probability of recurrence in a cohort of 50 prostate cancer patients receiving radical prostatectomy (RP). By contract, the DEGs related to prostate tumor spheroids did not correlate significantly with prognosis. To further explore this association, we prioritized the genes and applied supervised classification algorithms whereby identified a 39-gene structure-associated prognosis signature (SAPS) that shows a remarkable predictivity for the likelihood of post-RP recurrence (overall accuracy 100%, P &lt; 0.001). The SAPS outperformed standard clinicopathological variables, including Gleason scores, as well as existing multigene prognostic predictors of prostate cancer. Our results suggest a distinct contribution by the glandular structural differentiation program to prostate cancer pathology and the usefulness of a robust and biologically relevant genomic predictor of the prognosis of prostate cancer (Supported by NHRI CA-099-PP-19 and Department of Health of Taiwan H99-TD-C-111-004 to KKC).
Insulin-like growth factor receptor 1(IGFIR) is overexpressed in a subset of triple negative breast cancers
Authors: Kline Jessica , Chervoneva Inna , Freydin Boris , solomides Charalambos , Witkiewicz Agnieszka K. , Martin Carl , Peiper Stephen 
Published: May 2015

Abstract
Insulin-like growth factor receptor 1 (IGF-1R) has a key regulatory role in malignancy and is the target of several drugs currently tested in clinical trials. Few studies have shown that IGF-IR expression is associated with estrogen receptor positive breast cancer. However, there are no systematic studies of IGF1R expression in triple negative breast carcinoma (TNBC). The aim of this study was to evaluate IGF1R protein expression and gene amplification in TNBC.
Material and Methods: Ninety-seven TNBC (73 from Caucasian and 24 from African American women) were stained with anti-IGF1R antibody (clone G11, Ventana Medical Systems, Tucson, AZ, USA). IGF1R protein expression was scored according to standardized criteria originally developed for HER 2. Chromogenic in situ hybridization for IGF1R gene was performed on 35 cases using experimental Ventana probe. The tumor was interpreted as positive for gene amplification when the ration of IGF1R gene signal to chromosome 15 signal was ≥ 2.2. For statistical analysis, the IGF1R scores (0, 1, 2, 3) were dichotomized as low (0-2) vs. high (3). Association between IGF1R protein expression and clinicopathologic variables (lymph node metastases, grade, race, age) was analyzed using Fisher's exact test. The association between tumor size and IGF1R expression was analyzed using the Wilcoxon two-sample test. The overall survival was analyzed using LogRank test and Cox proportional hazard model.
Results: A significant association was observed between IGF1R protein expression and IGF1R gene amplification (p&lt;0.001). Respectively, the agreement between IGF1R 3+ protein expression and gene amplification was high (kappa=0.84, 95% CI: 0.62, 1.0; p&lt;0.001). Low (0-2+) IGF1R expression was associated with lymph node metastases (p=0.033) while cases with high (3+) expression had borderline significantly (p=0.080) smaller tumor size. There was no statistically significant association between IGF1R expression and grade or race. In younger patients (&lt;55 years), high IGF1R score was associated with longer survival (HR=0.13; 95% CI: 0.02- 1.00; p=0.050), while in older patients, no significant survival differences were observed between patients with low and high IGF1R scores.
Conclusion: This study suggests that IGF1R is overexpressed and amplified in a subset of TNBC and may be a potential therapeutic target.
A kinase-directed RNAi screen identifies GSK-3b/a as a target to overcome drug resistance of p53-null colon cancer cells
Authors: Grassilli Emanuela , Narloch Robert , Federzoni Elena , Leone Biagio Eugenio , Helin Kristian , Lavitrano Marialuisa 
Published: May 2015

