A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease

We cloned a novel splicing variant for nuclear coactivator p120(alpha), designated as p120beta and studied its function and expression in several human prostate diseases. Transfection assays demonstrated that p120beta functions as a strong coactivator for androgen receptor (AR), but weakly for other nuclear receptors. GST-pull down assay showed that a glutamine-rich region of the p120 bound to the ligand-binding domain of AR. Interestingly, p120beta mRNAs were expressed predominantly in the normal prostate, androgen-responsive prostate cancers and an androgen-sensitive prostate cancer cell line, LNCaP, but weakly in recurrent cancers and the androgen-insensitive prostate cancer cell lines PC3 and DU145. Furthermore, knockdown of p120alpha by siRNA abolished coactivator activity on thyroid hormone receptors (TR) and PPARgamma, but did not affect that of ARs in PC3 cells. In addition, competitive assay with other nuclear receptors demonstrated that TR and PPARgamma did not inhibit p120beta-induced stimulation. These findings suggested that while p120alpha was essential for ligand-dependent stimulation of TRs and PPARgamma, p120beta acted as a coactivating protein predominantly for AR.     

Clinical usefulness of the immunostaining of the tumor markers in pancreatic cancer

The effect of the rapid immunostaining of gastrointestinal cancer-associated antigens, CA19-9, CEA, DUPAN2, and CA50 was discussed for intraoperative pathological diagnosis of pancreatic cancer. The method can be completed in only 13 minutes with microwave irradiation to accelerate the incubation of the primary antibody. Only 3 seconds of irradiation at 500 W for fresh-frozen sections produced specific antigen staining of greater intensity than that obtained with longer incubation by the conventional method. Preservation of the tissue structure was satisfactory with minimal nonspecific background staining enabling us to diagnose the intrapancreatic spread of cancer. This method was also applied to intraoperative peritoneal washing cytology. As with frozen section biopsy, the sensitivity of intraoperative cytology is greater than by the conventional staining method, which is able to achieve more precise staging of pancreatic cancers. Our rapid immunoperoxidase staining method on the cryostat section of pancreatic biopsy specimens and on cytology samples provides important information to determine an appropriate operative approach for pancreatic cancer.     

螺旋CT检测冠状动脉钙化的临床应用

目的：研究螺旋CT检测冠状动脉钙化(CAC)在冠心病诊断中的应用价值。方法：27例既往确诊为冠心病或经心电图负荷试验和／或冠状动脉造影临床确诊的冠心病患(冠心病组)和35例非冠心病患(对照组)分别进行螺旋CT检查。结果：受检随着年龄的增长钙化率逐渐增高，冠心病组冠状动脉钙化率比对照组明显增高，但随年龄的增长冠心病组钙化的特异性降低(降至11．12％)。钙化血管以累及一支血管最常见，多为左前降支(LAD)，三支血管钙化主要见于60岁以上。结论：螺旋CT检测冠状动脉钙化对早期诊断冠心病和预测冠心病事件有与病理相符的临床价值。     

Fixed-ratio combinations of basal insulin and glucagon-like peptide-1 receptor agonists as a promising strategy for treating diabetes

The maintenance of appropriate glycemic control is important for the prevention of diabetic complications in people with type 2 diabetes(T2D). Numerous oral antidiabetic drugs are now clinically available, but in particular, the introduction of injection regimens using insulin and/or glucagon-like peptide-1 receptor agonist(GLP-1RA)s represents promising step-up options for oral antidiabetic drug treatment. The recently licensed fixed-ratio combination(FRC) products,which comprise basal insulin ...     

Exacerbation of Established Collagen-Induced Arthritis in Mice Treated with An Anti—T Cell Receptor Antibody

Objective. To investigate the effect of T cell depletion on established collagen-induced arthritis (CIA) in mice, using monoclonal antibodies (MAb) to T cell receptor α/β (TCRα/β). In addition, experiments using anti-CD3 MAb were performed for comparison. Methods. CIA was induced in male DBA/1 mice by immunizing them twice with bovine type II collagen (CII). The arthritis score and anti-CII antibody titers were examined serially. Proportions of T cells were determined by fluorescence-activated cell sorter (FACS) analysis on spleen cells or peripheral blood cells. Results. When anti-TCRα/β MAb was injected on the day of CII priming, no arthritis was detected in association with depressed anti-CII antibody titers. Unexpectedly, however, when MAb was given after arthritis was established, a rapid exacerbation of arthritis was observed, which resulted in ankylosis of most joints. Anti-CII antibody titers were not affected. The addition of anti-TCRγ/δ MAb had no effect on the augmented arthritis. T cell depletion by anti-CD3 MAb during established CIA also caused an enhancement of arthritis, which was, however, weak and only transient. FACS analysis revealed that the early improvement of arthritis after the transient augmentation seen in the mice treated with anti-CD3 MAb paralleled the early recovery of α/β T cells in the periphery. Conclusion. The present results support the concept that α/β T cells, in general, may play a regulatory role in the clinical course of murine CIA after disease onset. Therefore, caution is recommended when using intensive T cell—targeted therapy in patients with rheumatoid arthritis.     

Evidence of the extrathymic development of tyrosinase-related protein-2-recognizing CD8+ T cells with low avidity

The majority of the human tumour‐associated antigens characterized to date are derived from non–mutated self‐proteins. However, nothing is known about the development of autoreactive and tumour‐associated antigen‐recognizing T cells. Tyrosinase‐related protein (TRP)‐2 is a non‐mutated melanocyte differentiation antigen and TRP‐2‐recognizing CD8⁺ T cells are known to show responses to melanoma both in humans and mice. In addition, TRP‐2‐reactive T cells with low avidity have been suggested to be readily induced from the spleen cells of naïve mice. On the other hand, recent reports suggest that self antigen‐reactive CD8⁺ T cells can be positively selected in the periphery. In this study, we tested the possibility that TRP‐2‐reactive CD8⁺ T cells in naïve mice could develop via the extrathymic pathway. As a consequence, TRP‐2‐reactive CD8⁺ T cell precursors in naïve C57BL/6 mice were suggested to express both interleukin‐2 (IL‐2) receptor β chain (IL‐2Rβ) and CD44 molecules, in a manner similar to that of extrathymically developed T cells. Furthermore, IL‐2Rβ⁺ CD44⁺ CD8⁺ T cells were detected in the adult thymectomized and bone marrow‐reconstituted mice, and functional TRP‐2‐reactive T cells were generated from their spleen cells. Overall, these results suggest that low avidity CD8⁺ T cells recognizing TRP‐2 can be developed extrathymically.