Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration

Purpose: Investigation of cell migration and proliferation of human glioma cell line spheroids (CLS) and evaluation of morphology, apoptosis, and immunohistochemical expression of MIB-1, p53, and p21 of organotypic muticellular spheroids (OMS) following cisplatin (CDDP) and irradiation (RT). Material and methods: Spheroids of the GaMg glioma cell line and OMS prepared from biopsy tissue of six glioblastoma patients were used. Radiochemosensitvity (5 μg/ml CDDP followed by RT) was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. Results: Combination treatment led to a migration inhibition of 38% (CDDP 13%; RT 27%) and specific growth delay of 2.6 (CDDP 1.3; RT 2.1) in CLS. Cell cycle analysis after combination treatment showed an accumulation of cells in the G2/M phase. In OMS, apoptosis increased, cell proliferation decreased, and p53/p21 expression increased more pronounced following CDDP+RT. No morphological damage was observed. Conclusion: CDDP can lead to enhancement of the RT effect in spheroids of both human glioma cell line spheroids and biopsy spheroids from glioblastoma specimens. The exerted effect is additive rather than synergistic.     

Thymidylate synthase level as the main predictive parameter for sensitivity to 5-fluorouracil, but not for folate-based thymidylate synthase inhibitors, in 13 nonselected colon cancer cell lines.

Thymidylate synthase (TS), a critical enzyme in the de novo synthesis of thymidylate, is an important target for fluoropyrimidines and folate-based TS inhibitors. In a panel of 13 nonselected human colon cancer cell lines, we evaluated the role of TS levels in sensitivity to 5-fluorouracil (5FU) and four folate-based TS inhibitors that have been introduced recently into the clinic: ZD1694 (Tomudex, Raltitrexed, TDX), GW1843U89 (GW), LY231514 (LY), and AG337 (Thymitaq, AG). Because the latter compounds have different transport and polyglutamylation characteristics, we also related these parameters with drug sensitivity, measured by the sulforhodamine B assay after 72 h of drug exposure. For 5FU, the IC50s varied from 0.8 to 43.0 microM. Leucovorin (LV) potentiated the activity of 5FU in only 4 of 13 cell lines. Sensitivity to folate-based TS inhibitors was variable; IC50s were in the range of: 5.3-59.0 nM TDX; 11.0-1570 nM LY; and 0.5-8.9 nM GW. Eleven of 13 cell lines had an IC50 for AG between 1.3 and 5.3 microM. Two cell lines were resistant to AG, Colo201 and SW1116, with IC50s of 27 and 29 microM, respectively. TS catalytic activity (conversion of dUMP to dTMP) varied from 62 to 777 pmol/h/10(6) cells. The number of FdUMP binding sites varied from 32 to 231 fmol/10(6) cells. Regression analysis showed a significant relation between TS catalytic activity and IC50s for 5FU and 5FU/LV. Kis for FdUMP showed a significant Spearman rank correlation with the IC50s of AG and GW. The role of antifolate transport, accumulation, and polyglutamylation was determined with [3H]methotrexate (MTX) as a reference compound. [3H]MTX influx via the reduced folate carrier varied from 18.6 to 150 fmol/10(6) cells/min. Folylpolyglutamate synthetase (FPGS) activity showed a range from 47 to 429 pmol/10(6) cells/h. A total of 24 h of [3H]MTX accumulation showed a 20-fold variation, from 1.2 to 21.8 pmol/10(6) cells. FPGS levels showed a Spearman rank positive correlation with cytotoxicity to TDX. In conclusion, in a heterogeneous nonselected human colon cancer cell line panel, the best predictor for sensitivity to 5FU and 5FU/LV was TS activity. Multiple sensitivity determinants were of importance for antifolate TS inhibitors, including FPGS activity and TS enzyme kinetics.     