Abstract
Evasion from chemotherapy-induced apoptosis strongly contributes to drug resistance and tumor relapse. In particular, p53 loss renders colon carcinoma cells resistant to 5-fluorouracil-induced apoptosis. We have used the 5-fluorouracil-resistant HCT116p53KO colon carcinoma cell line and a kinase-directed retroviral shRNA library to identify kinases whose inactivation reverts resistance to drug-induced apoptosis. In this way we have identified 29 kinases whose downregulation abolished colony growth after 5-fluorouracil treatment. Silencing of these kinases in other drug-resistant p53-null colon cell lines also abolished cellular growth, suggesting that the effect is independent of the genetic background. We focused on GSK-3 since by tissue microarray we found that GSK-3 is overexpressed/activated in tumoral biopsies of infiltrating and invasive colon carcinomas. We demonstrated that GSK-3 silencing in different colon carcinoma cell lines reverts resistance not only to 5-fluorouracil, but also to oxaliplatin and the 2 drugs used in combination. Interestingly, we found that 5-fluorouracil-treated p53-null GSK-3-depleted colon carcinoma cells undergo caspase-independent but PARP-dependent and tBid- and AIF-mediated cell death. Therefore, we propose that GSK-3 is an excellent potential target for the development of anti-cancer therapy. Our results suggest that inhibitors of GSK-3 can be used in combination with chemotherapy to kill cancer cells unable to trigger caspase-dependent apoptosis.
Development of a panel of biomarkers for the diagnosis of prostate cancer
Authors: Fallon Rachel A. , Wheeler Colin , Koopmann Jens , Workman Nick , McAndrew Mike B. 
Published: May 2015

Abstract
The issues surrounding the use of PSA in the diagnosis of prostate cancer (PC) are well documented. In community practice the PSA cut-off point of 4 ng/mL is considered sensitive but relatively non-specific (sensitivity of 86% and specificity of 33%)1 and there is a need for a diagnostic test with greater discriminatory power. The development of autoantibodies associated with prostate cancer has been described2. In general, the appearance of such antibodies can precede disease symptoms by many years, making them attractive as potential biomarkers for early diagnosis.
We have developed a unique “functional protein” array platform which utilises 925 correctly folded proteins chosen for their roles in disease and used this to detect autoantibodies in PC serum samples. We have taken advantage of the multiplex nature of array assays and applied complex data analysis strategies to identify panels of biomarkers which may have clinical utility in the diagnosis of prostate cancer.
Serum samples (case; n = 73 and control; n = 60) were analysed using protein arrays. Data analysis was performed using a multi-scaling and outlier removal step for quadruplicate signals from all 133 protein arrays. Data were arbitrarily split into test and training sets and the data from the training set was then used with both support vector machines and genetic programming to identify classifiers which would successfully distinguish case from control samples. Classifiers were assessed for performance by referring to the combined sensitivity and specificity (S+S score) using the test set. Data were repeatedly split into test and training sets and analysis cycles repeated until a stable set of classifiers was identified.
A set of biomarkers was identified which can distinguish PC from control samples with both sensitivity and specificity above 90%. Further development and validation of this panel is on-going with a larger cohort. 1. Hoffman et al. Prostate-specific antigen testing accuracy in community practice. BMC Family Practice (2002) 3:19. 2. Wang et al. Autoantibody signatures in prostate cancer. N Engl J Med. (2005) 353:1224.
Population-based engineered tumor models as a platform for biomarker discovery in cancer
Authors: Jiang Feng , Lin Jie , Sun Xiaojian , Feng Bin , Nicoletti Richard , Li Guangmu , Chiu M. Isabel , Esteves Brooke , Al-Adhami Mohammed , Bhargava Pankaj , Robinson Murray O. 
Published: May 2015

Abstract
This abstract is being presented as a short talk in Plenary Session 1. A full abstract is printed in the Proffered Abstracts section (PR1) of the Conference Proceedings.
Functional analysis of human tumor response to signal transduction inhibitors: Ex vivo analysis of programmed cell death (EVA-PCD) in 1° culture microspheroids
Authors: Nagourney Robert A. , Kenyon Kaylee R. , Frederico Eric , Bernard Paula , Evans Steven S. 
Published: May 2015

