bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Trial to Evaluate Antibody-Dependent Cellular Cytotoxicity of Cetuximab and Lenalidomide in Advanced Colorectal and Head and Neck Cancer
Authors: Bertino Erin M. , McMichael Elizabeth L. , Mo Xiaokui , Trikha Prashant , Davis Melanie , Paul Bonnie , Grever Michael , Carson William E. , Otterson Gregory A. 
Published: July 2016

AbstractmAbs can induce antibody-dependent cellular cytotoxicity (ADCC) via the innate immune system's ability to recognize mAb-coated cancer cells and activate immune effector cells. Lenalidomide is an immunomodulatory agent with the capacity to stimulate immune cell cytokine production and ADCC activity. This phase I trial evaluated the combination of cetuximab with lenalidomide for the treatment of advanced colorectal and head and neck squamous cell cancers (HNSCC). This trial included patients with advanced colorectal cancer or HNSCC. Treatment consisted of cetuximab 500 mg/m2 i.v. every two weeks with lenalidomide given orally days 1–21 on a 28-day cycle. Three dose levels of lenalidomide were evaluated (15, 20, 25 mg). Correlative studies included measurement of ADCC, FcγRIIIA polymorphism genotyping, measurement of serum cytokine levels, and flow cytometric analysis of immune cell subtypes. Twenty-two patients were enrolled (19 colorectal cancer, 3 HNSCC). Fatigue was the only dose-limiting toxicity. One partial response was observed and 8 patients had stable disease at least 12 weeks. The recommended phase II dose is cetuximab 500 mg/m2 with lenalidomide 25 mg daily, days 1–21. Correlative studies demonstrated a dose-dependent increase in natural killer cytotoxic activity with increasing doses of lenalidomide. Cetuximab and lenalidomide were well tolerated. There was a lenalidomide dose-dependent increase in ADCC with higher activity in patients enrolled in cohort 3 than those enrolled in cohorts 1/2. Although response was not a primary endpoint, there was evidence of antitumor activity for the combination therapy. Further investigation of lenalidomide as an immunomodulator in solid tumors is warranted. Mol Cancer Ther; 15(9); 2244–50. ©2016 AACR.
Abstract 1091: miR-125 family of miRNAs mediates prostate cancer cell proliferation and migration
Authors: Aherne Sinead T. , O’Neill Fiona , Madden Stephen F. , Clynes Martin , Lynch Conor C. 
Published: July 2016

Abstract
Background: Prostate cancer is the second most common malignancy in American men and causes ∼27540 deaths per annum. microRNAs (miRNAs) are a class of short non-coding RNAs that regulate the expression of protein-coding genes via either mRNA degradation or translational repression. These small molecules are known to be aberrantly expressed in prostate cancer (PCa) and possess both tumor suppressive and oncogenic properties. miR-125 is a highly conserved miRNA family comprised of three homolog members hsa-miR-125a, hsa-miR-125b-1, and hsa-miR-125b-2. Members of this family have been attributed both disease suppressing and promoting functions in certain contexts however their role in PCa has yet to be fully elucidated.
Methods: miRNA expression was evaluated in a publicly available dataset (GSE21032) comprised of 28 normal, 98 primary PCa and 13 metastasis samples. miR-125 expression was assessed in a panel of 8 prostate cell lines comprising PrEC prostate epithelial cells, RWPE-1, BPH1, DU145, LNCaP, C4-2B, PC3, and PC3-2M cell lines using the Qiagen miScript system. MirWalk was used to identify predicted targets of the miRNAs. miR-125 expression was transiently inhibited in LNCaP, C4-2B, PC3, and PC3-2M cell lines using miScript miRNA inhibitors and miRNA and target mRNA expression, cell proliferation and migration were measured post-transfection.
Results: Analysis of human data revealed miR-125a-3p was significantly up-regulated in metastasis samples compared to both primary PCa and normal tissues (log fold change (FC) 1.743, p-value 9.01E-08 logFC = 1.536 p-value = 8.80E-08 respectively). Next, we validated miR-125 family member expression in prostate cancer cell lines compared to PrEC and RWPE-1 prostate epithelial cells. Most notably, we observed that miR-125b-2 expression was significantly higher in all prostate cancer cell lines. Inhibition of miR-125b-2, significantly reduced the proliferation of the LNCaP, C4-2B, and PC3-2M cell lines. Moreover, inhibition of this miRNA significantly impaired prostate cancer cell migration by 43.8% (p-value = 0.003). Using MirWalk, we examined potential targets for regulation by miR-125b-2 and identified the potent tumor suppressor Quaking family as top hit. Our results show that inhibition of miR-125b-2 significantly enhanced the expression of Quaking family members (1.79 fold).
Conclusions: Our results demonstrate that the miR-125 family of miRNAs plays a role in regulating prostate cancer cell proliferation and migration, potentially by mitigating Quaking activity.
Citation Format: Sinead T. Aherne, Fiona O’Neill, Stephen F. Madden, Martin Clynes, Conor C. Lynch. miR-125 family of miRNAs mediates prostate cancer cell proliferation and migration. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1091.
Abstract 1133: Prevalence of activated NOTCH receptor in solid tumors and chronic lymphocytic leukemia
Authors: Oakley Gerard , Riegle Lisa , Benhadji Karim , Schade Andrew 
Published: July 2016