Substantial sick-leave costs savings due to a graded activity intervention for workers with non-specific sub-acute low back pain

The objective of this study is to compare the costs and benefits of a graded activity (GA) intervention to usual care (UC) for sick-listed workers with non-specific low back pain (LBP). The study is a single-blind, randomized controlled trial with 3-year follow-up. A total of 134 (126 men and 8 women) predominantly blue-collar workers, sick-listed due to LBP were recruited and randomly assigned to either GA (N = 67; mean age 39 ± 9 years) or to UC (N = 67; mean age 37 ± 8 years). The main outcome measures were the costs of health care utilization during the first follow-up year and the costs of productivity loss during the second and the third follow-up year. At the end of the first follow-up year an average investment for the GA intervention of €475 per worker, only €83 more than health care utilization costs in UC group, yielded an average savings of at least €999 (95% CI: −1,073; 3,115) due to a reduction in productivity loss. The potential cumulative savings were an average of €1,661 (95% CI: −4,154; 6,913) per worker over a 3-year follow-up period. It may be concluded that the GA intervention for non-specific LBP is a cost-beneficial return-to-work intervention.     

Influence of growth hormone on the craniofacial complex of transgenic mice

Growth hormone (GH) secretion affects bone and cartilage physiology. This study investigated the effect of GH on the size of the craniofacial structures and their angular relationship. Three different models of mice with a genetically altered GH axis were used: GH excess (giant), dwarf GH antagonist (dwarf-Ant), and dwarf GH receptor knockout (dwarf-KO) mice. Each model was compared with the corresponding wild type (Wt). Five craniofacial distances were analysed: craniofacial length, upper face height, mandibular anterior height, mandibular ramus length, and mandibular corpus length. In addition, upper and lower incisor lengths and four angular relationships, nasal bone with cranial base, maxillary plane with cranial base, mandibular plane with cranial base, and the angle of the mandible, were determined. Data were analysed by one-way ANOVA. Craniofacial length, upper face height and mandibular corpus length were significantly increased in the giant mice and significantly reduced in the dwarf mice. Mandibular anterior height and mandibular ramus length were significantly affected in the dwarf-KO mice but not in the giant mice. The length of both the upper and lower incisors was significantly increased and reduced in the giant and dwarf-KO mice, respectively. In addition, the angle of the mandible was significantly increased in the giant mice and significantly reduced in the dwarf mice. It is concluded that GH plays a major role in the growth and development of the craniofacial complex by directly and indirectly modulating the size and the angular relationships of the craniofacial structures, including the incisor teeth.     

The Effects of a Graded Activity Intervention for Low Back Pain in Occupational Health on Sick Leave,Functional Status and Pain: 12-Month Results of a Randomized Controlled Trial

Introduction: Behaviorally oriented graded activity interventions have been suggested for sick-listed workers with low back pain on return to work, but have not been extensively evaluated. Methods: One hundred and thirty-four workers were randomly assigned to either a graded activity intervention (n = 67) or usual care (n = 67) and followed-up for 12 months. Results: The graded activity group returned back to work faster with a median of 54 days compared to 67 days in the usual care group. The graded activity intervention was more effective after approximately 50 days post-randomization (HRR = 1.9, CI = 1.2–3.1, p = 0.01). Differences between the groups in number of recurrent episodes, total number of days of sick leave due to low back pain, and total number of days of sick leave due to all diagnoses, were in favor of the graded activity group, although not statistically significant. No effects of the graded activity intervention were found for functional status or pain. Conclusion: Graded activity intervention is a valuable strategy to enhance short-term return to work outcomes.     

Effectiveness of a return-to-work intervention for subacute low-back pain

The effectiveness of return-to-work intervention for subacute low-back pain on work absenteeism, pain severity, and functional status was examined by means of a systematic review of randomized controlled trials. Publications in English that met the selection criteria were identified in a computer-aided search and assessed for methodological quality. A best-evidence synthesis was performed instead of statistical data pooling, because of the heterogeneity of the interventions and study populations. Five of nine studies comparing return-to-work intervention with usual care were identified as methodologically high-quality studies. Strong evidence was found for the effectiveness of return to work intervention on the return-to-work rate after 6 months and for the effectiveness of return-to-work intervention on the reduction of days of absence from work after > or = 12 months. It can be concluded that return-to-work interventions are equal or more effective regarding absence from work due to subacute low-back pain than usual care is.