bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mammary adipose tissue and cancer cell growth: The role of adipose tissue in the tumor microenvironment
Authors: Carroll P. A. , Healy L. , Lysaght J. , Griffin M. , Dunne B. , Boyle Mr. T. , Reynolds J. V. , Kennedy M. J. , Pidgeon G. , Connolly E. M. 
Published: August 2020

e22009 Background: Worldwide, the prevalence of obesity is rapidly increasing, correlating with a direct increase in cancer rates1. Adipose tissue is considered an important endocrine organ producing several important hormones and cytokines including leptin and adiponectin. Mechanisms for the role of obesity in cancer states includes the excess or unregulated secretion of adipocytokines from adipose tissue, and potentially the metabolic syndrome (a cluster of co-morbidities linked to metabolic dysregulation). Mammary adipose tissue is proposed to play a vital role in the microenvironment of normal and tumour states within the breast2. Breast adipose tissue is a good candidate to investigate effects of obesity and metabolic disturbances on cancer states. Methods: Peritumoural (PT) adipose tissue adjacent to the tumour and distal adipose tissue (D) within the breast was sampled in 10 patients. The tissue was processed and cultured for 72hrs in serum free minimal cytokine media. A-MB-231 and MCF-7 breast cancer cell lines were then cultured with this adipocyte conditioned media (ACM) and cell proliferation response was then measured using BrDU assays. The adipocytokine profile at the mRNA and protein level was measured in ACM and adipose tissue for comparative differences using RT-PCR, ELISA and Cytokine Profiler technology. Results: ACM from both sites promoted tumour cell survival. There was however, a differential cell proliferation response noted between the peritumoural (PT) ACM and that from the distant (D) ACM. Pro-inflammatory mediators (VEGF, TNF-α, EGF) were also demonstrated a trend to be differentially expressed between the 2 sites. Conclusions: Proliferation of breast cancer cell lines occurs in response to ACM, with differential effects seen between peritumoural ACM and distant ACM. This may be mediated through increased pro-inflammatory or pro- mitogenic adipocytokine production in adipose tissue surrounding tumour. Further analysis will determine what role obesity and the metabolic syndrome plays in the results noted. No significant financial relationships to disclose.
HIF expression and Max-SUV-18F-FDG-PET in non-small cell lung cancer (NSCLC) patients
Authors: Lopez R. , Gallardo E. , Ruibal A. , Leon L. , Sanchez-Salmon A. , Abdulkader I. , Gude F. , Curiel T. , Barandela J. , Gayoso L. 
Published: August 2020

e22010 Background: Tumor hipoxia induces the up-regulation of several genes via the hipoxia-inducible transcription factors (HIF) 1 and 2. HIF-2 alpha (HIF-2 α) and HIF-1 alpha (HIF-1α) are associated with the prognosis of operable NSCLC patients. We studied the immunohistochemical expression of HIF-1α and HIF-2 α in patients with NSCLC and the possible correlation with the maximum standardised uptake value (max SUV) of 18F-FDG as well as other biological parameters. Methods: We used a Tissue Arrayer device (Beecher Instruments. WI) to construct a TMA block, according to conventional protocols for the study of immunohistochemical expression of HIF-1α, HIF-2 α, EGFR, bcl-2, MIB1, p16, p63 and cyclins A, B1, D1 and D3. Sections were scored as positive if >10% of cells stained positively. Staining patterns were correlated to clinical variables. Results: HIF- 1α expression was observed in 84/96 patients (34/39 adenocarcinomas and 50/57 squamous cell carcinomas), however it did not correlate with clinical stage (I-II: 41/45 vs III-IV: 44/51). HIF-1α correlated positively with HIF-2 α (p:0,001) and EGFR (p:<0,001) expressions. The maxSUV values of 18F-FDG-PET were higher (p:0,039) in HIF-1α -positive (17,1±8,6) than in negative tumors (11,8±4,4). HIF-2 α expression was observed in 60/103 cases (27/42 adenocarcinomas and 33/61 squamous cell carcinomas) and it did not correlate with clinical stage ((I-II: 28/45 vs III-IV: 32/57). HIF-2 α correlated positively with HIF-1α (p:0,001), MIB1 (p:0,045) and EGFR (p:0,091) expressions. After multivariate analysis, only the clinical stage (RR: 2,2) was a prognostic factor. Conclusions: 1) HIF-1α and HIF-2 α expressions are frequent in patients with NSCLCs and it did not correlate with clinical stage; 2) maxSUVs FDG-PET values were higher in HIF1alpha positive than in HIF-1α negative patients; 3) HIF-1α was correlated with EGFR expression, while HIF-2 α was correlated with MIB1 expression. No significant financial relationships to disclose.
The incidence of low-level HER2 gene amplification and chromosome 17 polysomy in cases of newly diagnosed breast cancer and their association with clinical prognostic markers
Authors: Diamond J. R. , Amaria R. , O'Donnell C. I. , Meltesen L. , Swisshelm K. , Melancon D. , McGavran L. , Singh M. , Elias A. , Borges V. F. 
Published: August 2020

