Etoposide: four decades of development of a topoisomerase II inhibitor

Podophyllin-containing materials have been used as folk medicines for centuries. In the 1950s, scientists began a search to identify a more effective podophyllotoxin derivative. These efforts eventually resulted in the development of a new class of antineoplastic agents which target the DNA unwinding enzyme, topoisomerase II. The history of the development of one of the first identified topoisomerase II inhibitors, etoposide, is reviewed in this paper. Critical developments in etoposide's mechanism of action, pharmacology and administration schedule are summarised. The clinical benefits of the recently marketed etoposide prodrug, etoposide phosphate (Etopophos) are also detailed. The current status of other clinically approved anticancer agents which target topoisomerase II is briefly reviewed.     

Clinical applications of anticancer drugs targeted to topoisomerase II

Agents which 'poison' the enzyme topoisomerase II, have proven to be useful drugs for cancer treatment. Six antineoplastic drugs, which target topoisomerase II (doxorubicin, daunorubicin, idarubicin, mitoxantrone, etoposide and teniposide) are currently approved for clinical use in the United States. In this paper, the strategies and goals of cancer chemotherapy are summarized for the non-clinician. The use, pharmacology and toxicity of each of the six currently approved topoisomerase II inhibiting agents are reviewed.     

Dark fermentative hydrogen production from sucrose and molasses

There are many factors affecting the dark fermentative hydrogen production. The interaction of these factors, that is, their combined effects, should be investigated for better design of the systems with stable and higher hydrogen yields. This study aimed to investigate the combined effects of initial substrate, pH, and biomass (or initial substrate to biomass) values on hydrogen production from sucrose and sugar‐beet molasses. Therefore, optimum initial chemical oxygen demand (COD), pH, and volatile suspended solids (VSS) or initial substrate to biomass (VSS) ratio (S/X_o) values leading to the highest dark fermentative hydrogen production were investigated in batch reactors. An experimental design approach (response surface methodology) was used. Results revealed that when sucrose was the substrate, maximum hydrogen production yield (HY) of 2.3 mol H₂/mol sucrose_added was obtained at initial pH of 7 and COD of 10 g/L. Initial S/X_o values studied (4–20 g COD/g VSS) had no effect on HY, while the initial pH was found as the parameter mostly affecting both HY and hydrogen production rate (HPR). When substrate was molasses, initial COD concentration was the only variable affecting HY and HPR. Maximum of both was achieved at 10 g/L initial COD. Initial VSS values studied (2.5–7.5 g/L) had no effect on HPR and HY. This study also indicated that molasses leads to homoacetogenesis for potentially containing intrinsic microorganism and/or natural constituents; thus, sucrose is more advantageous for hydrogen production via fermentation. Homoacetogenesis should be prevented for effective optimization via response surface methodology, if substrate is a natural carbon source potential to have intrinsic microorganisms. Copyright © 2017 John Wiley & Sons, Ltd.     

纳秒级d－T聚变反应的16．7MeVγ测量

ｄ－Ｔ聚变反应产生的１６７ＭｅＶγ射线很弱，必须从很强的γ、中于混合场中筛选出来，故要求探测系统有高的信噪比，快的时间响应和宽的动态范围。利用高能γ与介质相互作用的康普顿效应及其定量对应关系，由扇形聚焦磁场一次偏转，用ＣＯ２气体切连科夫探测器（ＧＣＤ）探测电子束，或由扇形聚焦磁场（ＳＣＤ）二次偏转，用有机玻璃切连科夫探测器测电子束。仔细考虑了探测装置的辐射屏蔽和探测系统的电磁屏蔽。分别在“闪光－１”装置、ＤＨＪ－２５回旋加速器和２ＭＶ直线加速器上对探测装置进行了模拟检验实验和标定实验。在实际测试中，首次获得了纳秒级ｄ－Ｔ聚变反应产生的１６７ＭｅＶγ波形。     

Induction of telomerase activity by UV-irradiation in Chinese hamster cells

Telomerase is a ribonucleoprotein whose activity has been detected in germline cells and in neoplastic and immortal cells. Telomerase compensates the telomere loss arising by the end replication problem by synthesizing telomeric repeats at the 3' end of the eukaryotic chromosomes. Telomerase is reactivated during cancer progression in human and mice. In order to determine whether the telomerase activity can be upregulated in vitro in response to DNA damaging agents, we examined the telomerase activity in five Chinese hamster cell lines following exposure to 5 J/m2 or 40 J/m2 UV-C radiation. All the cell lines tested showed an increase in telomerase activity in the PCR-based telomeric repeat amplification protocol (TRAP) in a dose dependent manner. This increase in telomerase activity correlated well with the number of cells being in the S and G2/M phase after UV exposure. However, in unirradiated control cells, similar levels of telomerase activity were observed in different phases of the cell cycle. Furthermore, telomeric signals were clustered in one or more parts of the disintegrating nuclear particles of the apoptotic cell as detected by fluorescence in situ hybridization (FISH). This is the first study to demonstrate the induction of telomerase activity following exposure to DNA-damaging agents like UV radiation in Chinese hamster cells in vitro.     

