Psychological Care, Patient Education, Orthotics, Ergonomics and Prevention Strategies for Neck Pain: An Systematic Overview Update as Part of the ICON Project.

OBJECTIVES: To conduct an overview on psychological interventions, orthoses, patient education, ergonomics, and 1°/2° neck pain prevention for adults with acute-chronic neck pain. SEARCH STRATEGY: Computerized databases and grey literature were searched (2006-2012). SELECTION CRITERIA: Systematic reviews of randomized controlled trials (RCTs) on pain, function/disability, global perceived effect, quality-of-life and patient satisfaction were retrieved. DATA COLLECTION & ANALYSIS: Two independent authors selected articles, assessed risk of bias using AMSTAR tool and extracted data. The GRADE tool was used to evaluate the body of evidence and an external panel to provide critical review. MAIN RESULTS: We retrieved 30 reviews (5-9 AMSTAR score) reporting on 75 RCTs with the following moderate GRADE evidence. For acute whiplash associated disorder (WAD), an education video in emergency rooms (1RCT, 405participants] favoured pain reduction at long-term follow-up thus helping 1 in 23 people [Standard Mean Difference: -0.44(95%CI: -0.66 to -0.23)). Use of a soft collar (2RCTs, 1278participants) was not beneficial in the long-term. For chronic neck pain, a mind-body intervention (2RCTs, 1 meta-analysis, 191participants) improved short-term pain/function in 1 of 4 or 6 participants. In workers, 2-minutes of daily scapula-thoracic endurance training (1RCT, 127participants) over 10 weeks was beneficial in 1 of 4 participants. A number of psychosocial interventions, workplace interventions, collar use and self-management educational strategies were not beneficial. REVIEWERS' CONCLUSIONS: Moderate evidence exists for quantifying beneficial and non-beneficial effects of a limited number of interventions for acute WAD and chronic neck pain. Larger trials with more rigorous controls need to target promising interventions.

Preclinical antitumor activity of the oral platinum analog satraplatin.

PURPOSE: Satraplatin is an orally available platinum analog. The purpose of this study was to better characterize satraplatin's preclinical antitumor efficacy in a variety of sensitive and resistant human tumor cell lines and in a prostate cancer xenograft model and to evaluate the effect of satraplatin on PSA expression and/or secretion in a prostate cancer cell line. METHODS: Satraplatin and its primary metabolite JM-118 were preclinically tested for their cytotoxic activity in a range of cancer cells including: human prostate, those forming the NCI drug screening panel, and those resistant to anti-cancer drugs. Also, the antiproliferative efficacy of satraplatin was tested in vivo in a human prostate cancer model. The effect of satraplatin and JM-118 on PSA transcription was measured by quantitative real time PCR. RESULTS: Satraplatin and JM-118 inhibited in vitro and in vivo the growth of prostate cancer cells in a dose-dependent fashion. The IC50 cytotoxicity values for satraplatin ranged from 1 to 3 microM for androgen-insensitive cells and was 11 microM for the androgen-sensitive cell line. Interestingly, JM-118 was up to 16-fold more potent than satraplatin. Oral administration of satraplatin to nude mouse PC-3 xenograft models inhibited the growth of these human tumors. Satraplatin had no direct effect on PSA transcription and the observed decrease in secreted PSA correlated with a decrease in cell number. When evaluated in the NCI drug-screening panel, satraplatin was most active in leukemia and small cell lung cancer cell lines. Both satraplatin and JM-118 were tested on cells resistant to chemotherapeutic agents. Satraplatin and JM-118 were equally active in the cisplatin-resistant A129cp80 ovarian carcinoma cell line, with activity comparable to that observed in the parent line. Neither expression of MDR1, BCRP, MRP1, nor altered tubulin or topoisomerase I were found to mediate resistance to satraplatin or JM-118. Although these resistance mechanisms contribute to drug resistance for a number of chemotherapeutics, they do not appear to play a role in satraplatin resistance. CONCLUSIONS: These results demonstrate that satraplatin and JM-118 have preclinical antitumor activity in human prostate cancer and other tumor types as well, including several cell lines displaying drug resistance to cisplatin, docetaxel and mitoxantrone. In addition, the results suggest that PSA should be further evaluated as a relevant marker of clinical response in patients with prostate cancer treated with satraplatin.

MASPIT: three-hybrid trap for quantitative proteome fingerprinting of small molecule-protein interactions in mammalian cells.

Organic small molecules generally act by perturbing the function of one or more cellular target proteins, the identification of which is essential to an understanding of the molecular basis of drug action. Here we describe the application of methotrexate-linked small molecule ligands to a mammalian three-hybrid interaction trap for proteome-wide identification of small molecule targets, quantification of the targeting potency of unmodified small molecules for such targets in intact cells, and screening for inhibitors of small molecule-protein interactions. During the course of this study we also identified the pyrido[2,3-d]pyrimidine PD173955, a known SRC kinase inhibitor, as a potent inhibitor of several ephrin receptor tyrosine kinases. This finding could perhaps be exploited in the design of inhibitors for this kinase subfamily, members of which have been implicated in the pathogenesis of various diseases, including cancer.

A proteome-wide CDK/CRK-specific kinase inhibitor promotes tumor cell death in the absence of cell cycle progression.

The identification of molecular determinants of tumor cell survival is an important objective in cancer research. Here, we describe a small-molecule kinase inhibitor (RGB-286147), which, besides inhibiting tumor cell cycle progression, exhibits potent cytotoxic activity toward noncycling tumor cells, but not nontransformed quiescent fibroblasts. Extensive yeast three-hybrid (Y3H)-based proteome/kinome scanning with chemical dimerizers revealed CDK1/2/3/5/7/9 and the less well-characterized CDK-related kinases (CRKs) p42/CCRK, PCTK1/3, and PFTK1 as its predominant targets. Thus, RGB-286147 is a proteome-wide CDK/CRK-specific kinase inhibitor whose further study could yield new insight into molecular determinants of tumor cell survival. Our results also suggest that the [1, 3, 6]-tri-substituted-pyrazolo[3,4-d]-pyrimidine-4-one kinase inhibitor scaffold is a promising template for the rational design of kinase inhibitors with potential applications to disease indications other than cancer, such as neurodegeneration, cardiac hypertrophic growth, and AIDS.