e22012 Background: The purpose of this study is to describe the frequency of low level HER2 gene amplification and chromosome 17 polysomy, and its association with known clinical prognostic markers. Methods: We retrospectively reviewed all cases of newly diagnosed invasive breast cancer referred to the Colorado Cytogenetic laboratory for FISH testing from either the University of Colorado Breast Center or St. Mary's Hospital in Grand Junction, CO between October 2000 and May 2005, excluding patients treated with HER2-directed therapy. Cases were classified into positive for HER2 gene amplification (FISH ratio ≥ 2.2), negative for HER2 gene amplification (FISH ratio <1.8), or intermediate for HER2 gene amplification (FISH ratio of 1.8- 2.1 or presence of chromosome 17 polysomy). IRB approved chart review was performed . Results: Of the 177 patients referred for FISH testing during the study period, 27.7 % (49/177) had intermediate HER2 gene amplification as defined as a FISH ratio of 1.8–2.1 or chromosome 17 polysomy. There was a statistically significant increase in stage, lymph node involvement, and histologic grade at diagnosis in the intermediate HER2 group compared to negative controls ( Table ). Conclusions: The incidence of intermediate HER2 gene amplification is clinically significant and associated with higher histologic grade and stage at diagnosis compared to HER2 negative controls. This patient population should be investigated further for long term disease outcomes and impact of HER2 - based targeted therapy. [Table: see text] No significant financial relationships to disclose.
Investigation of HDAC inhibition targeting of BRCA1 expression as a mechanism to enhance platinum sensitivity in breast and ovarian cancer
Authors: Weberpals J. I. , O'Brien A. , Garbuio K. , Clark-Knowles K. , Dimitroulakos J. 
Published: August 2020

e22017 Background: The improved outcome of Breast-Cancer 1 (BRCA1)-deficient breast and ovarian cancer may be linked to the impaired ability to repair double strand breaks caused by DNA-damaging chemotherapy (CTX), such as platinum compounds. Therapeutically relevant agents that target BRCA1 expression to sensitize tumors to platinum have not been identified. In this study, we explore the effect of histone deacetylase inhibition (HDACi) on platinum sensitivity and BRCA1 expression in a breast and ovarian cancer cell line model. Methods: The efficacy of HDACi to potentiate the cytotoxicity of platinum-based chemotherapeutics was evaluated in a range of breast and ovarian tumor cell lines using the MTT cell viability assay and confirmed by flow cytometry. BRCA1 mRNA and protein expression was determined by Q-PCR and Western blot, respectively. The effect on DNA damage was measured by immunofluorescence staining and flow cytometry for γH2A.X foci, a hallmark for the presence of DNA double strand breaks. Results: Baseline BRCA1 expression was variable in two ovarian (A2780s, cisplatin-sensitive and A2780cp, cisplatin-resistant) and four breast cancer cell lines (MCF7, T47D, BT549 and HCC1937) with minimal and absent protein expression in BT549 and HCC1937, respectively. The addition of the HDACi, M344 increased the sensitivity of cells to cisplatin and carboplatin treatment in those cell lines with significant BRCA1 levels. Expression of BRCA1 protein decreased in response to the addition of HDACi to platinum in all cell lines. BRCA1 mRNA levels decreased with the addition of HDACi to platinum in all breast cancer lines and in A2780cp. A2780s and MCF7 cells subjected to combination platinum and HDACi treatment demonstrated increased levels of DNA damage, as assessed by the presence of phosphorylated γH2A.X foci. Conclusions: This study supports a novel mechanism of HDAC inhibition to sensitize breast and ovarian cancer cells to platinum via inhibition of the DNA repair protein BRCA1. BRCA1 expression changes may represent a novel biomarker to assess the activity of this combinational therapeutic approach in clinical evaluations of breast and ovarian cancer patients. No significant financial relationships to disclose.
Expression profile of hepatic drug transporters in patients with hepatocellular carcinoma
Authors: Higuchi K. , Terada T. , Ogasawara K. , Aoki M. , Fukudo M. , Katsura T. , Hatano E. , Ikai I. , Inui K. 
Published: August 2020

