bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meta-analysis of cancer cell lines genomes based on their response to ttfields.
Authors: Giladi Moshe , Wasserman Yoram , Schneiderman Rosa S. , Porat Yaara , Munster Mijal , Weinberg Uri , Kirson Eilon David , Palti Yoram 
Published: March 2020

e22125 Background: Tumor Treating Fields (TTFields) therapy is an established anti-mitotic treatment modality. The inhibitory effect of TTFields was demonstrated in numerous cancer cell lines with some cell lines exhibiting higher treatment sensitivity than others. The goal of the present study is to compare genomic characteristics of cell lines based on their response pattern to TTFields. Methods: Fifteen different human cancerous cell lines were treated using TTFields at their optimal frequency with the same nominal intensity (1.8 V/cm). The distribution of the response to TTFields was found to be bimodal with inhibitions of 30-40% and 50-60% compared to controls. Cell lines were divided into regular and high sensitivity groups according to their response to TTFields. Both groups were characterized based upon the distribution of mutated genes using the Cancer Cell Line Encyclopedia (CCLE) database. Results: Based on the distribution of mutated genes we identified 1 gene with significantly higher probability (P=0.017) to be present in the regular than the high sensitivity group. This gene (NEK3) is a never-in-mitosis (NIMA) related kinase 3 responsible for deacetylation of microtubules. In addition, 2 genes were found with significantly higher probability (P<0.05) to be present in the high- than the regular sensitivity group; ASPH, an aspartate beta-hydroxylase involved in negative regulation of cell proliferation through modulation of calcium homeostasis and TEC, a protein tyrosine kinase involved in immunological signaling pathways. Conclusions: The possible involvement of NEK3 mutations in determining sensitivity to TTFields is interesting in view of the known interference of TTFields with spindle microtubule assembly. ASPH mutations could release cells from negative regulation of proliferation, increasing their replication rate, and thus increasing their sensitivity to TTFields. In order to further test this hypothesis, a comparison of the effect of TTFields needs to be performed on wild type and knockout cell lines for these genes. A comparison of the mutation of these genes in tissue samples from patients whose tumors show high sensitivity to TTFields, may lead to a personalized approach to the use of TTFields clinically.
Ratios between VEGF ligands and receptors in tumor and stroma have impact on the outcome in resectable NSCLC.
Authors: Jantus-Lewintre Eloisa , Usó Marta , Sanmartin Elena , Gallach Sandra , Sirera Rafael , Blasco Ana , Hernando Cristina , Martinez Nieves , Figueroa Santiago , Casimiro Enrique , Camps Carlos 
Published: March 2020

e22147 Background: In tumor angiogenesis there is a complex interplay between endothelial, stromal and tumor cells. Some key regulators of this process are the members of the vascular endothelial growth factor (VEGF) family of ligands and receptors and the neuropilins (NRP). This study analyzes the correlations between the expression of these angiogenic factors in tumor cells and tumor stroma, and their prognostic role in tissue samples from resected non-small cell lung cancer (NSCLC) patients. Methods: Representative tumor and stroma areas from FFPE tissue samples of 125 early-stage NSCLC patients were carefully micro-dissected. RNA isolated from the samples was retrotranscripted and preamplified. RTqPCR was performed using hydrolysis probes (TaqMan, Applied Biosystems) and relative quantification was calculated using GAPDH and CDKN1B as endogenous controls. Results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p<0.05. Results: Paired Wilcoxon test revealed differences between tumor and stroma gene expression for VEGFB (p<0.0001), VEGFC (p<0.0001), VEGFR-1 (p<0.0001), VEGFR-2 (p=0.020), VEGFR-3 (p< 0.0001), NRP-1 (p=0.001) and NRP-2 (p< 0.0001). Survival analyses showed that those patients with higher levels of the Ratio Stromal-VEGFA/ Tumoral-VEGFR-2 had worse time to progression (TTP) (median 26.23 months vs NR, p=0.013) and overall survival (OS) (median 29.50 months vs NR, p=0.001). Similarly, those patients with higher levels of the Ratio Stromal-VEGFC/Tumoral-VEGFR-3 had worse TTP (median 23.30 vs 70.53 months, p=0.015) and OS (median 37.20 months vs NR, p=0.023). Conclusions: Our results show significant differences in the expression of VEGF family members between tumor and stromal cells. This may indicate the importance of the tumor-stroma interaction when trying to understand the angiogenic process. Furthermore, the combination of the ligands expression in stroma and their receptors in tumor may have a prognostic value in NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.
Genetic variation in CYP19A1 and occurrence of adverse events in exemestane treatment with early breast cancer patients in the Dutch TEAM trial.
Authors: Houtsma Danny , Fontein Duveken , van der Straaten Tahar , Baak-Pablo Renee , Wessels Judith A.M. , Seynaeve Caroline , Van De Velde Cornelis J. H. , Nortier J. W. R. , Gelderblom Hans , Guchelaar Henk-jan 
Published: March 2020

