tbuckley/cabot-search huggingface dataset:
Abstract 5407: MicroRNA expression analysis of advanced colorectal cancer reveals a microRNA signature with prognostic and predictive value
Authors: Zhaolei Zeng, Jiahua Lu, Zhixiang Zuo, Qi Zhao, Ruihua Xu
Journal: Cancer Research (2018)

Abstract Background Prognostic and predictive markers are needed to predict the clinical outcomes of patients with advanced colorectal cancer (CRC) who receive standard first-line treatments. We performed a prospective cohort study in patients with advanced CRC to identify a miRNA signature that could predict the benefit of receiving first-line chemotherapy for these patients. Methods Twenty-one paired tumours and adjacent normal tissues were collected from patients with advanced CRC and analysed by miRNA microarrays. Between tumour and normal tissues, 33 miRNAs were differentially expressed. The differential expression of these miRNAs was confirmed by qRT-PCR using paraffin-embedded specimens from another group of 76 patients from a prospective cohort study. A two-miRNA-based signature was obtained using the least absolute shrinkage and selection operator (LASSO) Cox regression model based on the association between the expression of each miRNA and the progression-free survival (PFS) time of individual patients. Internal and external validation cohorts, including 45 and 50 patients with advanced CRC, respectively, were performed to validate the prognostic and predictive accuracy of this signature. Results A signature based on two miRNAs, miR-125b-2-3p and miR-933, was built by the LASSO model. CRC patients were classified into high- and low-risk groups for disease progression based on this tool. The patients with high risk scores generally had worse PFS than those with lower risk scores. In the training set, the average PFS was 23.906 months for the low-risk group and 9.010 months for the high-risk group (hazard ratio [HR] 2.535, 95% CI 1.478-4.348, p=0.001). In the internal validation set, the average PFS was 14.029 months for the low-risk group and 6.334 months for the high-risk group (HR 3.173, 95% CI 1.415-7.116, p=0.005). In the external validation set, the average PFS was 16.815 months for the low-risk group and 7.657 months for the high-risk group (HR 2.498, 95% CI 1.281-4.871, p=0.007). Furthermore, we detected miR-125b-2-3p associated with CRC cell sensitivity to first-line chemotherapy. The two-miRNA-based signature was an independent prognostic factor for predicting the outcome of patients with metastatic CRC receiving first-line chemotherapy. Citation Format: Zhaolei Zeng, Jiahua Lu, Zhixiang Zuo, Qi Zhao, Ruihua Xu. MicroRNA expression analysis of advanced colorectal cancer reveals a microRNA signature with prognostic and predictive value [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5407.
Utility of Real-Time 3-Dimensional Echocardiography and Magnetic Resonance Imaging for Evaluation of Danon Disease
Authors: HiroshiTada, YoshieHarimura, HiroYamasaki, YukioSekiguchi, TomokoIshizu, YoshihiroSeo, SatoruKawano, KazutakaAonuma
Journal: Circulation (2010)
Abstract 1521: Role of Trim28 in prostate cancer
Authors: Ka-Wing Fong, Jonathan Zhao, Bin Zheng, Jindan Yu
Journal: Cancer Research (2018)

