Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.

After hepatectomy, survival of patients with recurrent mCRC is strongly predicted by the patterns of recurrence, and the recurrence pattern can be predicted with a simple model. This can also be extended to create a scoring system that estimates expected survival.

The prognostic significance of lymphovascular invasion (LVI) in melanoma remains controversial. Clinicopathologic data from a prospective trial of patients with melanoma were analyzed with respect to LVI. Disease-free survival and overall survival (OS) were evaluated by Kaplan-Meier (KM) analysis. Univariate and multivariate analyses were performed to evaluate factors predictive of tumor-positive sentinel nodes (SLN) and survival. A total of 2183 patients were included in this analysis; 171 (7.8%) had LVI. Median follow-up was 68 months. Factors associated with LVI included tumor thickness, ulceration, and histologic subtype ( P < 0.05). LVI was associated with a greater risk of SLN metastasis ( P < 0.05). By KM analysis, LVI was associated with worse OS ( P = 0.0009). On multivariate analysis, age, gender, thickness, ulceration, anatomic location, and SLN status were predictors of OS; however, LVI was not an independent predictor of OS. Among patients with regression, the 5-year OS rate was 49.4 per cent for patients with LVI versus 81.1 per cent for those with no LVI ( P < 0.0001). LVI is associated with a greater risk of SLN metastasis. Although LVI is not an independent predictor of OS in general, it is a powerful predictor of worse OS among patients who have evidence of regression of the primary tumor.

Factors associated with an R1 resection reflect a biologically more aggressive tumor, with a higher likelihood of microvascular invasion and increased positive lymph node ratio.

No abstract