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.     

An abrupt transition in colony founding behaviour in the ant Messor pergandei

Transitions in behaviour across a continuous distribution of organisms can provide valuable information on how variation in behaviour is maintained. We used analyses developed for interspecific hybrid zones to examine geographic variation in colony founding strategy in the desert seed-harvester ant, Messor pergandei. Newly mated females initiate new colonies either alone (haplometrosis) or cooperatively with other foundresses (pleometrosis). The incidence of these founding strategies were surveyed across the species' range and found to occur in geographically distinct regions joined by a narrow transition zone. Foundresses collected from haplometrotic sites were more likely to display aggression and found solitary nests than foundresses from pleometrotic sites, suggesting that geographical variation in metrosis is due to genotypic divergence. Foundresses from transitional sites were generally not aggressive and tended to co-found nests in the laboratory, yet rarely formed associations in the field. Such an abrupt shift in behaviour indicates that variation in colony founding strategy is maintained by selection rather than the result of secondary contact of neutral characters. Level of aggression displays a wider cline than founding strategy and is likely under selection only when accompanied by active strategy preference. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.     

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.     

Fibular shortening in poliomyelitis

We have determined the nucleotide and encoded amino acid sequences of the capsid, membrane precursor, membrane, envelope, and nonstructural NS1 protein genes of a dengue-2 virus (D2-04) isolated from a patient in Hainan, China. The sequenced region contains a gene organization similar to that of other flaviviruses. The overall amino acid sequence similarity between D2-04 and other dengue-2 viruses is greater than 92%, whereas that between D2-04 and members of the other dengue serotypes is about 65%.     

Optimal head related transfer functions for hearing and monaural localization in elevation: a signal processing design perspective

Localization of sound sources by human listeners has been widely studied and theories and various models of the localization and hearing mechanism have been constructed. In the classical "duplex" theory, sound localization in azimuth is explained by interaural time or equivalently, phase differences at low frequencies, and by interaural amplitude differences at higher frequencies. Head related transfer functions (HRTF's) present a linear system approach to modeling localization by representing the direction-dependent transformation the sound undergoes at each ear. Localization in elevation is explained by directional differences in the HRTF's, which also explains monaural localization. We conjecture that the HRTF's evolved during the course of nature (due to the evolution of the shape and structure of the ear etc.) are optimal with respect to several physically realizable criteria. In this paper, we investigate the problem of defining the design constraints which when optimized yield a set of HRTF's for hearing and monaural vertical localization in an attempt to better understand, and if possible, duplicate nature's design. We pursue an engineer's design perspective and formulate a constrained optimization problem, where the desired set of HRTF's is optimized according to a cost function based on several criteria for localization, hearing and smoothness, and also by imposing physically realizable constraints on the HRTF's such as nonnegativity, energy etc. The value of the cost function for a candidate set of HRTF's is an indication of the similarity of that set of HRTF's with respect to the ideal solution (measured HRTF data). The final optimization results we present are similar to the actual HRTF's measured in human subjects, and the associated cost function values are found to be almost equal. This points to the fact that the optimization criteria defined are quite relevant. The significant outcome of this research is the identification of a relevant set of mathematical criteria that could be optimized in the human auditory system to facilitate good hearing and localization. These criteria along with the associated constraints represent the desirable characteristics of the HRTF's in an HRTF-based localization system, and could lead to a better understanding and modeling of the auditory system.     

Fibrous myopathy. A rheumatic complication of drug abuse

A progressive fibrous myopathy may result from chronic intramuscular drug abuse. This complication may mimic other rheumatic disorders and early recognition may prevent disability. The patient described here presented with fixed flexion and extension contracture of hips and knees, respectively, after abusing meperidine and other agents for 3 years. Soft tissues of thighs and buttocks were "wood hard," EMG showed absence of action potentials in affected muscles, and biopsy revealed extensive replacement of muscle with dense, acellular fibrous tissue. Possible mechanisms are discussed.     

Preoperative radiotherapy for adenocarcinoma of the rectosigmoid

Ninety-seven patients with adenocarcinoma of the rectosigmoid have been treated with high dose (5000-6000 rad) preoperative irradiation from 1960 through 1972 at the University of Oregon Health Sciences Center. Fifty-seven were initially clinically resectable and 40 were initially inoperable. Forty of the 57 initially clinically resectable patients had "curative" resections and are at risk for more than 5 years. An increase in 5-year survival (from 38% to 53%) and an absence of pelvic recurrence have occurred in those patients receiving preoperative irradiation and "curative" resection. Four of the 40 initially inoperable patients are alive without tumor. Three of the four survivors had irradiation and surgery; one had irradiation only. An additional four patients had no evidence of tumor at death. Tumor was totally sterilized by irradiation and nine patients and reduced to microfocal extent in an additional three of the 97 patients. Incidence of complications was no greater than has been reported in a surgical series from the same institution.     

ARTIFICIAL INTELLIGENCE GOES MOBILE

New mobile computing technologies require new paradigms for infrastructure and interaction with mobile and networked devices. For building smart mobile companions for new intelligent services, a number of challenges have to be addressed. We argue that artificial intelligence is a key to a new generation of mobile systems. In this introduction to AI in mobile systems, we present some of the challenges and solutions in this exciting field of research.