Background: Emerging evidence has suggested that Notch signaling pathway may be involved in the development, progression and metastasis of prostate cancer (PCa). In the present study, we investigated the expression levels of Jagged-1 and Notch-1 in human prostate tumors and their associations with prostate cancer progression and metastasis. Methods: Immunohistochemistry (IHC) for Jagged-1 and Notch-1 was performed on tissue microarray (TMA) slides containing 286 formalin-fixed and paraffin-embedded tissue specimens with various prostatic disorders, including benign changes, high grade prostatic intraepithelial neoplasia (HGPIN), low and high grade prostate cancers as well as metastatic prostate cancers. The expression levels of Jagged-1 and Notch-1 were reported as a final IHC score calculated as staining extent score (0-3) multiplied by intensity score (0-3); with a maximal score equal to 9. ANOVA and t-test were employed to analyze the difference of IHC scores among and between different pathologic categories Results: Jagged-1 cytoplasmic IHC scores in both metastatic PCa (5.92 ± 2.12, Mean ± SD) and high grade PCa (5.74 ± 2.45) were significantly higher than those in low grade PCa (3.55 ± 2.02, p = 9.02E-07 and 4.65E-08, respectively), in HGPIN (4.50 ± 2.34, p = 0.023 and 0.030, respectively), and in prostatic tissues with benign changes (3.39 ± 1.85, p = 7.96E-07 and 2.47E-07, respectively). In addition, Jagged-1 membranous IHC scores in both metastatic PCa (3.05 ± 3.52) and high grade PCa (2.41 ± 2.90) were also significantly higher than those in low grade PCa (0.71 ± 1.42, p = 1.48E-05 and 3.40E-06, respectively) and in prostatic tissues with benign changes (0.82 ± 1.28, p = 3.19E-04 and 0.001, respectively). Similarly, Notch-1 cytoplasmic IHC scores in both metastatic PCa (2.22 ± 2.11) and high grade PCa (1.10 ± 1.68) were significantly elevated when compared with the IHC scores observed in low grade PCa (0.51 ± 1.15, p = 3.63E-06 and 0.023, respectively) and in prostate tissues with benign changes (0.48 ± 1.01, p = 3.37E-06 and 0.017, respectively). Furthermore, significantly more highly expressed Jagged-1 in membrane was observed in Caucasians (vs. African Americans) and in positive surgical resection margin group (vs. negative surgical resection margin group). Conclusions: Our results provide strong evidence that dysregulation of Jagged 1-Notch1 signaling plays a role in PCa progression and metastasis and suggest that Jagged-1 and Notch-1 may be useful markers in distinguishing indolent and aggressive prostate cancers. Citation Format: He Zhu, Xinchun Zhou, Samantha Redfield, Jack Lewin, Lucio Miele. Elevated Jagged-1 and Notch-1 expression in high grade and metastatic prostate cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 410. doi:10.1158/1538-7445.AM2013-410
Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC score of any S1PR (cytoplasmic or nuclear) between benign and malignant changes. Conclusion This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue.
The expression level of Notch1 has been studied in many primary tumor types, but has not been widely investigated in metastatic lesions from human malignancies. Using immunohistochemistry (IHC), the expression level of Notch1 was evaluated and compared between primary and metastatic tumors in 12 different cancers. The mean IHC score of Notch1 was significantly increased in metastatic hepatocellular carcinoma (HCC; 5.4 ± 0.7) and in metastatic renal cell carcinoma (RCC; 5.0 ± 2.3) compared with primary HCC (3.1 ± 0.7, P = .035) and RCC (1.3 ± 0.6, P = .049), respectively. Similarly, the expression level of Notch1 showed an increasing trend in the metastatic malignancies in the larynx, prostate, and stomach compared with corresponding primary malignancies (P values are .055, .072, and .074, respectively). The results demonstrate elevated expression of Notch1 in some metastatic tumors, suggesting that Notch1 may play an important role in the development or maintenance of metastatic lesions, and targeting of Notch1 might be a therapeutic approach against tumor metastasis.
Sacred Heart Hospital Laboratory and the emergency department (ED) educator joined forces to improve throughput in the ED by examining process and focusing on recollect samples. Recollects prolong patient care and increase labor for nurses, techs, and laboratory scientists. The most common compromised samples that are rejected by the laboratory are hemolyzed, clotted, quantity not sufficient for test, and improper specimens. The laboratory and ED educator worked together to address the sample rejection/recollect issue. We educated all associates on sample collection and handling, causes of common compromised samples, and the consequences. One-on-one real-time education (1 week quarterly) was done by following up with the associate collecting the sample as soon as it was discovered in the laboratory. We also provided accountability by publishing a weekly "recollect" list with associates employee numbers and the type of compromised sample they collected the previous week. Ongoing education is provided for all new hires. The results of this incentive were slow and steady. The education and heightened awareness of the issue and consequences of rejected specimens became known throughout the ED and the laboratory. The relationship between the laboratory and ED staff improved as we worked together toward a common goal. Numbers of rejected samples steadily decreased as we continue to monitor and provide feedback. With focused education, follow-up, and continuous accountability, the percentage of recollect samples has decreased. When we began this incentive in 2007, we had as many as 40 rejected samples each week. Today in 2012, the average number of rejected samples per week has been as low as fewer than 10 and averages about 15 per week. We are sustaining this improvement with continued monitoring, ongoing education, and feedback. Category:Practice and Quality Management
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