bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3976: Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy
Authors: Reid Glen , Williams Marissa , Kirschner Michaela B. , Mugridge Nancy , Weiss Jocelyn , Brahmbhatt Himanshu , MacDiarmid Jennifer , van Zandwijk Nico 
Published: August 2015

Abstract
MicroRNA expression is commonly suppressed in cancer, contributing to tumor cell biology. Recently we demonstrated that multiple members of the miR-15/16 family are downregulated and have tumor suppressor functions in malignant pleural mesothelioma (MPM), an asbestos-related cancer for which few treatments are available. These results are similar to previous findings in prostate and non-small cell lung cancer (NSCLC). Using mimics to restore levels of miR 15a, miR-15b or miR-16 led to growth inhibition and induction of apoptosis of MPM cells in vitro. The miR-16 mimic, packaged in bacterially-derived, EGFR antibody-targeted, EDV(TM)nanocells, inhibited xenograft tumor growth in vivo. As multiple microRNAs from the same family are downregulated in MPM, we investigated whether a single synthetic mimic based on the consensus sequence of all family members could restore activity of the entire family. To this end we generated four novel mimics derived from the consensus sequence of the miR-15/16 family and tested them in a range of tumor cell lines. Compared with a mimic corresponding in sequence to native miR-16, the consensus mimics had enhanced growth inhibitory activity in MPM, NSCLC and prostate cancer lines, three tumor types in which miR-15/16 expression is suppressed. They were also active in cell lines derived from breast and colon cancer. When packaged in minicells, the synthetic mimics inhibited growth of MPM xenograft tumors in vivo. Based on these preclinical studies a Phase I clinical trial has been initiated for patients with MPM or NSCLC failing standard therapy. This represents only the second trial of microRNA replacement as a cancer therapy, and the first for thoracic cancer.
Citation Format: Glen Reid, Marissa Williams, Michaela B. Kirschner, Nancy Mugridge, Jocelyn Weiss, Himanshu Brahmbhatt, Jennifer MacDiarmid, Nico van Zandwijk. Targeted delivery of a synthetic microRNA-based mimic as an approach to cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3976. doi:10.1158/1538-7445.AM2015-3976
Abstract 3980: Recurrence prediction model using microRNA expression in hormone receptor positive and tamoxifen treated breast cancer
Authors: Kim Aeree , Kim Chungyeul 
Published: August 2015

Abstract
Hormone receptor positive breast cancer patients have relatively good prognosis after tamoxifen treatment but still about 40% of patients experience treatment failure (1). Recently microRNAs (miRNAs) have been spotlighted as a new biomarker for predicting prognosis and treatment response. The purpose of this study is to identify microRNAs (miRNAs) that related with distant recurrence after tamoxifen and standard treatment and then build an early recurrence prediction model.
Methods: Our study measured the expression of 5 miRNAs (miR-134, miR-125b-5P, miRNA-30a, miR-10a-5p, and miR-222) that are selected as a tamoxifen resistant related miRNA by previous micro-array experiment and paper review. 176 FFPE tumor tissues of 176 patients who have hormone receptor positive breast cancer with tamoxifen were measured miRNA expression by quantitative real-time PCR (qRT-PCR).
Results: We identified all 5 miRNAs are up-regulated in distant recurrence cases within 5 years after surgery. Other clinico-pathological parameters that are tumor grade, pathologic stage, HER2 statue and P53 status didn't have any specific correlation with expression of miRNAs. The results suggest that distant recurrence during tamoxifen treatment might be affected by tamoxifen resistant related miRNAs. Kaplan-Meier survival analyses based on expression cut-offs determined by receiver characteristics curves show high expression of miR-134, miR-125b-5P, miRNA-30a, miR-10a-5p, and miR-222 were associated with short relapse-free time(log-rank P = 0.006, P&lt;0.0001, P&lt;0.0001, P&lt;0.0001,and P&lt;0.0001, respectively) Conclusion: The altered expression of miRNAs in hormone receptor positive breast cancer is distinctly related to distant recurrence during tamoxifen treatment. Our results suggest that combination of miRNAs expression model can categorize high-risk subset of patients with short relapse-free and has decent predictive value (AUC = 0.891, p-value&lt;0.0001).
Citation Format: Aeree Kim, Chungyeul Kim. Recurrence prediction model using microRNA expression in hormone receptor positive and tamoxifen treated breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3980. doi:10.1158/1538-7445.AM2015-3980
Abstract 3986: Introduction of PTEN pseudogene in murine breast cancer upregulates PTEN, p53 and activating protein 2 gamma and delays tumor growth
Authors: Yndestad Synnøve , Austreid Eilin , Skaftnesmo Kai Ove , Lønning Per Eystein , Eikesdal Hans Petter 
Published: August 2015

