Project description:Background: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients' life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. Objective: To identify predictive serum biomarkers for Abi treatment. Design, setting, and participants: We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection methods were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Outcome measurements and statistical analysis: Serum levels were correlated with patients‘ clinicopathological parameters and survival. Results and limitations: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering methods four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p<0.001 and p=0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. Conclusions: Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1. Patient summary: In this study, we identified serum FSCN1 as a marker that may help to predict PCa patients who derive less benefit from Abi but not Doc treatment.
Project description:Leiomyoma with bizarre nuclei (LM-BN) is a rare variant of leiomyoma with a benign clinical course. In contrast, leiomyosarcoma (LMS) is a high-grade, malignant neoplasm characterized by high recurrence rates and poor survival. While LM-BN and LMS show distinct morphologies, they share similar immunoprofile and molecular alterations, with both considered “DNA unstable”. Rare cases of LM-BN associated with LMS have been reported, however the histogenesis and molecular relationship between these two tumors remains unclear. In this study, we assessed 11 cases of LMS arising in conjunction with LM-BN and further analyzed the clinical, histologic, and molecular characteristics of these lesions. Tumor slides were examined by histology and immunohistochemistry to confirm the presence of both LMS and LM-BN components. LM-BN and LMS had similar p16 and p53 IHC patterns, but LMS had a higher Ki-67 index and lower ER/PR expression. Digital image analysis based on nuclear and cytologic features revealed spatial relationships between LMS and LM-BN. Genomic copy number alteration (CNA) demonstrated the same clonal origin of LMS from existing LM-BN through conserved copy number alterations. LMS harbored higher CNAs and frequent loss of the TP53, Rb, PTEN, and/or CDKN2A genomic region than LM-BN, indicative of tumor progression. Spatial transcriptome analysis defined uniquely expressed gene signatures in a geographical distribution, demonstrating molecular evidence of regional cell specific differences of LM-BN and LMS. Mutation analysis of large oncogenic panel revealed many shared functional gene alterations in both LM-BN and LMS, but more highly enriched in LMS. Our findings for the first time suggest that a subset of LMS arise from an existing LM-BN.
Project description:LAPC4 cells were starved for 2 days and stimulated with 1µM 5α-Abi or 0.1nM DHT. Gene expression profiles are detected to determine the effect of 5a-Abi on prostate cancer cell line.
Project description:To find out acute rejection (AR) associated microRNAs, we have employed Agilent microRNA microarray as a discovery platform to identify microRNAs with the potential to distinguish AR from controls. We first established a rat Orthotopic liver transplantation (OLT) model with AR, using Brown Norway (BN) rats that received OLT with liver grafts from Lewis rats (Lewis to BN). OLT with BN rats as the donors and recipients were also performed (BN to BN), and these rats served as the control group (non-rejection group, NR group). Then, global microRNA expression profiles of the plasma and grafts were evaluated and validated with high throughout microarray and RT-qPCR.
Project description:Gene expression profile of LSK-enriched population of hematopoietic progenitor cells from Abi-1 KO mice indicates activation of the NFκB pathway. In this dataset, we include the expression data obtained from Lineage-, Sca-1+, cKit+ (LSK)-enriched population of hematopoietic progenitor cells isolated from the bone marow of Abi-1 KO and WT animals. Abi1(fl/fl);Tg (Mx1- cre(-)) or Abi1(fl/fl);Tg (Mx1-cre(+)) mice were subjected to polyinosinic:polycytidylic acid [poly(I:C)]-induced activation of the Cre recombinase under control of the Mx1 promoter to obtain animals with an Abi1(fl/fl);Tg (Mx1-cre(-)) (Abi-1 WT) or Abi1(-/-);Tg (Mx1-cre(+)) (Abi-1 KO) genotype.
Project description:Comparison of gene expression levels in ductus arteriosus (DA) and aorta in full-term (21 days) neonates of Brown-Norway (BN) and Fischer344 (F344) rats We analyzed the fold difference between BN and F344 rats in ductus arteriosus in order to identify the down-regulated and up-regulated genes specifically in BN rat's DA. The differences in aorta was also examined for additional comparison.