Abstract
Advances in cancer therapy increasingly reflect the application of genomics and proteomics to target tumor-specific phenomena. Several insights have accelerated this process including the primacy cell survival signals in carcinogenesis and drug resistance and the growing appreciation of tumor biology as contextual. Ex vivo analysis of programmed cell death (EVA/PCD™) addresses both issues by measuring metabolic and morphologic features of drug induced cell death (apoptotic and non-apoptotic) using native state 1° cultures isolated from surgical specimens and cytologically (+) fluids. The predictive validity of the EVA/PCD™ established for cytotoxics, e.g,. 2CDA in hairy cell leukemia; purine-alkylator synergy in NHL (Nagourney et al, B.J. Cancer, ‘93) and platin-gemcitabine activity/synergy in breast and gynecologic cancers (Nagourney et al, Deoxynucleoside analogs in cancer therapy, Humana Press, 2006) has led to this platforms current focus on signal transduction with a growing emphasis on NSCLC. A recent report in NSCLC provided an ORR of 62%, med TTP of 9.5 mos and med OS of 22.3 mos, including the identification of durable responders to EGFr-TKIs (Nagourney RA Proc ASCO, 2010). An EVA/PCD™ exploration of “vertical” and “horizontal” signal inhibition (Nagourney et al Proc AACR, 2010) favored “horizontal” strategies in NSCLC providing very durable clinical responses with dual EGFr/VEGFr and clinical response for dual EGFr/mTOR salvage following single agent EGFr-TKI failure. By expanding beyond current FDA-approved drugs into the new agents that target PI3K, AKT, TORC1&2, MEK/ERK and c-MET, the EVA/PCD™ can facilitate developmental therapeutics. Analyses are now examining the activity and synergy of EGFr-TKIs with VEGF, mTOR, MEK/ERK, PI3K, AKT and c-MET inhibitors in NSCLC and other diseases as will be reported. Supported in part by a research grant from Biophysica, Ltd, the Vanguard Cancer Foundation and The Nagourney Institute.
Pathways of angiogenic resistance in glioblastoma: Adaptations in growth factor signaling in response to VEGF and HGF attenuation
Authors: Graves Christian A. , Camphausen Kevin 
Published: May 2015

Abstract
Background: Glioblastoma is the most common and lethal central nervous system malignancy with a median survival often less than 18 months. Despite promising initial responses to anti-angiogenic therapies many patients with this disease develop resistance to treatment via poorly understood mechanisms. Here we demonstrate that glioblastoma cell lines grown under growth factor antagonizing conditions exhibit an altered phenotype with changes in growth factor signaling, gene expression as well as in vivo tumorigenesis.
Methods: U87 cells were cultured under constant pressure with bevacizumab (3.0 mg/mL), AMG102 (1.0 µg/mL), or a combination of both drugs long term (seven or more passages) in adherent culture. In vitro expression analysis was carried out by growth factor and receptor tyrosine kinase arrays, cDNA microarray, and ELISA. Intracranial xenograft studies demonstrated resultant differences in growth kinetics and survival.
Results: Hepatocyte growth factor (HGF), glial derived neurotrophic factor (GDNF), and platelet-derived growth factor AA (PDGFAA) were elevated at 5.3, 4.5, and 3.9 fold in combinatorially treated cells versus controls, respectively. These changes correlated with relative increases in corresponding receptor mRNA and protein expression. Furthermore, AMG102 and combinatorially pressured cells were highly tumorigenic as compared to control and bevacizumab treated cells in vivo (Median survival 10 ± 1 vs. 32 ± 2 days, respectively).
Conclusion: Herein we describe concomitant increases of various oncogenic growth factors which might potentiate tumor survival and therapeutic resistance. These results suggest several potential molecular bypass mechanisms facing proposed angiogenic strategies. Evaluation of resistant phenotypes provides insight on the adaptive complexity of glioblastoma and offers potential for targeting recurrent disease.
Early detection of colorectal cancer from patient blood plasma using microRNA-based q-rt-PCR
Authors: Nielsen Søren J. , Jacobsen Nana , Fog Jacob U. , Willenbrock Hanni , Baker Adam , Blondal Thorarinn , Vincent Martin , Oerntoft Torben , Nielsen Hans Joergen , Christensen Ib J. , Andersen Claus L. , Møller Søren , Stenvang Jan , Brünner Nils 
Published: May 2015