e22026 Background: Hepatocellular carcinoma (HCC) does not respond sufficiently to chemotherapy. It has been demonstrated that several transporters can cause drug resistance in tumor cells. In human liver, various drug transporters are expressed and play pivotal roles in hepatic uptake and excretion of drugs. In HCC, the expression profile of hepatic drug transporters may be altered due to pathophysiological changes. However, limited data are available on their expression and regulation in HCC tissues. The aims of this study were to determine the expression levels of hepatic drug transporters in HCC patients and to identify transporter specifically regulated in HCC tissues. Methods: The mRNA expression levels of 17 drug transporters, including 9 solute carrier (SLC) transporters (OAT2, OAT7, OATP1B1, OATP1B3, OATP2B1, OCT1, OCTN2, MATE1 and PEPT1) and 8 ATP-binding cassette (ABC) transporters (R1, MRP1–6 and BCRP), were determined by real-time RT-PCR in cancerous and non-cancerous liver tissues from 57 patients with HCC. Protein expression level was evaluated by Western blot analysis. In addition, DNA methylation status in promoter region of transporter gene was analyzed using bisulfite sequencing. Results: The mRNA expression levels of 11 transporters (OAT7, OCTN2, MATE1, PEPT1, R1, MRP1–6) were significantly increased (1.45 to 4.74-fold, p<0.05) in HCC tissues compared with non-cancerous liver tissues, whereas only OCT1 mRNA was significantly decreased (0.61-fold, p=0.0004). Notably, MRP4 mRNA showed the highest increase, which was consistent with the marked augmentation in the protein level. The frequency of methylation in MRP4 promoter region was comparable between HCC and non-cancerous liver tissues, suggesting other mechanisms than DNA methylation for MRP4 up-regulation. Interestingly, the mRNA expression levels of MRP4 did not change with the differentiation of HCC. Conclusions: It was revealed that most of the hepatic drug transporters were elevated in HCC tissues. Furthermore, we first identified that MRP4 showed remarkable increase in protein as well as mRNA expression levels. These findings suggest that MRP4 is a novel candidate for diagnostic marker and a target molecule to reverse multidrug resistance in chemotherapy for HCC. No significant financial relationships to disclose.
Prognostic significance of serum vascular endothelial growth factor per platelet count in gastric cancer patients
Authors: Seo H. , Sung H. , Choi I. , Oh S. , Seo J. , Shin S. , Kim Y. , Park K. , Kim J. 
Published: August 2020

e22031 Background: Recent studies have shown that VEGF expression not in tissues but in serum sample is correlated with tumor vascularity, and high serum VEGF levels could predict poor prognosis in cancer patients. However there are limited data regarding the clinical and prognostic significance of serum VEGF levels per platelet count in advanced gastric cancer. In this study, we conducted a study to evaluate the prognostic implication of serum VEGF per platelet count in patients with advanced gastric cancer. Methods: 111 patients with histologically confirmed gastric cancer, 10 patients with early gastric cancer were included and control serum samples were acquired from 10 healthy volunteers. The levels of VEGF were measured using human VEGF quantitative enzyme-linked immunosorbent assay (ELISA). Survival curves were calculated using the Kaplan-Meier method and survival comparisons were made by the log rank test in metastatic gastric cancer. The Cox proportional hazards regression model was utilized for multivariate analyses after univariate analysis defined relevant prognostic variables. Results: A trend toward a significant positive correlation between serum VEGF and platelet counts was observed in patients of AGC (r = 0.477, P = 0.000) and there was a significant correlation between serum VEGF levels and differentiation of tumor (p = 0.014), stage (p = 0.036). The overall survival (log rank, p =0.0432) and the progression free survival (median 4.5 vs. 8.9 months; log rank, p =0.0116) were significantly shorter in patients with high VEGF per platelet count (≥1.626 pg/106). In the multivarivate analysis, performance status (P=0.025), the presence of peritoneal carcinomatosis (P=0.006), serum VEGF per platelet (P=0.005) were found to be significantly associated with poor progression free survival. Conclusions: This study demonstrated that serum VEGF per platelet count are correlated with poor overall survival and progression free survival in patients with advanced gastric cancer. Therefore measurement of serum VEGF per platelet might be useful markers for predicting disease progression and prognosis of advanced gastric cancer. No significant financial relationships to disclose.
Incomplete surgical resection of DCIS results in activation of HER-2 in residual breast cancer cells
Authors: Singer C. F. , Hudelist G. , Fuchs E. , Köstler W. , Fink-Retter A. , Gschwantler-Kaulich D. , Gnant M. , Lamm W. , Lamm W. , Rudas M. , Kubista E. 
Published: August 2020