Abstract
Background:
While PTEN is frequently downregulated in breast cancer, the mechanism remains obscure. PTEN pseudogene (PTENP1) is reported to function as a decoy adsorbing micro RNAs (miRNAs) targeting PTEN for degradation in prostate cancer cells. A potential role of PTENP1 in PTEN regulation in breast cancer has not been assessed systematically.
Method:
We transfected murine C3HBA breast cancer cells lacking endogenous PTENP1 with a lentiviral PTENP1 construct to investigate the influence of the pseudogene on PTEN and Akt-mTOR downstream signaling, global gene expression, as well as in vitro and in vivo tumor growth characteristics.
Results:
Upregulated PTENP1 3´UTR by lentiviral transfection increased PTEN protein levels and reduced cell cycle progression in vitro, but despite this increased Akt phosphorylation was observed. Similarily, PTENP1 transfection decreased tumor growth in C3HBA murine breast cancer in syngeneic, immunocompetent C3H mice, corresponding with upregulated PTEN, but without inhibition of Akt-mTOR signaling. In stead, increased protein levels of p53 and its downstream target activating protein-2 gamma (AP-2γ) was observed as possible tumor suppressors in this setting.
Conclusion:
In the murine C3HBA breast cancer cell line, PTENP1 transfection was associated with upregulated endogenous PTEN, p53 and AP-2γ protein levels and tumor growth inhibition.
Citation Format: Synnøve Yndestad, Eilin Austreid, Kai Ove Skaftnesmo, Per Eystein Lønning, Hans Petter Eikesdal. Introduction of PTEN pseudogene in murine breast cancer upregulates PTEN, p53 and activating protein 2 gamma and delays tumor growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3986. doi:10.1158/1538-7445.AM2015-3986
Abstract 3988: MicroRNA expression associated with response grade in gastric cancer patients’ tumors
Authors: Barcelos Baldoni Michelle Maccarini , Coutinho Camillo Cláudia Malheiros , Puga Renato David , Begnami Maria Dirlei Ferreira 
Published: August 2015

Abstract
Background: Many chemotherapy schemes have been used in neoadjuvant treatment scenario to improve the overall and disease-free survival of gastric cancer (GC) patients treated with surgery alone. However, in some cases, the objective clinical response is not achieved, and this lack of response to neoadjuvant chemotherapy may delay curative surgery and increase surgical complications. Therefore, a major challenge for improving clinical outcomes is to understand the molecular mechanisms that may play essential roles in patients responses of GC treatments. The expression levels of several miRNAs have been found to be correlated with GC prognosis and could determine the clinical response for neoadjuvant chemotherapy. Therefore, our goal was to analyze the relation between miRNA profile and the pathological response grade of GC patients tumors treated with neoadjuvant chemotherapy or surgery alone. Methods: We selected 34 biopsy tumor samples of patients treated with neoadjuvant chemotherapy (collected before the treatment) and 23 tumor samples of patients submitted to surgery without adjuvant treatment. All patients treated with neoadjuvant chemotherapy received ECF, DCF or ECX prior the surgery, and subsequently they were submitted to a complete resection. The identification of differentially expressed miRNAs was done by TLDA Quantitative Real Time PCR. Results: After categorizing neoadjuvant chemotherapy patients according to percentage of viable tumor cells present in gastric resection and the surgical patients according to their 5 years of follow up status we could segregate those with and without response for both treatments. The comparison between response grade versus miRNAs showed 9 and 14 downregulated miRNAs in samples of patients without response for neoadjuvant chemotherapy and surgery alone, respectively. We also could observe 3 common downregulated miRNAs between patients without response in both groups. Conclusion: We identified some downregulated miRNAs involved in gastric cancer pathways and mechanisms of drug resistance that should manage to determine a predictable miRNA signature to perform a correct patient selection for GC treatments.
Note: This abstract was not presented at the meeting.
Citation Format: Michelle Maccarini Barcelos Baldoni, Cláudia Malheiros Coutinho Camillo, Renato David Puga, Maria Dirlei Ferreira Begnami. MicroRNA expression associated with response grade in gastric cancer patients’ tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3988. doi:10.1158/1538-7445.AM2015-3988
Abstract 3996: Integrated analysis of miRNA profiling and bioinformatics reveals the potential key miRNAs in gastric cancer
Authors: Zhang Xiaojing , Feng Xianling , Peng Yin , Yang Mengting , Huang Yong , Fan Xinmin , Meltzer Stephen J. , Jin Zhe 
Published: August 2015