e22152 Background: Aromatase inhibitors (AI) are an important part of treatment of endocrine sensitive breast cancer. Adverse events in patients treated with AI’s often cause treatment discontinuation. The most common adverse events, such as arthralgia, myalgia and hot flushes are probably caused by estrogen deprivation and predict treatment efficacy. It is unclear which patients are at risk to develop these adverse events. The aim of this study was to examine if SNP’s in the CYP19A1 gene can predict the occurrence of adverse events in breast cancer patients treated with adjuvant exemestane. Methods: Patients of whom tissue was available and were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial. DNA was isolated from tumor samples and 30 SNPs were identified using a tagging SNP approach, aiming for 80% coverage of CYP19A1. Genotypes were determined with taqman assays. Primary endpoint of the study was the occurrence of adverse events. Secondary endpoints were the occurrence of hot flushes, arthralgia, and myalgia. Results: 807 patients were included in the analyses and genotypes were obtained in 722 cases. One SNP, rs8031311, was associated with a higher incidence of adverse events with an odds ratio of 2.8. Four SNP's were associated with an increased incidence of hot flushes: rs934635, rs4775928, rs16964189, rs6493496 with odds ratio’s of 2.9, 1.8, 1.8 and 2.6 respectively. No association was found between variation in CYP19A1 and the occurrence of arthralgia or myalgia. Conclusions: Germline variation in the CYP19A1 gene is related to the occurrence of adverse events, specifically hot flushes, in early breast cancer patients treated with exemestane. These findings may contribute to the individualization of hormonal therapy in breast cancer. [Table: see text]
Association between the founder brazilian TP53 p.R337H mutation and HER2-positive status.
Authors: Giacomazzi Juliana , Graudenz Marcia S. , Osorio Cynthia ABT , Koehler-Santos Patricia , Palmero Edenir Inez , Michelli Rodrigo Augusto Depieri , Fernandes Gabriela Carvalho , Scapulatempo Neto Cristovam , Achatz Maria Isabel Waddington , Martel-Planche Ghyslaine , Soares Fernando A , Caleffi Maira , Goldim Jose Roberto , Hainaut Pierre , Camey Suzi Alves , Ashton-Prolla Patricia 
Published: March 2020

e22154 Background: Recent studies in North American and British series have suggested an association between germline TP53 mutations and early onset HER2-positive breast cancer (BC). Mutations in the TP53 gene are estimated to occur in 1:2,000-1:5,000 individuals of the general population. Among women with BC who are unselected for family history they occur in up to 0.25%. In women with early-onset BC (<30 years) they occur in up to 7%. A specific germline TP53 mutation (c.1010G>A; p.R337H) has been encountered in 0.3% of the general population, in 13.3% of Li-Fraumeni-like families and in 0.5-2.4% of BC-affected women in Brazil. In an exploratory approach, the aim of this study was to investigate, in our series, if there is an association between human epidermal growth factor receptor 2 (HER2) amplification and the germline TP53 p.R337H mutation in a series of BC-affected women. Methods: A series of 718 Brazilian BC-affected women was genotyped in our previous study and 64 (8.9%) were mutation carriers. These cases were recruited from 3 centers and HER2 analysis was performed by immunohistochemistry (IHC) in each center according to validated protocols. Statistical analysis was done using SPSS software. Results: In 47 of 64 mutation carriers (73.5%), BC showed HER expression (either 1+, 2+ or 3+) while among 654 non-carriers, this immunophenotype was observed in 320 (48.9%) (p<0.001). This pattern was still observed after stratification of groups according to age at diagnosis (≤45 and ≥55 years) (p<0.001 and 0.03, respectively) and was independent of recruiting center. Conclusions: These results indicate that BC developing on a background of the founder Brazilian TP53 p.R337H mutation shows more frequently some amplification of HER2, consistent with recent studies showing an association between germline TP53 mutations and BC with HER2 hyperexpression. These findings should be confirmed in larger series to understand the significance of the association. If confirmed, this finding may justify germline TP53 p.R337H mutation testing in all HER2-positive Brazilian BC patients and would have a significant impact on patient and family counseling as well as on treatment.
A score based in toll-like receptors expression to predict prognostic in molecular subtypes of breast cancer treated with neoadjuvant chemotherapy (NAC).
Authors: Pinto Joseph A. , Flores Claudio J. , Valdiviezo Priscila I. , Velazco Rodolfo , Garay MIguel , Suazo Juan F. , Aguilar Alfredo , Gomez Henry , Vallejos Carlos S. 
Published: March 2020

