Five-axis milling may be performed with a constant tool-orientation or varying optimal tool-orientation. When applying a constant tool orientation, the inc
The carbocyclic analogues of the potent and selective antiherpes agents (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), (E)-5-(2-iodovinyl)-2'-deoxyuridine (IVDU), and (E)-5-(2-bromovinyl)-2'-deoxycytidine (BVDC) were synthesized by conventional methods with use of carbocyclic 2'-deoxyuridine as starting material. C-BVDU, C-IVDU, and C-BVDC were equally selective, albeit slightly less potent, in their antiherpes action than BVDU, IVDU, and BVDC. Although resistant to degradation by pyrimidine nucleoside phosphorylases, C-BVDU did not prove more effective than BVDU in the systemic (oral, intraperitoneal) or topical treatment of HSV-1 infections in mice.
In addition to its inhibitory activity against viral DNA polymerases and reverse transcriptase, the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine (PMEA) also markedly inhibits the replicative cellular DNA polymerases alpha, delta, and epsilon. We have previously shown that PMEA is a strong inducer of differentiation in several in vitro tumor cell models and has marked antitumor potential in vivo. To elucidate the molecular mechanism of the differentiation-inducing activity of PMEA, we have now investigated the effects of the drug on cell proliferation and differentiation, cell cycle regulation, and oncogene expression in the human erythroleukemia K562 cell line. Terminal, irreversible erythroid differentiation of PMEA-treated K562 cells was evidenced by hemoglobin production, increased expression of glycophorin A on the K562 cell membrane, and induction of acetylcholinesterase activity. After exposure to PMEA, K562 cell cultures displayed a marked retardation of S-phase progression, leading to a severe perturbation of the normal cell cycle distribution pattern. Whereas no substantial changes in c-myc mRNA levels and p21, PCNA, cdc2, and CDK2 protein levels were noted in PMEA-treated K562 cells, there was a marked accumulation of cyclin A and, most strikingly, cyclins E and B1. A similar picture of cell cycle deregulation was also observed in PMEA-exposed human myeloid THP-1 cells. However, in contrast to the strong differentiation-inducing activity of PMEA in K562 cells, the drug completely failed to induce monocytic maturation of human myeloid THP-1 cells. On the contrary, THP-1 cells underwent apoptotic cell death in the presence of PMEA, as demonstrated by prelytic, intracellular DNA fragmentation and the binding of annexin V to the cell surface. We hypothesize that, depending on the nature of the tumor cell line, PMEA triggers a process of either differentiation or apoptosis by the uncoupling of normally integrated cell cycle processes through inhibition of DNA replication during the S phase.
No abstract is provided for this article.
Purpose This paper presents an investigation into residual stresses in selective laser sintering (SLS) and selective laser melting (SLM), aiming at a better understanding of this phenomenon. Design/methodology/approach First, the origin of residual stresses is explored and a simple theoretical model is developed to predict residual stress distributions. Next, experimental methods are used to measure the residual stress profiles in a set of test samples produced with different process parameters. Findings Residual stresses are found to be very large in SLM parts. In general, the residual stress profile consists of two zones of large tensile stresses at the top and bottom of the part, and a large zone of intermediate compressive stress in between. The most important parameters determining the magnitude and shape of the residual stress profiles are the material properties, the sample and substrate height, the laser scanning strategy and the heating conditions. Research limitations/implications All experiments were conducted on parts produced from stainless steel powder (316L) and quantitative results cannot be simply extrapolated to other materials. However, most qualitative results can still be generalized. Originality/value This paper can serve as an aid in understanding the importance of residual stresses in SLS/SLM and other additive manufacturing processes involving a localized heat input. Some of the conclusions can be used to avoid problems associated with residual stresses.