Abstract
Recent reports identified high expression of Notch 1 receptor in various tumors including adenoid cystic carcinomas (ACC). Notch 1 receptor is activated by gamma secretase cleavage to exert transcriptional control of processes including cellular differentiation and proliferation. Notch is also known to be activated in approximately 60% of T-cell acute lymphoblastic leukemias. We investigated the prevalence of Notch 1, 2 and 3 activation in different tumors by immunohistochemistry (IHC) designed separately for Notch 1, 2 and 3. Our proprietary antibodies recognize the post-gamma secretase cleavage activated Notch intracellular domain (NICD) fragments of Notch 1, Notch 2 and Notch 3, allowing direct measurement of activation of these receptors, in addition to their expression level by the tumor cells.
In total we tested 48 ACCs of the salivary glands, 19 breast cancer, 35 chronic lymphocytic leukemias (CLL), 7 glioblastomas, and 35 non-small cell lung carcinomas (NSCLC) We found that at least 65% (31 out of 48) of ACCs were positive for Notch 1 activation using our assay. Of other tumor types, 4 out of 7 glioblastomas (57%), 14 out of 35 CLLs (40%), 7 out of 35 NSCLC (20%) and 2 out of 19 breast cancer cases (11%) were positive for Notch 1. Within NSCLC, 5 of the 16 tested squamous cell carcinomas were positive for Notch 1 activation (31%). Notch 2 and Notch 3 showed only rare activation in these tumors. We conclude that high levels of Notch 1 activation are identifiable in different tumor types including high prevalence in ACC, CLL and glioma. These tumors may benefit from therapeutic Notch pathway inhibition.
Citation Format: Gerard Oakley, Lisa Riegle, Karim Benhadji, Andrew Schade. Prevalence of activated NOTCH receptor in solid tumors and chronic lymphocytic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1133.
Abstract 1308: Enhanced antitumor activity of rapamycin and genipin, a UCP-2 inhibitor, in lung cancer
Authors: Su Wen-Pin , Chang Jang-Yang , Kuo Ching-Chuan , Su Wu-Chou 
Published: July 2016

Abstract
mTOR is constitutively activated in lung cancer. Deletion of TOR1 increases expression of OXPHOS proteins, and mitochondrial uncoupling proteins 2 (UCP-2) expression promotes chemoresistance. Therefore, we evaluated whether adding genipin, a UCP-2 inhibitor, to rapamycin has better antitumor effect in lung cancer. Combined with genipin and rapamycin have a synergistic effect with more cellular apoptosis in A549, H460 and CL1-0 cells. The similar phenomenon was found in the combination treatment with genipin and everolimus or BGT226 (a dual PI3K/mTOR inhibitor) in this three lung cancer cells. It is said that NrF2 may affect UCP-2 expression, and we found NrF2 was activated in lung cancer A549, H460 and CL1-0 cells treated with rapamycin. Everolimus and dual PI3K/mTOR inhibitor, BGT226, also induced NrF2 nuclear translocation in these lung cancer cells. It is said that under oxidant stress, p62 activates NrF2 through P62 Ser351-phosphorylation. We found that rapamycin induced ROS generation, p62 serine phosphorylation and NrF2 downstream mRNA and protein expression, including UCP-2. ROS inhibitor, NAC, and down-regulation of p62 by siRNA suppressed rapamycin-induced UCP-2 expression. Overexpression of p62 by cDNA transfection enhanced NrF2 activation and then UCP-2 expression in lung cancer cells. Moreover, rapamycin-induced increased UCP-2 expression, leading decreased mitochondrial membrane potential and mild increased oxygen consumption rate. Finally in A549 subcutaneous tumor mode in SCID mice, combined genipin and everolimus also demonstrated the greatest antitumor activity. Therefore, inhibition UCP-2 by genipin enhances anticancer effect of rapamycin in lung cancer.
Citation Format: Wen-Pin Su, Jang-Yang Chang, Ching-Chuan Kuo, Wu-Chou Su. Enhanced antitumor activity of rapamycin and genipin, a UCP-2 inhibitor, in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1308.
Abstract 145: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Mori Seiichi , Gotoh Osamu , Sugiyama Yuko , Kato Kazuyoshi , Takazawa Yutaka , Noda Tetsuo 
Published: July 2016

