Disability weights for the burden of oral disease in South Australia

BACKGROUND: Australian burden of disease estimates appeared inconsistent with the reported repetitive and ubiquitous nature of dental problems. The aims of the study were to measure the nature, severity and duration of symptoms for specific oral conditions, and calculate disability weights from these measures. METHODS: Data were collected in 2001–02 from a random sample of South Australian dentists using mailed self-complete questionnaires. Dentists recorded the diagnosis of dental problems and provided patients with self-complete questionnaires to record the nature, severity and duration of symptoms using the EuroQol instrument. Data were available from 378 dentists (response rate = 60%). RESULTS: Disability weights were highest for pulpal infection (0.069), caries (0.044) and dentinal sensitivity (0.040), followed by denture problems (0.026), periodontal disease (0.023), failed restorations (0.019), tooth fractures (0.014) and tooth wear (0.011). Aesthetic problems had a low disability weight (0.002), and both recall/maintenance care and oral hygiene had adjusted weights of zero. CONCLUSIONS: Disability weights for caries (0.044), periodontal disease (0.023) and denture problems (0.026) in this study were higher than comparable oral health conditions in the Australian Burden of Disease and Injury Study (0.005 for caries involving a filling and 0.014 for caries involving an extraction, 0.007 for periodontal disease, and 0.004 for edentulism). A range of common problems such as pulpal infection, failed restorations and tooth fracture that were not included in the Australian Burden of Disease and Injury Study had relatively high disability weights. The inclusion of a fuller range of oral health problems along with revised disability weights would result in oral health accounting for a larger amount of disability than originally estimated

A phase II trial of gefitinib with 5-fluorouracil, leucovorin, and irinotecan in patients with colorectal cancer

Inhibition of epidermal growth factor receptor (EGFR) signalling contributes to the therapy of colorectal cancer. Gefitinib, an oral EGFR tyrosine kinase inhibitor, shows supra-additive growth inhibition with irinotecan and fluoropyrimidines in xenograft models. We designed a study to determine the tolerability and efficacy of gefitinib in combination with irinotecan, infusional 5-fluorouracil (5-FU) and leucovorin (LV), on a 2-week schedule. Among 13 patients with advanced colorectal cancer, 10 required dose reductions of irinotecan and 5-FU because of dehydration, diarrhoea, and neutropenia, seven of whom required hospitalisation, three with neutropenic fever. One patient achieved partial response and seven had disease stabilisation. The combination of this standard chemotherapy regimen with gefitinib is associated with excessive toxicity, suggesting an interaction at a pharmacokinetic or pharmacodynamic level

Effects of perceived cocaine availability on subjective and objective responses to the drug

<p>Abstract</p> <p>Rationale</p> <p>Several lines of evidence suggest that cocaine expectancy and craving are two related phenomena. The present study assessed this potential link by contrasting reactions to varying degrees of the drug's perceived availability.</p> <p>Method</p> <p>Non-treatment seeking individuals with cocaine dependence were administered an intravenous bolus of cocaine (0.2 mg/kg) under 100% ('unblinded'; N = 33) and 33% ('blinded'; N = 12) probability conditions for the delivery of drug. Subjective ratings of craving, high, rush and low along with heart rate and blood pressure measurements were collected at baseline and every minute for 20 minutes following the infusions.</p> <p>Results</p> <p>Compared to the 'blinded' subjects, their 'unblinded' counterparts had similar craving scores on a multidimensional assessment several hours before the infusion, but reported higher craving levels on a more proximal evaluation, immediately prior to the receipt of cocaine. Furthermore, the 'unblinded' subjects displayed a more rapid onset of high and rush cocaine responses along with significantly higher cocaine-induced heart rate elevations.</p> <p>Conclusion</p> <p>These results support the hypothesis that cocaine expectancy modulates subjective and objective responses to the drug. Provided the important public health policy implications of heavy cocaine use, health policy makers and clinicians alike may favor cocaine craving assessments performed in the settings with access to the drug rather than in more neutral environments as a more meaningful marker of disease staging and assignment to the proper level of care.</p

CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.Oncogene advance online publication, 10 April 2017; doi:10.1038/onc.2017.87

Anti-Cripto Mab inhibit tumour growth and overcome MDR in a human leukaemia MDR cell line by inhibition of Akt and activation of JNK/SAPK and bad death pathways

Doxorubicin (DOX) selection of CCRF-CEM leukaemia cell line resulted in multidrug resistance (MDR) CEM/A7R cell line, which overexpresses MDR, 1 coded P-glycoprotein (Pgp). Here, we report for the first time that oncoprotein Cripto, a founding member of epidermal growth factor-Cripto-FRL, 1-Criptic family is overexpressed in the CEM/A7R cells, and anti-Cripto monoclonal antibodies (Mab) inhibited CEM/A7R cell growth both in vitro and in an established xenograft tumour in severe combined immunodeficiency mice. Cripto Mab synergistically enhanced sensitivity of the MDR cells to Pgp substrates epirubicin (EPI), daunorubicin (DAU) and non-Pgp substrates nucleoside analogue cytosine arabinoside (AraC). In particular, the combination of anti-Cripto Mab at less than 50% of inhibition concentrations with noncytotoxic concentrations of EPI or DAU inhibited more than 90% of CEM/A7R cell growth. Cripto Mab slightly inhibited Pgp expression, and had little effect on Pgp function, indicating that a mechanism independent of Pgp was involved in overcoming MDR. We demonstrated that anti-Cripto Mab-induced CEM/A7R cell apoptosis, which was associated with an enhanced activity of the c-Jun N-terminal kinase/stress-activated protein kinase and inhibition of Akt phosphorylation, resulting in an activation of mitochondrial apoptosis pathway as evidenced by dephosphorylation of Bad at Ser136, Bcl-2 at Ser70 and a cleaved caspase-9

Epithelial-Mesenchymal Transition in Cancer: Parallels Between Normal Development and Tumor Progression

From the earliest stages of embryonic development, cells of epithelial and mesenchymal origin contribute to the structure and function of developing organs. However, these phenotypes are not always permanent, and instead, under the appropriate conditions, epithelial and mesenchymal cells convert between these two phenotypes. These processes, termed Epithelial-Mesenchymal Transition (EMT), or the reverse Mesenchymal-Epithelial Transition (MET), are required for complex body patterning and morphogenesis. In addition, epithelial plasticity and the acquisition of invasive properties without the full commitment to a mesenchymal phenotype are critical in development, particularly during branching morphogenesis in the mammary gland. Recent work in cancer has identified an analogous plasticity of cellular phenotypes whereby epithelial cancer cells acquire mesenchymal features that permit escape from the primary tumor. Because local invasion is thought to be a necessary first step in metastatic dissemination, EMT and epithelial plasticity are hypothesized to contribute to tumor progression. Similarities between developmental and oncogenic EMT have led to the identification of common contributing pathways, suggesting that the reactivation of developmental pathways in breast and other cancers contributes to tumor progression. For example, developmental EMT regulators including Snail/Slug, Twist, Six1, and Cripto, along with developmental signaling pathways including TGF-β and Wnt/β-catenin, are misexpressed in breast cancer and correlate with poor clinical outcomes. This review focuses on the parallels between epithelial plasticity/EMT in the mammary gland and other organs during development, and on a selection of developmental EMT regulators that are misexpressed specifically during breast cancer