Functional role of cell surface CUB domain-containing protein 1 in tumour cell dissemination

The function of CUB domain-containing protein 1 (CDCP1), a recently described transmembrane protein expressed on the surface of hematopoietic stem cells and normal and malignant cells of different tissue origin, is not well defined. The contribution of CDCP1 to tumor metastasis was analyzed by using HeLa carcinoma cells overexpressing CDCP1 (HeLa-CDCP1) and a high-disseminating variant of prostate carcinoma PC-3 naturally expressing high levels of CDCP1 (PC3-hi/diss). CDCP1 expression rendered HeLa cells more aggressive in experimental metastasis in immunodeficient mice. Metastatic colonization by HeLa-CDCP1 was effectively inhibited with subtractive immunization-generated, CDCP1-specific monoclonal antibody (mAb) 41-2, suggesting that CDCP1 facilitates relatively late stages of the metastatic cascade. In the chick embryo model, time- and dose-dependent inhibition of HeLa-CDCP1 colonization by mAb 41-2 was analyzed quantitatively to determine when and where CDCP1 functions during metastasis. Quantitative PCR and immunohistochemical analyses indicated that CDCP1 facilitated tumor cell survival soon after vascular arrest. Live cell imaging showed that the function-blocking mechanism of mAb 41-2 involved enhancement of tumor cell apoptosis, confirmed by attenuation of mAb 41-2–mediated effects with the caspase inhibitor z-VAD-fmk. Under proapoptotic conditions in vitro, CDCP1 expression conferred HeLa-CDCP1 cells with resistance to doxorubicin-induced apoptosis, whereas ligation of CDCP1 with mAb 41-2 caused additional enhancement of the apoptotic response. The functional role of naturally expressed CDCP1 was shown by mAb 41-2–mediated inhibition of both experimental and spontaneous metastasis of PC3-hi/diss. These findings confirm that CDCP1 functions as an antiapoptotic molecule and indicate that during metastasis CDCP1 facilitates tumor cell survival likely during or soon after extravasation.

Quantifying variability within technique and performance in elite fast bowlers : is technical variability dysfunctional or functional?

In fast bowling, cricketers are expected to produce a range of delivery lines and lengths while maximising ball speed. From a coaching perspective, technique consistency has been typically associated with superior performance in these areas. However, although bowlers are required to bowl consistently, at the elite level they must also be able to vary line, length and speed to adapt to opposition batters’ strengths and weaknesses. The relationship between technique and performance variability (and consistency) has not been investigated in previous fast bowling research. Consequently, the aim of this study was to quantify both technique (bowling action and coordination) and performance variability in elite fast bowlers from Australian Junior and National Pace Squads. Technique variability was analysed to investigate whether it could be classified as functional or dysfunctional in relation to speed and accuracy.

The role of cross-functional teams on the alignment between technology innovation effectiveness and operational effectiveness

Organisations are increasingly investing in complex technological innovations, such as enterprise information systems, with the aim of improving the operation of the business, and in this way gaining competitive advantage. However, the implementation of technological innovations tends to have an excessive focus on either technology innovation effectiveness, or the resulting operational effectiveness. Focusing on either one of them is detrimental to long-term performance. Cross-functional teams have been used by many organisations as a way of involving expertise from different functional areas in the implementation of technologies. The role of boundary spanning actors is discussed as they bring a common language to the cross-functional teams. Multiple regression analysis has been used to identify the structural relationships and provide an explanation for the influence of cross-functional teams, technology innovation effectiveness and operational effectiveness in the continuous improvement of operational performance. The findings indicate that cross functional teams have an indirect influence on continuous improvement of operational performance through the alignment between technology innovation effectiveness and operational effectiveness.

Functional heterogeneity as a two-dimensional concept : empirical evidence for new venture teams

Previous research on entrepreneurial teams has failed to settle the controversy over whether team heterogeneity helps or hinders new venture performance. Reconciling this inconsistency, this paper suggests a new conceptual approach to disentangle differential effects of team heterogeneity by modeling two separate heterogeneity dimensions, namely knowledge scope and knowledge disparity. Analyzing unique data on functional experiences of the members of 337 start-up teams, we find support for our contention of team heterogeneity as a two-dimensional concept. Results suggest that knowledge disparity negatively relates to both start-ups’ entrepreneurial and innovative performance. In contrast, we find knowledge scope to positively affect entrepreneurial performance, while it shows an inverse U-shaped relationship to innovative start-up performance.

Osteopontin is a downstream effector of the PI3-kinase pathway in melanomas that is inversely correlated with functional PTEN

The tumor suppressor PTEN antagonizes phosphatidylinositol 3-kinase (PI3K), which contributes to tumorigenesis in many cancer types. While PTEN mutations occur in some melanomas, their precise mechanistic consequences have yet to be elucidated. We sought to identify novel downstream effectors of PI3K using a combination of genomic and functional tests. Microarray analysis of 53 melanoma cell lines identified 610 genes differentially expressed (P<0.05) between wild-type lines and those with PTEN aberrations. Many of these genes are known to be involved in the PI3K pathway and other signaling pathways influenced by PTEN. Validation of differential gene expression by qRT-PCR was performed in the original 53 cell lines and an independent set of 18 melanoma lines with known PTEN status. Osteopontin (OPN), a secreted glycophosphoprotein that contributes to tumor progression, was more abundant at both the mRNA and protein level in PTEN mutants. The inverse correlation between OPN and PTEN expression was validated (P<0.02) by immunohistochemistry using melanoma tissue microarrays. Finally, treatment of cell lines with the PI3K inhibitor LY294002 caused a reduction in expression of OPN. These data indicate that OPN acts downstream of PI3K in melanoma and provides insight into how PTEN loss contributes to melanoma development.