e22165 Background: To evaluate toll-like receptors (TLRs1-9) and IRAK 1,3 and 4 expression in a breast cancer patients dataset that were treated with NAC as prognostic factors in terms of recurrence-free survival (RFS). Methods: Weretrieved normalized gene expression data from a public database (GEO: GSE25066) that includes 253 samples of breast cancer patients treated with NAC (antracyclines/taxanes) profiled with the U133A microarray. The median of RFS was 3.2 years (52 relapses observed). Distribution of molecular subtypes was: Luminal A (31.2%), Luminal B (17.4%), HER2 (7.1%), Basal (36.4%) and Normal (7.9%). We build a ratio of target gene/reference gen (ATCB) with to obtain replicable cut-points in other datasets. Levels of Gene expression were divided in three cut-points (Q1, Q2, and Q3). A cox-model was used to select gene expression cut-points with significant effects in the RFS. Results: According to molecular subtypes, there were significant differences in expression of TLR5 (higher in basal and Luminal A), TLR6 and IRAK1 (higher in basal and HER2). There were not differences of expression according to the pathologic response. The multivariate analysis shown that genes associated with the RFS were: TLR5 (HR=2.1 for the lower quartile), TLR6 (HR=2.4 for upper Q2), IRAK1 (HR=2.0 for upper quartile) and IRAK 3 (HR=2.2 for upper Q2). A TLR-Score was constructed (1 point added for each unfavorable gene-group). Cases were grouped in two categories (score 0-1 as good prognostic and score ≥ 2 as poor prognostic). There were and overall significant differences in both score-groups (poor prognostic: HR=4.9). In Basal and luminal B tumors there were significant differences (logrank test: P<0.001 and P=0.014, respectively), in HER2 tumors there were differences although not significant (P=0.143). There were not differences in Luminal A tumors. Conclusions: These data support the exploration of a TLR expression-based score to predict for RFS in breast cancer treated with NAC.
Feasibility study of SNPs detection associated with breast cancer by genome-wide association virtual studies.
Authors: Kooshyar Mohammad Mehdi , Nassiri Mohammadreza , Aslaminezad Aliasghar , Betaraf Morteza 
Published: March 2020

e22167 Background: Available genomic data and genome-wide association virtual studies (GWAS), provide possibility of genetic markers detection known to be associated with the complex diseases. Genome-wide association studies, involving direct testing of genetic polymorphisms in large series of disease cases versus controls, provide a powerful approach to identify lower penetrance alleles that cannot be detected by genetic linkage studies. Methods: By utilizing genotyping platforms that can type hundreds of thousands of SNPs simultaneously, it is possible to conduct association studies using sets of SNPs that tag most known common variants in the genome, and hence scan associations without prior knowledge of function or position. GWAS have been conducted in five of the most common cancer types: breast, prostate, colorectal, lung and melanoma. GWAS of breast cancer was performed by simulation of 7 known SNPs on chromosomes 2, 5, 6, 8, 10, 11 and 16 for 10,000 women. Results: The strongest associations were found for rs2981582 in the FGFR2 gene. SNPs: rs889312 ° rs2180341 and rs3817198 were associated with breast cancer in benferroni significant level. However, SNPs: rs 13387042 ° rs2180341 and rs13281615 on chromosomes 2, 6 and 8 were not associated with breast. Conclusions: Results of this research show that the detection of SNPs associated with disease is easily possible through employing virtual systems based on real data of Hap Map project by using R software.
Galectin-3: A possible complementary marker to the PSA blood test.
Authors: Raz Avraham , Balan Vitaly , Wang Yi , Nangia-Makker Pratima , Kho Dhonghyo , Heilbrun Lance K. , Bajaj Madhuri , Smith Daryn W. , Heath Elisabeth I. 
Published: March 2020