Abstract
microRNAs (miRNAs) constitute a recently discovered class of small RNAs (typically 21-23 nt) that function as post-transcriptional regulators of gene expression. Current estimates indicate that more than one third of the cellular transcriptome is regulated by miRNAs, and that each miRNA potentially regulates hundreds of different mRNAs. As a consequence, miRNAs have been proposed to be master regulators of cellular state. This hypothesis has been borne out by a large number of studies demonstrating a causal link between miRNA dys-regulation and numerous disease states, including a diverse array of human cancers. Furthermore, the high stability of miRNA in common clinical source materials (e.g. FFPE blocks, plasma, serum, urine, saliva, etc.) and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNA quantification as a promising new tool for a wide range of diagnostic applications.
Colorectal cancer (CRC) ranks 4th in terms of prevalence and second in numbers of deaths among cancers of the western world. Although early detection of CRC leads to a favorable prognosis, and though CRC can easily be detected in the locally restricted state using a variety of diagnostic procedures, frequent late diagnosis means that CRC is still a leading cause of cancer mortality worldwide. Current procedures suffer from one or more disadvantages within areas such as cost, safety, inconvenience to the patient with the consequence of low compliance, lack of trained personnel, sensitivity etc, thereby precluding their adoption as a population screening tool. There is therefore an unmet need for a generally acceptable CRC screening assay.
To facilitate discovery and clinical transfer of miRNA-based diagnostic markers, we developed a genome-wide LNA™-based miRNA q-rt-PCR platform with unparalleled sensitivity and robustness. The platform uses a single RT reaction to profile &gt;700 human miRNAs from 2 predefined 384 well plates and thus allows high-throughput profiling of miRNAs from important clinical sources without the need for pre-amplification. Using this system, we have profiled a large number of plasma samples from localized and regional CRC patients, and from matched healthy controls. An extensive QC system has been implemented in order to secure technical excellence and reveal any unwanted bias in the dataset. We will present our approaches to data normalization and the results of signature development using linear classification methods. We show that we can detect the majority of cancer cases with good specificity, using a cross-validation approach. In summary, our results show that minimally invasive early detection of CRC using a clinically viable approach is feasible.
Using SELDI-TOF MS to identify serum biomarkers in NSCLC
Authors: Baykara Onur , Buyru Nur , Ulutin Turgut , Dalay Nejat 
Published: May 2015

Abstract
Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide with poor differential diagnosis of the disease and with low response rates to standard chemotherapy. Individuals classified as Stage I by the present clinical-based scoring system may display survival characteristics ranging from 10 to 90 %. Identification of reliable biomarkers to detect NSCLC at early stages is therefore a subject of extensive research.
Surface-enhanced laser-desorption-ionization time-of-flight mass spectrophotometry (SELDI-TOF-MS) combines chromatographic surfaces with solid-state TOF-MS for the high throughput analysis of proteins in diverse clinical samples such as serum, urine, cerebrospinal fluids and has overcome the limitations of earlier proteomic approaches. The method has been widely used for biomarker discovery. Therefore, in this study we used the SELDI-TOF protein Chip system to achieve a stratification based on the protein expression profile and to identify differentially expressed proteins in sera from 50 patients with NSCLC and 50 healthy controls. IMAC 30-Cu protein chips were used to fractionate the proteins according to their metal binding affinity. The arrays were analyzed using the Ciphergen Protein Chip Reader PB IIa. The spectra were normalized to the total ion current of the mass to charge between 3000 — 10 000 Da. Protein peak clustering and classification analysis were performed using the Express 3.0 Biomarker Pattern Analysis Software.
Several proteins with masses ranging from 2000-20000 Da were differentially expressed between NSCLC patients and healthy controls. Among the peak clusters revealing differences we selected two specific clusters as prospective candidate biomarkers in sera of the patients. High expression of one peak and underexpression of the other with respect to the healthy control sera were evaluated in a blind test in terms of the ability to classify a separate group of patients and controls.
Phosphorylation and novel mutations of β-catenin in colon tumors
Authors: Dalay Nejat , Akisik Elif , Yamaner Sumer , Bugra Dursun 
Published: May 2015

