RNA interference against human papillomavirus oncogenes in cervical cancer cells results in increased sensitivity to cisplatin

Targeted inhibition of oncogenes in tumor cells is a rational approach toward the development of cancer therapies based on RNA interference (RNAi). Tumors caused by human papillomavirus (HPV) infection are an ideal model system for RNAi-based cancer therapies because the oncogenes that cause cervical cancer, E6 and E7, are expressed only in cancerous cells. We investigated whether targeting HPV E6 and E7 oncogenes yields cancer cells more sensitive to chemotherapy by cisplatin, the chemotherapeutic agent currently used for the treatment of advanced cervical cancer. We have designed siRNAs directed against the HPV E6 oncogene that simultaneously targets both E6 and E7, which results in an 80% reduction in E7 protein and reactivation of the p53 pathway. The loss of E6 and E7 resulted in a reduction in cellular viability concurrent with the induction of cellular senescence. Interference was specific in that no effect on HPV-negative cells was observed. We demonstrate that RNAi against E6 and E7 oncogenes enhances the chemotherapeutic effect of cisplatin in HeLa cells. The IC50 for HeLa cells treated with cisplatin was 9.4 mu M, but after the addition of a lentivirus-delivered shRNA against E6, the IC50 was reduced almost 4-fold to 2.4 mu M. We also observed a decrease in E7 expression with a concurrent increase in p53 protein levels upon cotreatment with shRNA and cisplatin over that seen with individual treatment alone. Our results provide strong evidence that loss of E6 and E7 results in increased sensitivity to cisplatin, probably because of increased p53 levels.

Prostanoids as friends, not foes: Further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats

Pharmacologists have generally been prejudiced against prostanoids, uncritically accepting their suppression as desirable therapy, especially for ‘quick-fix’ analgesia. This myopic perception for a long time ignored (a) the essentiality of prostanoid precursors in nutrition, (b) the physiological protective functions of natural prostaglandins (PGs) (vasculature, stomach, kidney), (c) resolution of inflammation after the expression of COX-2 and (d) increasing therapeutic use of either synthetic PGs (for erectile dysfunction, opthalmic disorders, inducing parturition, etc) or their natural precursors, e.g., ω3-rich polyunsaturated oils, to treat arthritis. Experimental studies in rats have indicated that prostaglandins (E series) are (i) useful, perhaps auto-regulators of established immunoreactivity and (ii) able to amplify (or even induce) anti-inflammatory activity with other agents. Furthermore, anti-prostanoid therapy (APT) can be arthritigenic!!, interfering with the acquisition of tolerance to some arthritigens. For patients with rheumatoid arthritis this additional side-effect of APT, barely recognised to date, may actually perpetuate their arthritis by impairing prostanoid-mediated remission processes. Hopefully, recent adverse publicity about COX-2 inhibitory drugs might stimulate serious re-assessment of some traditional anti-inflammatory therapies with low APT activity for the management of both acute pain (non-addictive cannabinoids, celery seed, etc.) and chronic inflammation, e.g., Lyprinol® (a mussel lipid extract).

Combating interference in an indoor wireless-communication system using a phased-array antenna with switched-beam elements

A phased-array antenna with switched-beam elements used to combat interference in an indoor wireless communication system is described. The array uses I-bit phase shifters applied to its elements in order to point its main beam in a desired direction and internal switching of elements in order to form nulls towards interference. The array's capability of suppressing interference is verified by studying its radiation patterns and by performing interference-rejection experiments in an indoor multipath environment. (c) 2005 Wiley Periodicals, Inc.

The effects of task complexity and practice on dual-task interference in visuospatial working memory

Although the n-back task has been widely applied to neuroimagery investigations of working memory (WM), the role of practice effects on behavioural performance of this task has not yet been investigated. The current study aimed to investigate the effects of task complexity and familiarity on the n-back task. Seventy-seven participants (39 male, 38 female) completed a visuospatial n-back task four times, twice in two testing sessions separated by a week. Participants were required to remember either the first, second or third (n-back) most recent letter positions in a continuous sequence and to indicate whether the current item matched or did not match the remembered position. A control task, with no working memory requirements required participants to match to a predetermined stimulus position. In both testing sessions, reaction time (RT) and error rate increased with increasing WM load. An exponential slope for RTs in the first session indicated dual-task interference at the 3-back level. However, a linear slope in the second session indicated a reduction of dual-task interference. Attenuation of interference in the second session suggested a reduction in executive demands of the task with practice. This suggested that practice effects occur within the n-back ask and need to be controlled for in future neuroimagery research using the task.