An artificial neural network model for virtual Superpave asphalt mixture design

This study presents an artificial neural network (ANN) model to predict the asphalt mixture volumetrics at Superpave gyration levels. The input data-set needed by the algorithm is composed of gradation of the mix, bulk specific gravity of aggregates, low- and high-performance grade of the binder, binder content of the mix and the target number of gyrations (i.e. N_ini, N_des and N_max). The proposed ANN model uses a three-layer scaled conjugate gradient back-propagation (feed-forward) network. The ANN was trained using data obtained from numerous roads with a total of 1817 different mix designs. Results revealed that the ANN was able to predict V_a within V_a (measured) ± 1.0% range 85–93% of the time and within V_a (measured) ± 0.5% range 60–70% of the time. Currently with the developed ANN model, Superpave mix design can take approximately between 1.5 and 4.5 days, which corresponds to 3–6 days of savings.     

XANES analysis of calcium and sodium phosphates and silicates and hydroxyapatite–Bioglass®45S5 co-sintered bioceramics

Bioglass®45S5 was co-sintered with hydroxyapatite at 1200 °C. When small amounts (< 5 wt.%) of Bioglass®45S5 was added it behaved as a sintering aid and also enhanced the decomposition of hydroxyapatite to β-tricalcium phosphate. However when 10 wt.% and 25 wt.% Bioglass®45S5 was used it resulted in the formation of Ca₅(PO₄)₂SiO₄ and Na₃Ca₆(PO₄)₅ in an amorphous silicate matrix respectively. These chemistries show improved bioactivity compared to hydroxyapatite and are the subject of this study. The structure of several crystalline calcium and sodium phosphates and silicates as well as the co-sintered hydroxyapatite–Bioglass®45S5 bioceramics were examined using XANES spectroscopy. The nature of the crystalline and amorphous phases were studied using silicon (Si) and phosphorus (P) K- and L_2,3-edge and calcium (Ca) K-edge XANES.Si L_2,3-edge spectra of sintered bioceramic compositions indicates that the primary silicates present in these compositions are sodium silicates in the amorphous state. From Si K-edge spectra, it is shown that the silicates are in a similar structural environment in all the sintered bioceramic compositions with 4-fold coordination.Using P L_2,3-edge it is clearly shown that there is no evidence of sodium phosphate present in the sintered bioceramic compositions. In the P K-edge spectra, the post-edge shoulder peak at around 2155 eV indicates that this shoulder to be more defined for calcium phosphate compounds with decreasing solubility and increasing thermodynamic stability. This shoulder peak is more noticeable in hydroxyapatite and β-TCP indicating greater stability of the phosphate phase. The only spectra that does not show a noticeable peak is the composition with Na₃Ca₆(PO₄)₅ in a silicate matrix indicating that it is more soluble compared to the other compositions.     

Telomere length regulation in mice is linked to a novel chromosome locus

Little is known about the mechanisms that regulate species-specific telomere length, particularly in mammalian species. The genetic regulation of telomere length was therefore investigated by using two inter-fertile species of mice, which differ in their telomere length. Mus musculus (telomere length >25 kb) and Mus spretus (telomere length 5-15 kb) were used to generate F1 crosses and reciprocal backcrosses, which were then analyzed for regulation of telomere length. This analysis indicated that a dominant and trans-acting mechanism exists capable of extensive elongation of telomeres in somatic cells after fusion of parental germline cells with discrepant telomere lengths. A genome wide screen of interspecific crosses, using M. spretus as the recurrent parent, identified a 5-centimorgan region on distal chromosome 2 that predominantly controls the observed species-specific telomere length regulation. This locus is distinct from candidate genes encoding known telomere-binding proteins or telomerase components. These results demonstrate that an unidentified gene(s) mapped to distal chromosome 2 regulates telomere length in the mouse.     

Solving the hub location problem with modular link capacities

This paper deals with a capacitated hub location problem arising in the design of telecommunications networks. The problem is different from the classical hub location problem in two ways: the cost of using an edge is not linear but stepwise and the capacity of a hub restricts the amount of traffic transiting through the hub rather than the incoming traffic. In this paper both an exact and a heuristic method are presented. They are compared and combined in a heuristic concentration approach to investigate whether it is possible to improve the results within limited computational times.