Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp +/-mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.

Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormonerefractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase-extracellular signalregulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017-24]

Purpose-Interorganizational innovation networks are providing opportunities to exploit superior resources that reside beyond the boundary of the firm. The shifting locus of innovation and value creation away from the 'sole firm as innovator' poses important questions about the nature of resources that exist in the spaces between firms, and the capabilities needed to leverage them for competitive advantage. The purpose of this research is to produce design-oriented knowledge, for configuring interorganizational networks as a means of accessing such resources for innovation. Methodology / Approach-This exploratory investigation conflates emerging constructs and themes analytically induced from a systematic survey of 142 scholarly and practitioner articles and 45 expert interviews with senior professionals operating in the biopharmaceuticals industry. Findings and Practical Implications-The findings identify 7 theoretically and empirically grounded technological rules associated with effective interorganizational networking for innovation. They embody evidence ex post of networking theory and practice. Based on van Aken's seminal work, they comprise vital design-oriented knowledge to provide a solution architecture of viable action options for managers, a priori, to purposefully design innovation networks. Collectively these rules represent a tentative taxonomy, a means of classifying design principles, to assist managers in navigating their decision making processes. Originality/value of paper-This study demonstrates the need for explicit design-oriented knowledge for configuring interorganizational networks. Finally, the implications of the findings for strategic management theory are discussed from a Dynamic Capabilities view. The significance of a dynamic capability which addresses the renewal of network-specific resources is highlighted.

Overexpression of the pro-survival protein heme oxygenase-1 (HO-1) and loss of the pro-apoptotic tumour suppressor PTEN are common events in prostate cancer (PCA). We assessed the occurrence of both HO-1 expression and PTEN deletion in two cohorts of men with localized and castration-resistant prostate cancer (CRPC). The phenotypic cooperation of these markers was examined in preclinical and clinical models. Overall, there was a statistically significant difference in HO-1 epithelial expression between benign, high-grade prostatic intraepithelial neoplasia (HGPIN), localized PCA, and CRPC (p < 0.0001). The highest epithelial HO-1 expression was noted in CRPC (2.00 ± 0.89), followed by benign prostate tissue (1.49 ± 1.03) (p = 0.0003), localized PCA (1.20 ± 0.95), and HGPIN (1.07 ± 0.87) (p < 0.0001). However, the difference between HGPIN and PCA was not statistically significant (p = 0.21). PTEN deletions were observed in 35/55 (63.6%) versus 68/183 (37.1%) cases of CRPC and localized PCA, respectively. Although neither HO-1 overexpression nor PTEN deletions alone in localized PCA showed a statistically significant association with PSA relapse, the combined status of both markers correlated with disease progression (log-rank test, p = 0.01). In a preclinical model, inhibition of HO-1 by shRNA in PTEN-deficient PC3M cell line and their matched cells where PTEN is restored strongly reduced cell growth and invasion in vitro and inhibited tumour growth and lung metastasis formation in mice compared to cells where only HO-1 is inhibited or PTEN is restored. In summary, we provide clinical and experimental evidence for cooperation between epithelial HO-1 expression and PTEN deletions in relation to the PCA patient's outcome. These findings could potentially lead to the discovery of novel therapeutic modalities for advanced PCA.

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Heme oxygenase-1 (HO-1) encoded by the HMOX1 gene is a 32-kDa stress protein that catabolizes heme to biliverdin, free iron, and carbon monoxide (CO). Glial HO-1 is over-expressed in the CNS of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). The HMOX1 gene is exquisitely sensitive to oxidative stress and is induced in brain and other tissues in various models of disease and trauma. Induction of the glial HMOX1 gene may lead to pathological brain iron deposition, intracellular oxidative damage, and bioenergetic failure in AD and other human CNS disorders such as PD and MS. Therefore, targeted suppression of glial HO-1 hyperactivity may prove to be a rational and effective therapeutic intervention in AD and related neurodegenerative disorders. In this study, we report the effects of QC-47, QC-56, and OB-28, novel azole-based competitive and reversible inhibitors of HO-1, on oxidative damage to whole-cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. We also report the effect of OB-28 on the behavior and neuropathology of APP swe /PS1 ΔE9 mice. OB-28 was found to reduce oxidative damage to whole-cell and mitochondrial compartments in rat astrocytes transfected with the HMOX1 gene. Moreover, OB-28 was found to significantly counter behavioral deficits and neuropathological alterations in APP swe /PS1 ΔE9 mice. Attenuation of AD-associated behavioral deficits and neuropathological changes suggests that HO-1 may be a promising target for neuroprotective intervention in AD and other neurodegenerative diseases.

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Work on evaluating and improving the relevance of web search engines typically use human relevance judgments or clickthrough data. Both these methods look at the problem of learning the mapping from queries to web pages. In this paper, we identify some issues with this approach, and suggest an alternative approach, namely, learning a mapping from web pages to queries. In particular, we use human computation games to elicit data about web pages from players that can be used to improve search. We describe three human computation games that we developed, with a focus on Page Hunt, a single-player game. We describe experiments we conducted with several hundred game players, highlight some interesting aspects of the data obtained and define the 'findability' metric. We also show how we automatically extract query alterations for use in query refinement using techniques from bitext matching. The data that we elicit from players has several other applications including providing metadata for pages and identifying ranking issues.