Abstract TRIM28 is an essential gene during embryonic development, which is involved in a wide range of biologic processes. From the pathologic viewpoint, TRIM28 overexpression was proved to broadly exist in pancreatic, liver, breast, glioma and lung cancer, and often expression of TRIM28 is correlated with clinical stage. Functional assays have demonstrated that TRIM28 promotes cancer cell growth and metastasis, further supporting TRIM28 as a promising target for therapeutic intervention. For past decade, TRIM28 is considered to be a transcriptional co-repressor due to TRIM28-dependent recruitment of histone modifiers such as CHD1/NuRD complex and SETDB1 for histone methylation and heterochromatin formation to achieve gene silencing. Surprisingly, transcriptome study revealed that TRIM28 can activate the expression of its target genes as much as it represses, hypothesizing the main role of TRIM28 may not lie in transcriptional repression. In addition, recent findings demonstrated that TRIM28 interacts with 7SK snRNP complex, which facilitates P-TEFb kinase module recruitment and productive transcription elongation at inducible genes. This evidence implicated that TRIM28 may form distinct complexes to induce or repress gene expression in context-dependent manner. On top of that, it remains unclear about the role of TRIM28 in prostate cancer. Our preliminary study revealed that TRIM28 is upregulated in castration-resistant prostate cancer (CRPC). TRIM28 knockdown markedly decreased prostate cancer cell proliferation, clonogenicity as well as CRPC-xenograft tumor growth. Moreover, proteomic analysis in LNCaP prostate cancer cells revealed that TRIM28 associates with a number of transcription co-activators. Gene expression profiling showed that androgen signaling is positively regulated by TRIM28. We proposed that TRIM28 forms the transcription activation complexes that modulate gene expression of various oncogenic pathway and promote PCa progression. Citation Format: Ka-Wing Fong, Jonathan Zhao, Bin Zheng, Jindan Yu. Role of Trim28 in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1521.
Abstract 16552: hHO-1 Overexpression is Cardioprotective After Acute Myocardial Infarction - Differences Between Pigs and Mice
Authors: RabeaHinkel, ElenaGottlieb, BjörnPetersen, DiQin, LangePhilipp, SeungminLee, PhilipWenzel, HeinerNiemann, ChristianKupatt
Journal: Circulation (2013)

Heme oxygenase-1 (HO-1) responds to stress by increased production of bilirubin, carbon monoxide and free iron. These reaction products attenuate oxidative stress, inflammation and apoptosis, all of which play a role in ischemia/reperfusion injury. Therefore, we investigated he cardioprotective potential of human HO-1 overexpression. Methods: Transgenic pigs (TG) were produced via somatic cell nuclear transfer. Pigs (wt, hHO-TG ± ZNPP, wt + adeno-associated virus (rAAV)-hHO-1 underwent LAD occlusion (I, 60min) and reperfusion (R, 24h). Apoptosis, leukocyte influx, capillary density, infarct size and myocardial function were assessed. Mice (HO-1 -/-, HO-1 +/+ +/- rAAV injection) underwent 45 min I/ 24h R. Global myocardial function (via Millar pressure tip catheter), infarct size (via SPECT and TTC staining) and inflammation were analyzed. Results: Infarct size in mice was not different between HO-1 -/- and HO-1 +/+ mice (28±3 and 28±2 % of left ventricle), whereas overexpression of HO-1 via AAV clearly re...
Abstract 5510: Loss of epithelial membrane protein 2 enhances Kras-driven lung tumorigenesis via FAK/AKT pathways
Authors: Ji Yun Jang, Mi Kyung Park, Chang Hoon Lee, Ho Lee
Journal: Cancer Research (2018)

Abstract Epithelial membrane protein-2 (EMP2) belongs to the growth arrest specific-3 (GAS3)/PMP22 family of tetraspan proteins. These family members are involved in the pathogenesis of human diseases, including malignancy. EMP2 is highly expressed in normal lung alveoli; however, its functional role in lung tumor is largely unknown. In this study, we focus a novel function for EMP2 in lung tumor progression. To investigate this possibility, EMP2 knock-out mice were crossed with KrasG12Dmice that carry an oncogenic mutation of the Kras gene (G12D) and develop lung adenocarcinoma. Incidence of lung tumor in KrasG12DEMP2-/- mice was higher than that in KrasG12DEMP2+/+ mice. We also found that loss of EMP2 accelerated lung tumor progression. Then, we investigated the role of EMP2 in lung cancer cell line. Expression of EMP2 was knocked out by CRISPR/Cas9 editing system in H1299 (KrasWT), H358 (KrasMut) and A549 cells (KrasMut). Loss of EMP2 induced that expression of integrin α5 is increased but expression of integrin α6 is decreased. Alteration of integrin expression activated FAK/AKT pathway. These results support the role of EMP2 loss in the control of lung cancer progression with oncogenic Kras. Taken together, these findings establish that EMP2 is a potent suppressor of Kras-driven lung tumorigenesis via FAK/AKT pathway. Citation Format: Ji Yun Jang, Mi Kyung Park, Chang Hoon Lee, Ho Lee. Loss of epithelial membrane protein 2 enhances Kras-driven lung tumorigenesis via FAK/AKT pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5510.
Abstract 458: Relationship between autophagy, activation and senescence in normal and cancer-associated human oral fibroblasts
Authors: May Leng Tan, Eric K. Parkinson, Lee Fah Yap, Ian C. Paterson
Journal: Cancer Research (2018)