Abstract
Supported by: National Natural Science Foundation of China, No.81172282; National Natural Youth Science Foundation of China, No.81302151; Shenzhen Peacock Plan, No.KQCX20130621101141669; Planned Science and Technology Project of Shenzhen, No.GJHS20120621142654087; the Key Laboratory Project of Shenzhen, No.ZDSY20130329101130496; Technological innovation group of SZU grants, No.T201202; NIH grants DK087454, CA146799, CA173390; an American Cancer Society Clinical Research Professorship.
Gastric cancer (GC) remains a major health threat worldwide, and is one of the leading causes of cancer-related deaths in China. The discovery of microRNAs (miRNAs) has provided a new and powerful tool for studying diagnostic biomarkers and effective therapeutic targets in GC. By using microarray analyses of benign and malignant gastric epithelial cell lines (HFE145, NCI-N87, MKN28, RF1, KATO III and RF48), we discovered dysregulated 16 miRNAs, of which 11 were validated by real-time qRT-PCR. Based on miRWalk online database scans, 2532 potential mRNA targets of these 16 miRNAs were identified. Bioinformatic analyses suggested that these predicted targets were principally involved in tumor pathogenesis, MAPK signaling, and apoptosis. Finally, miRNA-gene network analyses identified miRNA- 125b as being potentially vitally important in GC.
Citation Format: Xiaojing Zhang, Xianling Feng, Yin Peng, Mengting Yang, Yong Huang, Xinmin Fan, Stephen J. Meltzer, Zhe Jin. Integrated analysis of miRNA profiling and bioinformatics reveals the potential key miRNAs in gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3996. doi:10.1158/1538-7445.AM2015-3996
Abstract 4: ABT-263 is effective in a subset of non-small cell lung cancer cell lines
Authors: Kuroda Aoi , Ohgino Keiko , Yasuda Hiroyuki , Hamamoto Junko , Arai Daisuke , Ishioka Kota , Tani Tetsuo , Nukaga Shigenari , Kawada Ichiro , Naoki Katsuhiko , Soejima Kenzo , Betsuyaku Tomoko 
Published: August 2015

Abstract
Rationale:
ABT-263 (Navitoclax) is one of the BH3 mimetics targeting anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins such as Bcl-2, Bcl-XL, and Bcl-w, thereby inducing apoptosis. It has been reported that the response to ABT-263 is associated with expressions of myeloid cell leukemia-1 (Mcl-1), an anti-apoptotic protein. Given its effectiveness as a single agent in preclinical studies, ABT-263 is currently being evaluated in clinical trials for small cell lung cancer (SCLC) and leukemia. However, the efficacy of ABT-263 in non-small cell lung cancer (NSCLC) has not been fully evaluated. We examined the effect of ABT-263 on cell proliferation of NSCLC cell lines and investigated the underlying mechanisms.
Methods:
The following 9 NSCLC cell lines were examined: SK-LU-1, A549, H358, Calu3, H3122, H1975, H460, H441, and BID007. The effects of ABT-263 in NSCLC cell lines were evaluated by MTS assay. Apoptosis was examined by flowcytometry using staining for annexin V and propidium iodide (PI), and also western blotting for cleaved PARP. Quantitative RT-PCR was carried out to assess the mRNA expression levels of anti-apoptotic genes and pro-apoptotic genes. Immunoprecipitation and western blotting were performed to compare the levels of anti-apoptotic and pro-apoptotic proteins between the sensitive and resistant cell lines. In addition, knockdown of Mcl-1 was performed by siRNA.
Results:
By screening 9 NSCLC cell lines using MTS assay, we found Calu3 and BID007were sensitive to ABT-263. We also confirmed that apoptosis was induced only in the ABT-263 sensitive lines but not in the ABT-263 resistant cell lines after ABT-263 treatment. However, the expression levels of Bcl-2 family proteins, including Mcl-1, did not differ significantly among the ABT-263 sensitive and resistant cell lines. Unlike the results in previous reports regarding SCLC, Mcl-1 was not decreased in the sensitive cell lines. The ABT-263 resistant cell lines became sensitive to ABT-263 after knockdown of Mcl-1 by siRNA, while the ABT-263 sensitive cell lines maintained the same sensitivity.
Conclusion:
We found that Calu3 and BID007 were sensitive to ABT-263. In the sensitive NSCLC cell lines, ABT-263 induces apoptosis irrespective of Mcl-1 expression levels.
Citation Format: Aoi Kuroda, Keiko Ohgino, Hiroyuki Yasuda, Junko Hamamoto, Daisuke Arai, Kota Ishioka, Tetsuo Tani, Shigenari Nukaga, Ichiro Kawada, Katsuhiko Naoki, Kenzo Soejima, Tomoko Betsuyaku. ABT-263 is effective in a subset of non-small cell lung cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4. doi:10.1158/1538-7445.AM2015-4
Abstract 4000: The increase of oncogenic miRNA expression in tongue carcinogenesis of a mouse model
Authors: KAO YUYU , Lin Shu-Chun , Chang Kuo-Wei 
Published: August 2015

