The role of cell differentation in controlling cell multiplication and cancer

It has been suggested that cancer ought to be regarded as a disease of cell differentiation. In multicellular organisms, indeed, the control of cell multiplication is linked to cell specialization: During the process of differentiation embryonic cells, while cycling, acquire the ability to perform specialized functions. This ability is incompatible with cell cycling which, as a consequence, is repressed with forthcoming differentiation. Thus, the number of amplification divisions that occur during the period while differentiation is proceeding decides on the number of specialized cells produced. The progress in differentiation, contrary to usual assumptions, is accompanied by an increase in the cellular content of cytoplasm. The reason must be that cell specialization requires a specific amount and array of membrane-bounded cytoplasmic structures. Since the multiplication of these structures depends on membranous templates, their amount increases only if more cytoplasm is produced per cycle than required for a doubling, thus constituting an intracellular timer of differentiation: The larger the net rate of cytoplasmic growth per cell cycle, the fewer cycles occur. Extracellular signals modulate cell multiplication by altering the net rate of cytoplasmic growth. Each persisting alteration, however, that reduces this rate to zero, prevents differentiation, and thus causes the cells to retain embryonic capabilities and to initiate cancer. Cancer cells can be induced to differentiate and cease proliferation by support of cytoplasmic growth. This corroborates the suggestion that cancer must be regarded as a disease of cell differentiation and our conclusion that cancer is caused by a deficiency in cytoplasmic growth. Support of the latter must be an efficient principle in cancer therapy although limited by the organism's dependence on cell renewal

Edoxaban versus warfarin in patients with atrial fibrillation

Contains fulltext : 125374.pdf (publisher's version ) (Open Access)BACKGROUND: Edoxaban is a direct oral factor Xa inhibitor with proven antithrombotic effects. The long-term efficacy and safety of edoxaban as compared with warfarin in patients with atrial fibrillation is not known. METHODS: We conducted a randomized, double-blind, double-dummy trial comparing two once-daily regimens of edoxaban with warfarin in 21,105 patients with moderate-to-high-risk atrial fibrillation (median follow-up, 2.8 years). The primary efficacy end point was stroke or systemic embolism. Each edoxaban regimen was tested for noninferiority to warfarin during the treatment period. The principal safety end point was major bleeding. RESULTS: The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (hazard ratio, 0.79; 97.5% confidence interval [CI], 0.63 to 0.99; P<0.001 for noninferiority) and 1.61% with low-dose edoxaban (hazard ratio, 1.07; 97.5% CI, 0.87 to 1.31; P=0.005 for noninferiority). In the intention-to-treat analysis, there was a trend favoring high-dose edoxaban versus warfarin (hazard ratio, 0.87; 97.5% CI, 0.73 to 1.04; P=0.08) and an unfavorable trend with low-dose edoxaban versus warfarin (hazard ratio, 1.13; 97.5% CI, 0.96 to 1.34; P=0.10). The annualized rate of major bleeding was 3.43% with warfarin versus 2.75% with high-dose edoxaban (hazard ratio, 0.80; 95% CI, 0.71 to 0.91; P<0.001) and 1.61% with low-dose edoxaban (hazard ratio, 0.47; 95% CI, 0.41 to 0.55; P<0.001). The corresponding annualized rates of death from cardiovascular causes were 3.17% versus 2.74% (hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), and 2.71% (hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P=0.008), and the corresponding rates of the key secondary end point (a composite of stroke, systemic embolism, or death from cardiovascular causes) were 4.43% versus 3.85% (hazard ratio, 0.87; 95% CI, 0.78 to 0.96; P=0.005), and 4.23% (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.32). CONCLUSIONS: Both once-daily regimens of edoxaban were noninferior to warfarin with respect to the prevention of stroke or systemic embolism and were associated with significantly lower rates of bleeding and death from cardiovascular causes. (Funded by Daiichi Sankyo Pharma Development; ENGAGE AF-TIMI 48 ClinicalTrials.gov number, NCT00781391.)