e22035 Background: HER-2 amplification and consecutive overexpression is a predictor for poor prognosis in breast cancer patients. In addition, incomplete resection of HER2 overexpressing tumors leads to increased proliferation of residual breast cancer cells. While the local release of cytokines is thought to be responsible for the malignant behaviour of remaining tumor tissue, the exact mechanism is still unknown. Methods: We have analyzed EGFR, activated (p)EGFR, and activated (p)HER2 protein expression in HER2 overexpressing and in non-HER2 overexpressing tumors from patients who underwent breast surgery and consecutive reexcision for involved margins, and compared expression levels by IHC. Results: While overall HER2 protein expression in the initial and the reexcised sample were comparable, we observed an increase in pHER2 in DCIS in both, HER2 overexpressing (16/21 vs 24/24; p=0.018, Chi Square test) and non-HER2 overexpressing tumors (3/28 vs 5/12; p=0.025, Chi Square test). pHER2 was not increased in invasive tumors, regardless on whether the samples had been taken from a HER2 overexpressing (9/25 vs 6/17; p=0.261, Chi Square test), or a non-HER2 overexpressing tumor (1/27 vs 0/8; p=0.581, Chi Square test). EGFR expression was only detected in 1/47 HER2 overexpressing primary tumors and 2/48 non-HER2 overexpressing tumors, and was undetectable in reexcised specimen. Conclusions: Taken together, we have demonstrated an increase in HER2 receptor activation in incompletely resected preinvasive breast cancer. We hypothesize that receptor phosphorylation is caused by growth factor stimulation in response to intraoperative tissue damage, and perioperative inhibition of specific cytokines could become a promising therapeutic strategy. No significant financial relationships to disclose.
Molecular profiling in patients (pts) with upper gastrointestinal (UGI) cancers correlated with clinical outcome
Authors: Virk N. , Yang D. , Lenz H. J. , El-Khoueiry A. B. , Danenberg K. D. , Iqbal S. 
Published: August 2020

e22042 Background: Recent efforts have expanded our understanding of the molecular pathogenesis of UGI cancers and how oncogenes and tumor suppressor genes play a role in both carcinogenic and metastatic processes. These markers may serve as prognostic and/or predictive factors for recurrence following resection and resistance to radiotherapy and chemotherapy. Gene expression levels of thymidylate synthase (TS), thymidylate phosphorylase (TP), epidermal growth factor receptor (EGFR) and excision repair cross complementing (ERCC-1) have been shown to be associated with outcomes in lung, gastric and colon cancer. We evaluated TS, ERCC-1, EGFR and TP gene expression levels in patients with UGI cancers. Methods: This was a retrospective study of 80 pts with UGI cancers evaluated at USC who underwent molecular profiling. The primary objective was to determine a correlation between TS, TP, ERCC1 and EGFR and correlate with clinical outcome. Characteristics of these 80 pts: (16 females, 64 males ); median age 61 years (range 34–85); tumor types evaluated - 32 (40%) esophageal, 24(30%) gastric, 24(30%) GE junction; stages- 53 % IV, 21% III, 12% II, 2% I were evaluated for intratumoral gene expression of TS, TP, ERCC-1, & EGFR by real time quantitative PCR using Taqman technology from microdisected paraffin-embedded tumor sections. Results: High TS expression was associated with shorter OS (12.8 months vs. 23.7 months p=0.036). A significant correlation was found between TP & ERCC-1 (p=0.0078, r=0.37); TP & TS (p=0.0128, r=0.35); TP & EGFR (p=0.0065, r=0.39); TS & ERCC-1 (p=0.0004, r=0.39); ERCC-1 & EGFR (p=0.025, r=0.30). No statistically significant relationship was found between TS & EGFR (p=0.06,r=0.25). There was no correlation of ERCC-1, TP, & EGFR with OS that reached statistical significance. Conclusions: TS mRNA levels were shown to be associated with OS in UGI tumors, consistent with data reported in colon cancer. TS gene expression was significantly associated with expression levels of ERCC-1. In addition, ERCC1 was associated with EGFR. These data show for the first time that molecular pathways of cytotoxic agents are linked to the EGFR pathway suggesting that sensitivity to fluoropyrimidines, oxaliplatin, and EGFR inhibitors may be associated. No significant financial relationships to disclose.
The inducible cyclic adenosine 3’,5’-monophosphate early repressor (ICER) enhances drug sensitivity in acute myeloid leukemia
Authors: Pigazzi M. , Manara E. , Baron E. , Beghin A. , Basso G. 
Published: August 2020