Abstract
Oral carcinoma is one of the leading causes of cancer death in the world. To develop biomarkers for early detection may bestow substantial benefits in diagnosis and the prevention of tumor progression. An animal model simulating the human pathogenesis will also be useful for developing therapeutic strategies. miRNAs are short, non-coding RNAs, which play important roles in neoplastic process. The detection of biomarkers in body fluid may enable non-invasive diagnostic approaches. This study used mouse chemical carcinogenesis model to investigate the disruption of miRNA expression in oral tongue tissues, and to explore the miRNA level in saliva and blood during pathogenesis. Mice were fed with 4-Nitroquinoline 1-Oxide (4NQO) in drinking water for 12 weeks and were kept for extended periods for tumor induction. The histological examination showed the consecutive increase in the severity of epithelial pathogenesis from hyperkeratosis, hyperplasia to epithelial dysplasia and squamous tumors following the increase of 4NQO exposure. The increase of miR-21 and miR-31 staining, as well as p53, pAKT and Ki-67 immunoreactivity parallels the severity of epithelial pathogenesis in tongue tissues. A progressive increase of multiple oncogenic miRNAs in both saliva and blood samples was also noted. The increase of miR-21, miR-31 and miR-372 in the saliva and the increase of miR-146a and miR-184 in the blood sample were particularly eminent during the field cancerization process of tongue. In addition, the dysregulation of these oncogenic miRNAs and other molecular events in this model are similar to the disruption being identified in human counterparts. As these miRNAs are functionally oncogenic, their increase in the saliva and blood of mice may be valuable biomarkers to develop diagnosis and prevention strategies against oral carcinomas.
Keywords: chemical, carcinoma, miRNA, mouse, mouth
Note: This abstract was not presented at the meeting.
Citation Format: YUYU KAO, Shu-Chun Lin, Kuo-Wei Chang. The increase of oncogenic miRNA expression in tongue carcinogenesis of a mouse model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4000. doi:10.1158/1538-7445.AM2015-4000
Abstract 4010: Prognostic role of miRNAs in resectable non-small cell lung cancer
Authors: Gallach Sandra , Jantus-Lewintre Eloisa , Calabuig-Fariariñas Silvia , Blasco Ana , Guijarro Ricardo , Martorell Miguel , Camps Carlos 
Published: August 2015

