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Purpose: The major value of prognostic markers in potentially curable non-small cell lung cancer (NSCLC) should be to guide therapy after surgical resection. In this regard, the patients' immune status at the time of resection may be important and also measurable. The immune system has paradoxical roles during cancer development. However, the prognostic significance of tumorinfiltrating lymphocytes is controversial.The aim of this study is to elucidate the prognostic significance of epithelial and stromal lymphocyte infiltration in NSCLC. Experimental Design: Tissue microarrays from 335 resected NSCLC, stage I to IIIA were constructed from duplicate cores of viable and representative neoplastic epithelial and stromal areas. Immunohistochemistry was used to evaluate the epithelial and stromal CD4 No such relation was noted for epithelial CD4 + cells. Furthermore, a low level of stromal CD8 + lymphocyte infiltration was associated with an increased incidence of angiolymphatic invasion (P = 0.032). In multivariate analyses, a high number of stromal CD8 + (P = 0.043) and CD4 + (P = 0.002) cells were independent positive prognostic factors for disease-specific survival.Conclusions: High densities of CD4 + and CD8 + lymphocytes in the stroma are independent positive prognostic indicators for resected NSCLC patients. This may suggest that these cells are mediating a strong antitumor immune response in NSCLC.

Purpose: The vascular endothelial growth factors (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected non–small cell lung cancer tumors. Experimental Design: Tumor tissue samples from 335 resected patients with stage I to IIIA disease were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Microvessel density was assessed by CD34 immunohistochemical staining. Results: In univariate analyses, high tumor cell expression of VEGF-A (P = 0.0005), VEGFR-1 (P = 0.013), VEGFR-2 (P = 0.006), and VEGFR-3 (P = 0.0003) were negative prognostic indicators for disease-specific survival (DSS). In tumor stroma, however, high expression of VEGF-A (P = 0.017), VEGF-C (P = 0.003), VEGF-D (P = 0.009), VEGFR-1 (P = 0.01), and VEGFR-2 (P = 0.019) correlated with good prognosis. There was no significant correlation between microvessel density and DSS. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = 0.007) was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C (P = 0.004) expression had an independent positive survival impact. Conclusion: These are the first tissue microarray data in non–small cell lung cancers showing a positive prognostic impact by highly expressed angiogenic markers in tumor stroma, with VEGF-C as a major independent prognostic indicator.

PROBEX (PROBabilities from EXemplars), a model of probabilistic inference and probability judgment based on generic knowledge is presented. Its properties are that: (a) it provides an exemplar model satisfying bounded rationality; (b) it is a "lazy" algorithm that presumes no pre-computed abstractions; (c) it implements a hybrid-representation, similarity-graded probability. We investigate the ecological rationality of PROBEX and find that it compares favorably with Take-The-Best and multiple regression (Gigerenzer, Todd, & the ABC Research Group, 1999). PROBEX is fitted to the point estimates, decisions, and probability assessments by human participants. The best fit is obtained for a version that weights frequency heavily and retrieves only two exemplars. It is proposed that PROBEX implements speed and frugality in a psychologically plausible way.

Vimentin, nuclear factor-kB (NF-kB) p105, fascin, E-cadherin, TGF-b, Par6 and atypical PKC are molecular markers that play an important role in cell differentiation. Herein, we investigate their prognostic impact in primary non-small-cell carcinoma (NSCLC). Tumour tissue samples from 335 resected patients with stage I -IIIA were used. Tissue microarrays were constructed from duplicate cores of both neoplastic cells and stromal cells and were immunohistochemically evaluated. In univariate analyses, high tumour epithelial cell expressions of NF-kB p105 (P ¼ 0.02) and E-cadherin (P ¼ 0.03) were positive prognostic indicators for disease-specific survival (DSS), whereas high tumour epithelial cell expression of vimentin (P ¼ 0.001) was a negative prognostic indicator. High expression of NF-kB p105 (P ¼ 0.001) and Par6 (P ¼ 0.0001) in the stromal compartment correlated with a good prognosis. In multivariate analyses, the tumour epithelial cell expression of NF-kB p105 (P ¼ 0.0001) and vimentin (P ¼ 0.005) and the stromal cell expression of NF-kB p105 (P ¼ 0.007) and Par6 (P ¼ 0.0001) were independent prognostic factors for DSS. High expression of NF-kB p105 and low expression of vimentin in tumour epithelial cells are independent predictors of better survival in primary NSCLC. In stromal cells, high expressions of NF-kB p105 and Par6 are both favourable independent prognostic indicators.

Sorbitol dehydrogenase from sheep liver shows similarities to mammalian and yeast alcohol dehydrogenases.Comparisons based on peptides from segments of sorbitol dehydrogenase reveal that homologous regions with 38% identity include two ligands to the active site zinc atom in liver alcohol dehydrogenase, as well as further important residues. Similarities in other regions are less extensive, exactly as they are between different alcohol dehydrogenases. In all aspects, sorbitol dehydrogenase appears as a typical member of the alcohol dehydrogenase family. On the other hand, alcohol dehydrogenase from Drosophila, which has a shorter subunit, is not closely related to either of these enzymes, except for a region that probably corresponds to the first part ofthe coenzyme binding domain in many dehydrogenases. Instead, Drosophila alcohol dehydrogenase in its supposed catalytic region shows similarities toward Klebsiea ribitol dehydrogenase, which also has a small subunit. It may be concluded that both alcohol and polyol dehydrogenases show two types of protein subunit, reflecting an early subdivision of polypeptide types into "long" and "short" subunits rather than into different enzymatic specificities or quaternary structures. The relationships explain Imown properties of all these enzymes and provide insight into functional mechanisms and evolutionary interpretations.Sorbitol dehydrogenase (SDH) has some structural properties resembling those of mammalian and yeast alcohol dehydrogenases (ADHs) (1). All these enzymes have subunits ofsimilar size range, are sensitive to the same types of inhibitor, and contain reactive cysteine residues in similar structures, including one ofthe zinc ligands at the active site ofhorse liver ADH (LADH), 4226The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

We examine the success of knowledge transfer within an MNE network by unpacking aggregate knowledge flows into individual projects. We assess knowledge transfer performance along two dimensions: utilization of transferred knowledge and transfer cost. We argue that the substitutive versus complementary nature of subunits' activities is a key determinant of knowledge utilization at the target subunit. Further, we posit that headquarters' incentives and monitoring are crucial factors affecting both the utilization and transfer cost dimensions. Our empirical results, based on 141 individual intersubunit knowledge transfer projects involving 49 subunits in 12 European countries largely support our arguments. Our methodology highlights the fact that aggregate measures of interunit knowledge flows can be misleading since they may include individual projects with widely differing levels of success.

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