e22045 Background: The Inducible Cyclic Adenosine 3’,5’-monophosphate early repressor (ICER) is a transcription factor that principally counteracts the cAMP response element binding protein (CREB) activity. CREB was previously demonstrated to be overexpressed in acute leukemia, whereas ICER was found rapidly degradated being unable to control gene transcription. ICER exogenous expression was demonstrated to repress CREB targets preventing leukemia progression. We hypothesized that ICER restoration deserves a special consideration for playing a role in CREB oncogenic feature and in modeling leukemic cell phenotype. Methods: We constructed an expression vector for ICER and induced its exogenous expression in HL60 cells (HL60+ICER). We monitored transcription and translation of a series of genes involved in different pathways by quantitative gene expression and western blot analysis. We investigate ICER's role in cell death after treatment with chemotherapic drugs. Results: We revealed that ICER was able to control gene expression in leukemia, principally of genes involved in cell death and survival. In particular, we focused on DUSP1 and DUSP4 phosphatases which were found significantly repressed. HL60+ICER after being treated with drugs increased apoptosis. Cell cycle analyses revealed a block in G2 phase, a lowered cell proliferation and clonogenic potential with respect to HL60 treated at the same conditions. DUSPs downstream targets (IL6, RB, RAS) were lowered expressed and p38 constitutively phosphorylated confirming their role in mediating cellular stress. ICER driven apoptosis was found to be caspases mediated. An enhanced activity of p38 was observed in treated HL60+ICER, and by the use of specific p38 inhibitors apoptosis decreased. Other possible apoptotic pathways (AKT, ERK, JNK) were excluded because found severely disrupted. Conclusions: Finally, we described an enhanced sensibility to drugs in HL60 induced by ICER exogenous expression and that p38 stress signaling pathway is the direct target of this phenomenon. The ability of ICER to modify leukemic cells phenotype respect to chemotherapeutic treatment gave an important information for targets and therapeutic possibilities. No significant financial relationships to disclose.
Gene set enrichment analysis to evaluate expression of autoantigens in lung cancer
Authors: Johnson K. , Berger A. , Watkins T. , Cheadle C. , Casciola-Rosen L. , Levine S. M. 
Published: August 2020

e22048 Background: There is a well-established association between certain autoimmune diseases and the development of specific malignancies. It has been demonstrated that myositis-specific autoantigens are expressed at higher levels in tumors associated with myositis compared to normal tissue, suggesting that immune responses to antigens expressed in nascent tumors may contribute to the autoimmune process. Whether this observation is a general feature of autoantigen expression in tumor tissue, and whether the relative expression of these antigens is enriched in relation to the rest of the tumor transcriptome is currently unknown. Methods: Tumor tissue from ten lung cancer biopsies (adenocarcinoma (4), carcinoid (4), and squamous cell carcinoma (2)) and normal lung from the same patients were obtained. Total RNA was extracted and hybridized to Illumina Sentrix BeadChips. Hiearchical clustering was used to visualize the expression levels of 146 known autoantigens. Gene Set Enrichment Analysis was performed using 20 disease-specific autoantigen gene sets and 1892 gene sets from the Molecular Signatures Database. Protein levels of selected autoantigens were assessed by immunoblotting detergent tissue lysates. Results: Single-linkage hierarchical clustering analysis reveals groups of autoantigens that are differentially expressed between normal lung tissue, carcinoid tumors, and adenocarcinomas. Adenocarcinoma tumor samples were significantly enriched for myositis (nominal p-value <0.001, false discovery rate (FDR) q-value 0.009) and SLE autoantigens (p-value 0.004, FDR 0.029). Scleroderma autoantigens were enriched in carcinoid tumors (p-value 0.003, FDR 0.053). Increased protein expression of the autoantigens Mi-2 and topoisomerase-1 in carcinoid tumors was confirmed by immunoblotting. Conclusions: This study reveals that autoantigens targeted in several autoimmune diseases are both transcribed and expressed at high levels in malignancies known to associate with those disorders. While autoantigens comprise only a small fraction of the total transcriptome, they are disproportionately expressed in tumors known to associate with autoimmunity, supporting the hyporthesis that autoimmunity to these proteins may arise via nascent anti-tumor responses. No significant financial relationships to disclose.