METHODS: The proliferative effect of the identified protein on MCF-7 cells that interacted non-adhesively with BMSCs pre-treated with pioglitazone and/or rosiglitazone was evaluated using cell culture inserts and conditioned media. The mRNA expression of proliferation and lipid accumulation markers was also evaluated in the interacted MCF-7 cells by reverse transcription-quantitative PCR. Finally, the correlation between the identified protein and fibroblast growth factor 4 (FGF-4) protein in the conditioned media of the pre-treated BMSCs was evaluated by ELISA.
RESULTS: The present study identified vimentin as the specific protein among the complex intracellular proteins that likely plays a role in MCF-7 cell proliferation when the breast cancer cells interacted non-adhesively with BMSCs pre-treated with a combination of pioglitazone and rosiglitazone. The inhibition of this protein promoted the proliferation of MCF-7 cells when the breast cancer cells interacted with pre-treated BMSCs. Gene expression analysis indicated that pre-treatment of BMSCs with a combination of pioglitazone and rosiglitazone decreased the mRNA expression of Ki67 and proliferating cell nuclear antigen in MCF-7 cells. The pre-treatment did not induce mRNA expression of PPARγ, which is a sign of lipid accumulation. The level of vimentin protein was also associated with the FGF-4 protein expression level in the conditioned media of the pre-treated BMSCs. Bioinformatics analysis revealed that vimentin regulated the expression of FGF-4 through its interaction with SRY-box 2 and POU class 5 homeobox 1.
CONCLUSIONS: The present study identified a novel intracellular protein that may represent the promising target in pre-treated BMSCs to decrease the proliferation of breast cancer MCF-7 cells for human health and wellness.
METHODS: We randomised 429 children with newly diagnosed ALL to 15-minute vs 3-hour infusion for the first dose of VCR to study if prolonging the first dose of VCR infusion improved response. In a subgroup of 115 B-ALL and 20 T-ALL patients, we performed VCR plasma (n = 135 patients) and intracellular (n = 66 patients) pharmacokinetic studies. The correlations between pharmacokinetic parameters and intracellular VCR levels with early treatment response, final outcome and ABCB1 genotypes were analysed.
RESULTS: There was no significant difference between 15-minute and 3-hour infusion schedules in median Day 8 peripheral or bone marrow blast response. Plasma VCR pharmacokinetic parameters did not predict outcome. However, in B-ALL, Day 33 minimal residual disease (MRD) negative patients and patients in continuous complete remission had significantly higher median intracellular VCR24h levels (P = .03 and P = .04, respectively). The median VCR24h intracellular levels were similar among the common genetic subtypes of ALL (P = .4). Patients homozygous for wild-type ABCB1 2677GG had significantly higher median intracellular VCR24h (P = .04) than 2677TT.
CONCLUSION: We showed that in childhood B-ALL, the intracellular VCR24h levels in lymphoblasts affected treatment outcomes. The intracellular VCR24h level was independent of leukaemia subtype but dependent on host ABCB1 G2677T genotype.
SUMMARY: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.