Abstract
Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5%, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 84 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients.
Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Yutaka Takazawa, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 145.
Abstract 1485: Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment
Authors: van Hooren Luuk , Georganaki Maria , Huang Hua , Mangsbo Sara , Dimberg Anna 
Published: July 2016

Abstract
CD40-activating immunotherapy has potent anti-tumor effects due to its ability to activate dendritic cells and induce cytotoxic T-cell responses. However, its efficacy is limited by accumulation of immunosuppressive cells in the tumor and by endothelial anergy induced by pro-angiogenic growth factors. Here, we show that combining agonistic CD40 monoclonal antibody (mAb) therapy with vascular targeting using the tyrosine kinase inhibitor sunitinib significantly decrease tumor growth and improve survival in B16.F10 melanoma and T241 fibrosarcoma. Treatment of tumor-bearing mice with anti-CD40 mAb lead to increased activation of CD11c+ dendritic cells in the tumor draining lymph node, as evidenced by enhanced CD86 expression, while sunitinib treatment reduced vessel density. CD11b+Gr1+ myeloid derived suppressor cells accumulated in the tumor draining lymph nodes after anti-CD40 mAb treatment. This effect was reversed by co-treatment with sunitinib. Tumor endothelial expression of ICAM1 and VCAM1 adhesion molecules were increased only when anti-CD40 mAb treatment was combined with sunitinib. This was associated with enhanced tumoral infiltration of CD8+ T-lymphocytes. Our results show that combining CD40-stimulating immunotherapy with sunitinib treatment exert potent complementary antitumor effects mediated by dendritic cell activation, reduction in myeloid derived suppressor cells and increased endothelial activation, resulting in enhanced recruitment of cytotoxic T cells.
Citation Format: Luuk van Hooren, Maria Georganaki, Hua Huang, Sara Mangsbo, Anna Dimberg. Sunitinib enhances the antitumor responses of agonistic CD40-antibody by reducing MDSCs and synergistically improving endothelial activation and T-cell recruitment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1485.
Abstract 1638: Hypoxia-induced WSB1 promotes the metastatic potential of osteosarcoma cells
Authors: Wang Yijie , Cao Ji , Dong Rong , Lin Guanyu , Chen Zibo , Ding Ling , Ying Meidan , He Qiaojun , Yang Bo 
Published: July 2016

Abstract
Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease.
Citation Format: Yijie Wang, Ji Cao, Rong Dong, Guanyu Lin, Zibo Chen, Ling Ding, Meidan Ying, Qiaojun He, Bo Yang. Hypoxia-induced WSB1 promotes the metastatic potential of osteosarcoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1638.
Abstract 1642: Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis
Authors: Kim Soon-Chan , Hong Chang-Won , Jang Sang-Geun , Kim Yeh-Ah , Jung Seung-Yong , Park Jea-Gab , Ku Ja-Lok 
Published: July 2016

Abstract
(a) An introductory sentence indicating the purposes of the study Distant metastasis is the major cause of cancer-related death in colorectal cancer (CRC) patients. Although the Calponin family has emerged as a distinguishing feature in epithelial-to-mesenchymal transition (EMT) in human cancer, the role of CNN3 member in the metastatic CRC has not been investigated.
(b) A brief description of pertinent experimental procedures. Three pairs of primary CRC and corresponding matched metastasis cell lines were analyzed for gene expression by microarray and western blotting. CNN3 was transduced to CRC cell line with lower CNN3 expression level (SW-480), and CNN3 with higher CNN3 expression CRC cell lines (SW-620, HCT-116) was suppressed by lentiviral-induced shRNA. Functional analysis of CNN3 overexpression and suppression was investigated in these CRC cell lines for proliferation and invasion. Expression of several potential CNN3 target genes (ERK1/2) and EMT markers (E-cadherin and vimentin) in primary CRC and matching metastasis CRC cell lines was validated.
(c) A summary of the new, unpublished data. Global CNN3 expression levels were significantly higher in metastasis cell lines compared with the matched primary cell lines in both mRNA (FC = 2.3, p = 0.017) and protein levels. CRC cell lines with suppressed CNN3 showed decreased cell proliferation and reduced invasive behavior in CRC cell lines. Suppression of CNN3 in CRC cell lines with higher CNN3 expression resulted in increased E-cadherin and decreased vimentin. pERK1/2 were decreased in accordance with suppression of CNN3 in both SW-620 and HCT-116. Overexpression of CNN3 in CRC cell lines caused reduced E-cadherin in SW-480 and HT-29.
(d) A statement of the conclusions CNN3 is involved in mediating EMT and metastatic behavior in the colon. Its expression is accordantly related to EMT markers, and CNN3 may serve as a possible diagnostic marker and therapeutic target for patients with CRC.
Citation Format: Soon-Chan Kim, Chang-Won Hong, Sang-Geun Jang, Yeh-Ah Kim, Seung-Yong Jung, Jea-Gab Park, Ja-Lok Ku. Calponin-3, acidic (CNN3) mediates EMT-related genes in human colorectal cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1642.
Abstract 1741: The association between menopause symptoms and risk of postmenopausal breast cancer among non-users of hormone therapy
Authors: Li Tricia , Han Jiali , He Chunyan 
Published: July 2016