Abstract
A significant proportion of colon tumors have defects in the Wnt signaling pathway indicating that wnt signaling plays a major role in carcinogenesis. Mutations and aberrations in this pathway may result in constitutive activation. The β-catenin molecule is a key component of this pathway and in absence of wnt signaling the cellular β—catenin level is kept low through degradation of the protein. Disruption of the β-catenin regulation plays a critical rol ein tumor development. Four critical serine/threonine residues on the protein form the recognition site for the proteasomic degradation complex. Sequential phosphorylation of β —catenin at these sites regulates the degradation rate of the protein. Mutations in this region may block phosphorylation and the mutant protein can escape from destruction. In the present study we investigated β—catenin expression and phosphorylation of the protein at the Ser33, Ser37, Thr 41 and Ser45 sites in tumors and matched normal tissue samples from 77 patients with colon cancer. β—catenin protein expression and and phosphorylation were analyzed by Western Blotting. The phospho-β—catenin expressing SW 480 cell line was used as the normal control. β—catenin protein expression was higher in tumor tissue in % 57.1 of the patients but the difference was not significant. Likewise, no significant difference was observed between phosphorylation levels of the different sites in the tumor and normal tissue. However, phosphorylation of the Ser 33/37/Thr41 and the Ser45 sites were significantly correlated.
In the samples displaying differences in phosphorylation between the tumor and the corresponding normal tissue samples the β—catenin gene was analyzed for mutations. We observed a single nucleotide change which has not been described previously in three (5.8 %) patients. This mutation results from a A G transition and leads to the substitution of glutamic acid by lysine. DNA from matched normal colon tissue and peripheral blood of the patients was also analyzed. In none of the patients the mutation was present in the somatic cells.
Our data indicate that among the molecular alterations affecting the β—catenin molecule mutations rather than phosphorylation of the protein play a major role. Although not described so far, the mutation presented in this study may constitute a more common variant than some of the previously reported alterations.
CR-UK biomarker roadmaps
Authors: Lioumi Maria , Newell David 
Published: May 2015

Abstract
A clear consensus is developing in all organizations involved in cancer research and treatment — academic, commercial and governmental — that the effective management of the cancer problem will require a move towards personalized medicine, based on the use of targeted therapies guided by the results of biomarker studies.
Recognizing the importance of biomarkers, Cancer Research UK (CR-UK) undertook a strategic Review in Biomarkers in 2008. A major finding was that there is currently no well defined structure or common terminology for the biomarker development process as, for example, there is for the development of a new drug. Thus despite increasing investment in basic research to identify potential biomarkers and a demonstrable enthusiasm from clinicians for access to new biomarkers, the number of biomarkers that have been delivered into clinical practice is very small. As a result, the priority recommendation arising from the review was that “Working with national and international academic and commercial partners, CR-UK should develop a pathway and roadmap for biomarker and imaging discovery and development research.” CR-UK has developed biomarker roadmaps for risk/predisposition, diagnostic, prognostic and predictive, and pharmacological biomarkers. These roadmaps describe the process from initial biomarker discovery, assay development, initial correlation to clinical outcome and clinical qualification.
A novel method for mutation analyses using genomic DNA obtained from IHC-stained sections
Authors: Desai Rupal , Amler Lukas , Patel Rajesh , Stern Howard , Raja Rajiv 
Published: May 2015

Abstract
Biopsies obtained from patients are often limited in size. The ability to perform multiple diagnostic assays is dependent on the quantity and quality of tissue samples available from patients. Over the last few years, our laboratory has focused our efforts on developing novel methodologies for increased efficiency in use of tissue samples. Here we describe a method for performing immunohistochemistry (IHC) and genotyping using the same tissue section. We isolated genomic DNA (gDNA) from IHC-stained and unstained formalin-fixed paraffin-embedded (FFPE) tissue sections obtained from the same paraffin block. Quality and quantity of gDNA obtained from either section were compared. We demonstrate that quality of gDNA obtained is acceptable for down-stream analysis using PCR techniques. We also show comparable specificity and sensitivity in detecting mutations using either sources of gDNA. This method has proven highly valuable in performing mutation analysis in certain tissue types such as lung cancer where tissue can be extremely limited.