e22168 Background: The prostate-specific antigen (PSA) is a test widely used to detect, monitor, and predict the biology of prostate cancer (PCa). Galectin-3 (Gal-3) is a carbohydrate-binding protein and is present in the seminal fluid. It is a tumor-associated protein, which plays a role in metastasis, apoptosis, and tumor growth. We recently reported that PSA cleaves Gal-3. Cleavage status of Gal-3 in the prostate tissue might be associated with the tumor formation and progression of PCa. Therefore, we compared Gal-3 levels in the blood of non-cancer urology patients and metastatic PCa patients. Methods: Non-cancer and metastatic PCa patients were recruited from the genitourinary oncology clinics. Sixteen men (8 PCa patients and 8 controls) were recruited during their clinic visit from May to August 2012. The metastatic PCa patients could be either castrate-sensitive or castrate-resistant. The control patients could not have any history of invasive cancer. A blood sample was collected from each study patient. Levels of Gal-3 were analyzed by Western blot and ELISA. The study design was a small, prospective, single institution pre-pilot study. The primary statistical endpoint was the mean level of serum galectin-3. Within each of the two groups of patients, it was desired to estimate the mean Gal-3 level to within 0.50 standard deviations (SD’s) of the true mean, with 80% confidence. This study design required N=8 men per group. Results: The cancer-free control patients had lower levels of serum Gal-3 than did any of the 8 PCa patients (see Table). These results suggest that serum Gal-3 levels in metastatic PCa patients and cancer-free controls are quite different. The serum PSA distributions of these 2 patient groups overlap slightly, hence PSA did not distinguish them quite as well as did Gal-3. Conclusions: This is the first report to show serum Gal-3concentrations were uniformly higher in patients with metastatic PCa as compared to non-cancer control patients. [Table: see text]
Observational study of real world clinical performance of microrna molecular profiling for cancer of unknown primary (CUP).
Authors: Sanden Mats Olot , Wassman Robert , Ashkenazi Karin , Benjamin Hila , Spector Yael , Goren Eran 
Published: March 2020

e22173 Background: Molecular profiling of CUP may effectively identify the underlying tumor type and potentially influence treatment decisions and outcomes. A microRNA (miR) array has been shown in concordance studies at leading academic centers to perform well in correctly identifying the tumor of origin in CUP. This series of consecutive referrals tested in a CLIA-laboratory extends these findings to the real world clinical setting. Methods: MicroRNA was isolated from 258 consecutive specimens referred to Rosetta Genomics, analyzed on a 64 miR-based array, and interpreted for any of 42 specific tumor types as previously described. The laboratory medical director routinely collected follow-up information on correlation of test prediction with other clinical information, pathology findings, supplemental IHC, treatment response, and clinical course as well as physician perception of relevance and utility of test result. This information was scored categorically into 3 classes of concordance depending on agreement with clinical and/or pathological data. The composite data was de-identified and analyzed for assessment of overall test performance in this real world clinical setting. Results: Of 258 specimens submitted 90% were paraffin embedded tissue (FFPE). Sufficient tumor material was received in 217 (85%) cases, of which 192 (88%) were successfully processed and reported with a mean TAT of 7 days. The most common result was colorectal (12%), followed by breast (10.4%), upper body squamous cell (7.3%), ovarian (6.8%), and biliary tract/pancreatic (6.8%); and the remaining 109 cases (57%) represented 30 additional tumor types. Overall the concordance with the clinical and/or pathological best final diagnosis was 86%, and when the reporting algorithm yielded a single diagnosis (51% of cases) the concordance was 89%. Clinical utility as measured by consideration of a shift in therapy or significantly increased decisional certainty for therapy was observed in approximately 70% of the cases. Conclusions: MicroRNA analysis in CUP cases performs comparably in the real world setting to that previously reported in academic studies and adds information of value to the management of patients.
Evaluating the prognostic significance of JAK2 in distant breast cancer recurrence.
Authors: Blau Carl Anthony , Miller Christopher P. , Kortum Amanda N. , Thorpe Jason D. , Schummer Michel , O'Briant Kathy , Coy Catherine M. , Beatty J David , Urban Nicole D. 
Published: March 2020