Abstract Cancer-associated fibroblasts (CAFs) isolated from oral squamous cell carcinoma (OSCC) display an activated phenotype in that they express α-smooth muscle actin (αSMA) and are frequently prematurely senescent. OSCC cell lines can induce senescence in normal fibroblasts in vitro by a mechanism that involves TGF-β and reactive oxygen species. Another phenotype closely associated with senescence is autophagy, but the relationship between autophagy, activation and senescence in CAFs has not been examined in detail. We first examined autophagosome accumulation in normal human oral fibroblasts (NHOFs; n=3) and in a panel of CAFs (n=8) that exhibited different degrees of senescence. Autophagosome accumulation was observed in senescent CAFs, as shown by the increased expression of the LC3B-II protein and by the number of LC3B cytoplasmic puncta, which were quantified using immunofluorescence. The number of LC3B puncta was significantly greater (p&amp;lt;0.01) in senescent CAFs compared to NHOFs, and senescent CAFs contained a higher fraction of autophagic fibroblasts than NHOFs, as indicated by increased number of LC3B puncta per cell. Further, the number of LC3B puncta correlated positively with the degree of senescence, as demonstrated by senescence-associated β-galactosidase (SA β-Gal) activity. To investigate whether autophagy, activation and senescence develop simultaneously when fibroblasts are stimulated to undergo senescence, we examined the temporal induction of these phenotypes in NHOFs in response to TGF-β1. NHOFs were treated with TGF-β1 (4 ng/ml) for up to 10 days to induce autophagy, αSMA expression and SA β-Gal activity. The results showed that autophagic flux preceded fibroblast activation, which in turn was followed by senescence. In summary, our results demonstrate that CAFs from OSCC concomitantly display autophagic, activated and senescent phenotypes and that the induction of autophagy occurs before fibroblast activation and sensecence. Taken together, these data suggest that autophagy, activation and sensecence in fibroblasts may be part of a unified programme leading to the development of CAFs. Citation Format: May Leng Tan, Eric K. Parkinson, Lee Fah Yap, Ian C. Paterson. Relationship between autophagy, activation and senescence in normal and cancer-associated human oral fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 458.
Critical Role of Cyclin D1 Nuclear Import in Cardiomyocyte Proliferation
Authors: MimiTamamori-Adachi, HiroshiIto, PiyamasSumrejkanchanakij, SusumuAdachi, MichiakiHiroe, MasatoShimizu, JunyaKawauchi, MakotoSunamori, FumiakiMarumo, ShigetakaKitajima, Masa-AkiIkeda
Journal: Circulation Research (2003)

Mammalian cardiomyocytes irreversibly lose their capacity to proliferate soon after birth, yet the underlying mechanisms have been unclear. Cyclin D1 and its partner, cyclin-dependent kinase 4 (CDK4), are important for promoting the G1-to-S phase progression via phosphorylation of the retinoblastoma (Rb) protein. Mitogenic stimulation induces hypertrophic cell growth and upregulates expression of cyclin D1 in postmitotic cardiomyocytes. In the present study, we show that, in neonatal rat cardiomyocytes, D-type cyclins and CDK4 were predominantly cytoplasmic, whereas Rb remained in an underphosphorylated state. Ectopically expressed cyclin D1 localized in the nucleus of fetal but not neonatal cardiomyocytes. To target cyclin D1 to the nucleus efficiently, we constructed a variant of cyclin D1 (D1NLS), which directly linked to nuclear localization signals (NLSs). Coinfection of recombinant adenoviruses expressing D1NLS and CDK4 induced Rb phosphorylation and CDK2 kinase activity. Furthermore, D1NLS/CDK4 was...
Abstract 1483: Targeting oncogenic enhancer activity with a small-molecule CBP/P300 bromodomain inhibitor
Authors: Ryan Raisner, Russell Bainer, Emily Chan, Jesse Garcia, Mark Merchant, Karen Gascoigne
Journal: Cancer Research (2018)