Are the changes in postural control associated with low back pain caused by pain interference?

Background: Voluntary limb movements are associated with involuntary and automatic postural adjustments of the trunk muscles. These postural adjustments occur prior to movement and prevent unwanted perturbation of the trunk. In low back pain, postural adjustments of the trunk muscles are altered such that the deep trunk muscles are consistently delayed and the superficial trunk muscles are sometimes augmented. This alteration of postural adjustments may reflect disruption of normal postural control imparted by reduced central nervous system resources available during pain, so-called pain interference, or reflect adoption of an alternate postural adjustment strategy. Methods: We aimed to clarify this by recording electromyographic activity of the upper (obliquus extemus) and lower (transversus abdominis/obliquus internus) abdominal muscles during voluntary arm movements that were coupled with painful cutaneous stimulation at the low back. If the effect of pain on postural adjustments is caused by pain interference, it should be greatest at the onset of the stimulus, should habituate with repeated exposure, and be absent immediately when the threat of pain is removed. Sixteen patients performed 30 forward movements of the right arm in response to a visual cue (control). Seventy trials were then conducted in which arm movement was coupled with pain (pain trials) and then a further 70 trials were conducted without the pain stimulus (no pain trials). Results: There was a gradual and increasing delay of transversus abdominis/obliquus internus electromyograph and augmentation of obliquus externus during the pain trials, both of which gradually returned to control values during the no pain trials. Conclusion: The results suggest that altered postural adjustments of the trunk muscles during pain are not caused by pain interference but are likely to reflect development and adoption of an alternate postural adjustment strategy, which may serve to limit the amplitude and velocity of trunk excursion caused by arm movement.

Covariation and interference between physiological reflexes: Eye-blink startle cardiac defense, and skin conductance

Comparative studies of autonomic and somatic reflexes, such as cardiac defense and motor startle, are rare. However, examination of the pattern of covariation, independence, or interference among physiological reflexes may help to clarify their functional significance and elucidate their complex modulation by psychological factors. Here we report the results of a study that examined the pattern of interference of eye-blink startle on subsequent cardiac defense. Participants were 63 students (31 women) distributed into three groups according to the sensory modality of the eliciting stimulus during the startle trials: acoustic high intensity (105 dB), acoustic low intensity (65 dB), and visual modality. Startle trials consisted of 12 presentations of the eliciting stimulus with a duration of 50 ms, instantaneous risetime, and a variable inter-stimulus interval of 16 – 20 s.Defense trials began 20 s after the last startle trial and consisted, for all groups, of 3 presentations of the high intensity acoustic stimulus with a duration of 500 ms and an inter-stimulus interval of 215 s. Results showed a clear interference of the startle trials on the subsequent defense trials when both types of trials shared identical sensory modality (acoustic) independently of intensity: the expected pattern of cardiac defense in the first trial only appeared in the visual modality. Similar interference effects were observed in the skin conductance response. Subjective reactivity to the defense stimulus did not detect differences between conditions.

RNA interference for the treatment of cancer

RNA interference (RNAi) is the latest new technology in the field of genetic medicine in which specific genes can be turned off, or silenced, so as to affect a therapeutic outcome. It can be highly specific, works in the nanomolar range and is far more effective than the antisense approaches popular 10-15 years ago. Here we review the field and explore the potential role of RNAi in cancer therapy, highlighting recent progress and examining the hurdles that must be overcome before this promising technology is ready for clinical use. (C) 2006 Prous Science. All rights reserved.

Interference between propagating changes and its effect on system failure

Computer-based, socio-technical systems projects are frequently failures. In particular, computer-based information systems often fail to live up to their promise. Part of the problem lies in the uncertainty of the effect of combining the subsystems that comprise the complete system; i.e. the system's emergent behaviour cannot be predicted from a knowledge of the subsystems. This paper suggests uncertainty management is a fundamental unifying concept in analysis and design of complex systems and goes on to indicate that this is due to the co-evolutionary nature of the requirements and implementation of socio-technical systems. The paper shows a model of the propagation of a system change that indicates that the introduction of two or more changes over time can cause chaotic emergent behaviour.