e22178 Background: Estrogen, progesterone, and epidermal growth factor receptor ligands stimulate growth in a subset of breast cancers, however recent studies suggest roles for additional factors such as interleukins-6 and 8, prolactin, and erythropoietin. These and other growth factors act upon ligand-specific receptors to activate janus kinase 2 (JAK2), and JAK2 inhibitors are under investigation as a novel targeted therapy. We tested whether erythropoietin receptor (EPOR) or JAK2 mRNA levels are associated with distant breast cancer recurrence. Methods: We used quantitative RT-PCR to measure mRNA levels of JAK2, EPOR and a series of control genes using archival tumors from 112 women who experienced distant breast cancer recurrence (cases) and 112 tumors from women who did not (controls). Cases and controls were matched for tumor size, lymphovascular invasion, nodal status, extra-nodal extension, and ER/PR/HER2. Recurrence risks were evaluated using logistic regression. Associations between mRNA levels (via microarray data) and recurrence-free survival were validated in an independent cohort from the Netherlands Cancer Institute (n=295) using Cox proportional hazards regression. Results: Increasing JAK2 mRNA levels strongly correlated with a reduced risk of distant recurrence in our case control study (univariate p=0.0004, multivariate p=0.003), and with improved recurrence-free survival in the validation cohort (univariate p=0.0009; multivariate p=0.003). Remarkably, in the validation cohort, the ranking of the prognostic significance of JAK2 (top 3.5% of ~25,000 genes) was comparable to the known strong prognostic indicator of recurrence, ESR1 (top 1.3%). Similarly although less prominently, increasing EPORmRNA levels were significantly associated with reduced distant recurrence in our case control study (continuous model: univariate p=0.01, multivariate p=0.05) and with improved recurrence free survival in the validation cohort in univariate (p=0.03) but not multivariate analysis (p=0.35). Conclusions: JAK2 mRNA levels in breast tumors correlate with a reduced risk of recurrence. Understanding the mechanistic basis for this association is important for the rational application of JAK2 inhibitors.
Elimination of both cancer stem cells and progenitor cells as essential for tumor eradication.
Authors: Marak Creticus Petrov , Guddati Achuta Kumar 
Published: March 2020

e22179 Background: Cancer stem cells (CSC) have been identified in several malignancies. Elimination of CSCs requires precise identification of markers and development of mechanisms to target them specifically. It is possible that in spite of elimination of CSCs, the tumor may recur. Dedifferentiation of progenitor cells may help replenish cancer stem cells. Methods: A mathematical model of a cancer stem cell system with four layers has been constructed to reflect the hierarchy of cancer stem cells, progenitor cells and, transit-amplifying cells and pre-differentiated cells. This model is constructed in the lines of the phase space model described by Kirkland. Dedifferentiation parameters were introduced to allow for dedifferentiation when the stem cell pool receded below 40% of its normal size. The effects of stem cell antagonists (SCA) and differentiating agents (DA) were simulated to study the perturbations caused by them on the growth of the tumor. Results: SCAs when used alone result in the establishment of a new equilibrium across different layers within the tumor by de-differentiation. DAs which act only on progenitor cells cause an increase in the number of cells in the subsequent layers and contribute to an increase in the size of the tumor. DAs which act only on the pre-differentiated layer of cells move cells from this layer into a terminally differentiated layer of cells which results in a new but lower equilibrium. DAs which act on the progenitor, transit amplifying and pre-differentiated cells cause the establishment of a new equilibrium which is lower than that of all agents which act on individual layers of cells. A combination of an SCA and a DA which acts on multiple layers eliminates the re-establishment of a new equilibrium and leads to decline in cell populations in all the layers, thus reducing the possibility of recurrence. Conclusions: SCAs when used individually are not effective in eliminating the tumor. DAs which act only on progenitor cells can fuel tumor growth but DAs which act on multiple layers have a profound effect in slowing the growth of the tumor but do not eliminate the tumor. This model implies that a combination of an SCA and a DA which acts on multiple layers may have a better chance at eliminating the tumor.