Abstract
BACKGROUND MicroRNAs (miRNA) are a class of small RNAs that regulate gene expression, and are implicated in several diseases including cancer. The aim of this study was to analyze the prognostic implications of deregulated miRNAs identified by NGS in a previous study performed on resectable-NSCLC tumor samples.
MATERIAL AND METHODS Fresh-frozen tumor and normal adjacent lung tissue samples (N = 195) were obtained by surgical resection from NSCLC patients and storage in RNAlater® at -80°C until analysis. RNA was isolated biological specimens by Trizol based-methods. 22 deregulated miRNA were analyzed in paired tumor/normal samples by RTqPCR using TaqMan® microRNA assays. Statistical analyses were considered significant at p&lt;0.05.
RESULTS Patient's median age was 64 years [26-85], 88.2% were male, 66.7% had good performance status (PS = 0), 39.5% were adenocarcinomas and 54.9% presented stage I at the time of the diagnosis. For survival analysis, continuous variables were dichotomized as high (≥ median) and low (&lt; median), using the median expression of each miRNA as a cutoff. Of the 22 miRNAs analyzed only miR-21 and miR-188-5p had prognostic value. We found that patients with high levels of miR-21 and miR-188-5p had a significant reduction in PFS and OS rates. Interestingly, the group of patients with the combined high expression of both miRNAs (miR-21high & miR-188-5phigh) showed shorter PFS and OS (Table 1). Clinico-pathological and analytical variables were included in the multivariate analysis revealing that combined miRNAs is an independent prognostic marker for PFS (HR 0.485 [0.313-0.753]; p = 0.001) and OS (HR 0.389 [0.237-0.638]; p&lt;0.0001].
a P value with Bonferroni correction are shown in parenthesesOSOSPFSPFSMedian (months)PaMedian (months)PamiR-21 (High vs low)42.60 vs 82.600.01622.13 vs 66.970.017miR-188-5p (High vs low)46.67 vs NR0.00524.03 vs 66.970.023Combined miRNAs (miR21 high miR-188 high vs combonations)21.13 vs 83.570.002 (0.008)16.97 vs 56.830.001 (0.004)
CONCLUSION Expression of miR-21 and miR-188-5p seems to have a prognostic role in NSCLC, and the combination of both could be an independent prognostic marker in early-stage NSCLC.
Table 1. OS and PFS for miR-21 and miR-188-5p in NSCLC patients (univariate analysis) Supported by grants RTICC (RD12/0036/0025 and RD06/0020/1024), TRACE (TRA09-0132) and Beca Roche Oncohematología.
Citation Format: Sandra Gallach, Eloisa Jantus-Lewintre, Silvia Calabuig-Fariariñas, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Carlos Camps. Prognostic role of miRNAs in resectable non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4010. doi:10.1158/1538-7445.AM2015-4010
Abstract 4022: Fibroblast-derived PEDF inhibits tumor growth and angiogenesis and is suppressed by TGF-β and PDGF
Authors: Nwani Nkechiyere G. 
Published: August 2015

Abstract
Rationale and Objective: PEDF (pigment epithelium-derived factor) is an endogenous angiogenesis inhibitor and a type II tumor suppressor whose expression is often reduced/ lost in a variety of tumors, including malignant melanoma. To date, the mechanisms and consequences of PEDF loss on tumor progression have been investigated in neoplastic cells but not in the tumor-associated non-neoplastic cells. Fibroblasts are extremely abundant in the tumor microenvironment and can switch to the tumor-promoting phenotype in response to the tumor-associated factors. Here, we investigated how the loss of fibroblast-derived PEDF in the tumor microenvironment alters melanoma progression and the mechanisms, by which melanoma cells attenuate PEDF expression in fibroblasts.
Methods: We used lentiviral vectors for PEDF knockdown (shPEDF and control). Tumor growth was evaluated in immunodeficient mice (flank injections). Angiogenesis and proliferation in the tumor were measured by immunohistochemistry (IHC) for CD31 and Ki-67, respectively. Gene expression was evaluated by q-PCR and protein levels were detected by western blot/ IHC. The contribution of growth factors tested using specific pathway inhibitors.
Results: We have measured tumorigenesis of highly aggressive melanoma cell line C8161-HA co-mixed with shPEDF or control fibroblasts. PEDF loss in fibroblasts promoted tumor growth/ angiogenesis in xenografted human melanoma. Seeking mechanisms by which tumors attenuate PEDF expression in fibroblasts we found that it is mildly attenuated by hypoxia and potently down-regulated by the soluble factors produced by melanoma cells. Using recombinant growth factors and tumor conditioned media in combination with receptor and pathway-specific inhibitors we have identified TGF-β and PDGF as the main antagonists of PEDF expression. We have also discovered that PDGF directly blocks PEDF expression while regulation by TGF-β is indirect, whereby it elevates PDGFR expression by fibroblasts and thus increases their sensitivity to both paracrine and autocrine PDGF.
Conclusions: Together, our data demonstrate the key role of PEDF loss in non-neoplastic cells in the tumor microenvironment and the mechanisms by which tumors overcome its anti-cancer effects. Our data also indicate potential utility of PDGF inhibitors to restore PEDF in the tumor microenvironment.
Citation Format: Nkechiyere G. Nwani. Fibroblast-derived PEDF inhibits tumor growth and angiogenesis and is suppressed by TGF-β and PDGF. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4022. doi:10.1158/1538-7445.AM2015-4022