Mouse Anti-Human S100P monoclonal antibody, clone JID769

Intimate two-way interactions between the implantation-competent blastocyst and receptive uterus are prerequisite for successful embryo implantation. In humans, recurrent/repeated implantation failure (RIF) may occur due to altered uterine receptivity with aberrant gene expression in the endometrium as well as genetic defects in embryos. Several studies have been performed to understand dynamic changes of uterine transcriptome during menstrual cycles in humans. However, uterine transcriptome of the patients with RIF has not been clearly investigated yet. Here we show that several signaling pathways as well as many genes and microRNAs are dysregulated in the endometrium of patients with RIF (RIFE). Whereas unsupervised hierarchical clustering showed that overall mRNA and microRNA profiles of RIFE were similar to those of endometria of healthy women, many genes were significantly dysregulated in RIFE (cut off at 1.5 fold change). The majority (similar to 75%) of differentially expressed genes in RIFE including S100 calcium binding protein P (S100P), Chemokine (C-X-C motif) ligand 13 (CXCL13) and SIX homeobox 1 (SIX1) were down-regulated, suggesting that reduced uterine expression of these genes is associated with RIF. Gene Set Enrichment analyses (GSEA) for mRNA microarrays revealed that various signaling pathways including Leukemia inhibitory factor (LIF) signaling and a P-4 response were dysregulated in RIFE although expression levels of Estrogen receptor alpha (ER alpha) and Progesterone receptor (PR) were not significantly altered in RIFE. Furthermore, expression and phosphorylation of Signal transducer and activator of transcription 3 (STAT3) are reduced and a gene set associated with Janus kinase (JAK)-STAT signaling pathway is systemically down-regulated in these patients. Pairwise analyses of microRNA arrays with prediction of dysregulated microRNAs based on mRNA expression datasets demonstrated that 6 microRNAs are aberrantly regulated in RIFE. Collectively, we here suggest that dysregulation of several major signaling pathways and genes critical for uterine biology and embryo implantation may lead to uterine abnormalities in patients with RIF.

Immunohistochemistry for PAX8 and GATA3 are sensitive markers for renal cell carcinoma and urothelial carcinoma, respectively. However, there are limited data on these markers in sarcomatoid renal cell carcinoma (SARCRCC) and sarcomatoid urothelial carcinoma (SARCUC). Tissue microarrays (TMAs) were constructed from 45 cases of SARCRCC and 45 cases of SARCUC of the lower urinary tract, with an additional 11 SARCUCs of the upper tract. PAX8 and GATA3 were also evaluated in TMAs from 161 sarcomas from other sites, 14 atypical epithelioid angiomyolipomas (AMLs) of the kidney, 23 bladder inflammatory myofibroblastic tumors (IMTs), and 2 bladder and 4 renal leiomyosarcomas. In the SARCRCC, PAX8 and GATA3 were positive in the sarcomatoid areas in 31(69%) and 0 (0%) of cases, respectively. In the bladder SARCUC, GATA3 and PAX8 were positive in 14 (31%) and 2 (4%) of cases, respectively. Of the 11 SARCUCs of the upper urinary tract, 2 (18%) cases were PAX8 positive and 2 (18%) separate cases were GATA3 positive. Only 1 tumor present on the sarcoma TMAs, a Ewing sarcoma/primitive neuroectodermal tumor, was PAX8 positive, and all sarcomas were GATA3 negative. Of the AMLs, IMTs, and leiomyosarcoma, only 1 case of IMT showed moderate GATA3 positivity, and all were negative for PAX8. PAX8 can be used to distinguish SARCCRCC from atypical epithelioid AMLs and primary renal or retroperitoneal sarcomas. However, in a kidney/renal pelvic tumor, PAX8 shows overlap in staining between SARCUC and SARCRCC. GATA3 lacks sensitivity but is more specific for SARCUC. (C) 2013 Elsevier Inc. All rights reserved.