Abstract Transcriptional networks are often dramatically altered in cancer, this dysregulation occurring at both the genetic and epigenetic level. Recently much attention has been given to the role of enhancer-driven gene expression in cancer, with the observation that numerous key oncogenes are driven by super-enhancers. This opens up the possibility for therapeutic intervention with small molecules that modulate enhancer activity, leading to control of expression of otherwise un-drugable oncogenes. CBP/P300 are histone acetyl transferases (HATS) that are critical mediators of enhancer activity. Here we use a novel small molecule inhibitor of the CBP/P300 bromodomain to specifically probe the role of these HATS at enhancers, and more broadly evaluate the consequences of enhancer disruption on cancer cell growth in vitro and in vivo. Citation Format: Ryan Raisner, Russell Bainer, Emily Chan, Jesse Garcia, Mark Merchant, Karen Gascoigne. Targeting oncogenic enhancer activity with a small-molecule CBP/P300 bromodomain inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1483.
Abstract 2016: Potential role of polo-like kinase 1 in epithelial-mesenchymal transition in melanoma
Authors: Gagan Chhabra, Chandra K. Singh, Mary A. Ndiaye, Nihal Ahmad
Journal: Cancer Research (2018)

Abstract Mammalian polo-like kinase 1 (Plk1), an important serine/threonine kinase, has been shown to be a critical regulator of mitosis and cytokinesis. A number of studies, including those from our laboratory, have shown that Plk1 is significantly overexpressed in several cancers, including melanoma. Plk1 has also been linked with poor disease prognosis in cancer patients. A limited number of recent studies have suggested that Plk1 may be involved in epithelial-mesenchymal transition (EMT) in different cancers. However, the role of Plk1 in EMT process in melanoma has not been studied. Indeed, EMT plays a driving role in the acquisition of cancer metastasis and an important hallmark of EMT is downregulation of epithelial marker E-cadherin, and upregulation of mesenchymal marker, N-cadherin. In this study, we investigated whether the kinase activity of Plk1 plays a role in EMT process by modulating EMT markers in melanoma cells. To determine this, we performed western blots, RT-qPCR, cell migration and cell invasion assays using A375 melanoma cells stably transfected with plasmids for wild-type (WT) Plk1 overexpression, constitutively active Plk1 (T210D) and kinase-inactive (K82R) Plk1, as well as shRNA-mediated Plk1 knockdown. We observed that overexpression of WT Plk1 upregulated the mesenchymal markers N-cadherin, Vimentin, and Fibronectin, and downregulated the epithelial marker E-cadherin. We also found that the modulation in EMT markers by Plk1 in melanoma cells was associated with the upregulation of transcription factors Snail and Zeb1. Interestingly, downregulation of endogenous Plk1 by specific shRNA resulted in a downregulation of N-cadherin, Vimentin, Fibronectin, Snail and Zeb1. Further, when we assessed the EMT-related molecular changes in A375 melanoma cells containing constitutively active and kinase-inactive Plk1, the cells containing constitutively active Plk1 showed a significant decrease in epithelial marker as well as marked increases in mesenchymal markers. However, the cells containing kinase-inactive Plk1 showed the opposite trend. Moreover, A375 melanoma cells containing constitutively active Plk1 showed higher migration and invasion potential, whereas cells containing kinase-inactive Plk1 showed limited cell migration and invasion. Overall, these results suggest that Plk1 is involved in the EMT process and its kinase activity is important for EMT-related changes in melanoma cells. Further studies are in progress to determine the cause-and-effect molecular mechanisms of Plk1 mediated EMT regulation. Citation Format: Gagan Chhabra, Chandra K. Singh, Mary A. Ndiaye, Nihal Ahmad. Potential role of polo-like kinase 1 in epithelial-mesenchymal transition in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2016.
Incorporating diffusion- and perfusion-weighted MRI into a radiomics model improves diagnostic performance for pseudoprogression in glioblastoma patients
Authors: Jung Youn Kim, Ji Eun Park, Youngheun Jo, Woo Hyun Shim, Soo Jung Nam, Jeong Hoon Kim, Roh-Eul Yoo, Seung Hong Choi, Ho Sung Kim
Journal: Neuro-Oncology (2018)