Abstract
Background: Hot flashes are a common symptom among women during their menopause transition, likely due to the changes of endogenous hormone levels. Previous research suggested that hot flashes symptoms were associated with a reduced risk of cardiovascular diseases. Few studies have investigated the association of hot flashes symptoms with the risk of breast cancer. Furthermore, the confounding effect by hormone use has not been sufficiently addressed in previous studies.
Methods: We investigated the association between hot flashes symptoms and risk of postmenopausal breast cancer in the Nurses’ Health Study (NHS). In order to eliminate the confounding by hormone use, we investigated the association only among women who never used hormone therapy. We calculated relative risk of breast cancer using a multivariate Cox model, adjusting for potential confounders, including age, race, family history of breast cancer, age at menarche, age at menopause, parity, age at first birth, body mass index, smoking, alcohol use, and education. We further investigated the severity of hot flashes symptoms in association with risk of postmenopausal breast cancer.
Results: We documented 1079 incidence of breast cancer during 396,166 person-years of follow-up. Hot flashes symptoms were not associated with risk of postmenopausal breast cancer after adjustment for potential confounders (RR = 1.02, 95% CI, 0.90-1.15) among non-users of hormone therapy. Relative risk of breast cancer across symptom severity categories (mild, moderate, severe) were 1.01 (95% CI, 0.87-1.17), 1.04 (95% CI, 0.88-1.22), and 1.05 (95% CI, 0.75-1.46), respectively.
Conclusion: These data suggested that menopausal symptoms were not associated with risk of postmenopausal breast cancer.
Citation Format: Tricia Li, Jiali Han, Chunyan He. The association between menopause symptoms and risk of postmenopausal breast cancer among non-users of hormone therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1741.
Abstract 188: Isoform-specific AKT functions in thyroid carcinoma development
Authors: Ranieri Michela , Di Cristofano Antonio 
Published: July 2016

Abstract
Mammalian cells contain three genes that encode three AKT isoforms (AKT1-3). The three genes have &gt;85% sequence identity, and possess conserved threonine and serine residues that are critical for full activation. All AKT isoforms seem to have identical or similar substrate specificity, and it is not clear whether they possess different functional specificities in vivo.
Using conditional, organ-specific isoform deletion in a model of PI3K-dependent neoplastic transformation and progression, we are dissecting the molecular and biological roles of AKT1 and AKT2.
Thyroid-specific deletion of Pten (Ptenthy-/− mice) results in thyroid hyperplasia at birth which then slowly progresses to solid nodular lesions and finally to invasive carcinomas.
Simultaneous thyroid-specific deletion of Akt1 and/or Akt2 demonstrates that both AKT1 and AKT2 are necessary to confer proliferative ability to Pten−/- thyrocytes in an additive manner. However, with age, (Pten,Akt1)thy-/− mice have a significantly higher incidence of thyroid lesions compared to (Pten,Akt2)thy-/− mice. In addition, deletion of Akt2 is more effective than that of Akt1 to extend survival and reduce lesion aggressiveness in Ptenthy-/−/KrasG12D mice.
Transcriptomic and proteomic analyses have revealed that AKT2 loss rescues most of the expression and activation changes induced, in vivo, by Pten deletion, while AKT1 loss has more restricted effects.
Futhermore we have identified and are characterizing subsets of genes that are differentially regulated by AKT isoforms.
These data point to the existence of dramatically different molecular pathways associated with each AKT isoform in the thyroid, and represent a strong rationale for the development of less toxic, more effective treatments based on isoform-specific inhibitors.
Citation Format: Michela Ranieri, Antonio Di Cristofano. Isoform-specific AKT functions in thyroid carcinoma development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 188.