Pseudoprogression is a diagnostic challenge in early posttreatment glioblastoma. We therefore developed and validated a radiomics model using multiparametric MRI to differentiate pseudoprogression from early tumor progression in patients with glioblastoma.The model was developed from the enlarging contrast-enhancing portions of 61 glioblastomas within 3 months after standard treatment with 6472 radiomic features being obtained from contrast-enhanced T1-weighted imaging, fluid-attenuated inversion recovery imaging, and apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) maps. Imaging features were selected using a LASSO (least absolute shrinkage and selection operator) logistic regression model with 10-fold cross-validation. Diagnostic performance for pseudoprogression was compared with that for single parameters (mean and minimum ADC and mean and maximum CBV) and single imaging radiomics models using the area under the receiver operating characteristics curve (AUC). The model was validated with an external cohort (n = 34) imaged on a different scanner and internal prospective registry data (n = 23).Twelve significant radiomic features (3 from conventional, 2 from diffusion, and 7 from perfusion MRI) were selected for model construction. The multiparametric radiomics model (AUC, 0.90) showed significantly better performance than any single ADC or CBV parameter (AUC, 0.57-0.79, P < 0.05), and better than a single radiomics model using conventional MRI (AUC, 0.76, P = 0.012), ADC (AUC, 0.78, P = 0.014), or CBV (AUC, 0.80, P = 0.43). The multiparametric radiomics showed higher performance in the external validation (AUC, 0.85) and internal validation (AUC, 0.96) than any single approach, thus demonstrating robustness.Incorporating diffusion- and perfusion-weighted MRI into a radiomics model improved diagnostic performance for identifying pseudoprogression and showed robustness in a multicenter setting.
Abstract 5625: Myeloid derived suppressor cells (MDSCs) express Sialyl Tn (STn) and are a therapeutic target for anti-STn antibody drug conjugates
Authors: David A. Eavarone, Patricia E. Rao, Jillian M. Prendergast, Adam D. Curtis, Rong Zhang, Lindsay S. Shopland, Jenna N. Stein, Jeff Behrens, Daniel T. Dransfield
Journal: Cancer Research (2018)

Abstract Introduction: Myeloid derived suppressor cells (MDSCs) are functionally defined by their capacity to suppress T cell immunity; therefore inhibiting these cells is of great interest for immuno-oncology applications. STn, the sialylated version of the carbohydrate Tn antigen, is broadly expressed in human cancers such as breast, ovarian, bladder, cervical, colon, and lung and is rarely expressed in normal adult human tissues. The presence of STn in tumors is associated with metastatic disease, poor prognosis, and reduced overall survival. Tumor STn expression is well established and can be leveraged for targeted cancer therapy, however its expression on immuno-suppressive tumor infiltrating lymphocytes such as MDSCs has not been established. Methods: We generated humanized anti-STn mAbs having no cross-reactivity to the asialylated form of STn (Tn) or other glycan antigens. The epitope targeted by these mAbs is the STn glycan itself, not a particular glycopeptide or carrier protein, which offers the broadest potential to bind to multiple STn-glycosylated proteins on cell surfaces. We used these mAbs to quantify specifically the expression of tumor and MDSC STn expression across a set of patient tumor samples. We further treated mice with a humanized anti-STn-MMAE antibody-drug conjugate to evaluate targeted depletion of STn+ MDSCs. In order to evaluate the therapeutic potential of targeting this MDSC phenotype, we further evaluated the immunosuppressive environment of tumors containing STn+ and STn- MDSCs. Results: For the first time, we report the detection of STn on the surface of MDSCs in a growing body of patient tumor samples. Our data in patients as well as xenograft models additionally links STn expression on MDSCs to tumor cell STn expression. We have also demonstrated depletion of STn+ MDSCs after treatment with an anti-STn antibody-drug conjugate in an ovarian carcinoma xenograft model. Conclusions: Our data demonstrated that STn provides a uniquely glycan-specific and potent target for treatment of solid tumors. Anti-STn therapeutics offer the potential to go beyond tumor targeting to also directly target and deplete immune-suppressive MDSCs, thus fostering immune re-engagement and increasing the potential for better patient outcomes. Citation Format: David A. Eavarone, Patricia E. Rao, Jillian M. Prendergast, Adam D. Curtis, Rong Zhang, Lindsay S. Shopland, Jenna N. Stein, Jeff Behrens, Daniel T. Dransfield. Myeloid derived suppressor cells (MDSCs) express Sialyl Tn (STn) and are a therapeutic target for anti-STn antibody drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5625.