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.

Azurin of pathogenic Neisseria spp. is involved in defense against hydrogen peroxide and survival within cervical epithelial cells

Laz, a lipid-modified azurin of the human pathogens Neisseria gonorrhoeae and Neisseria meningitidis, is involved in defense against oxidative stress and copper toxicity; laz mutant strains are hypersensitive to hydrogen peroxide and copper. The N. gonorrhoeae laz mutant also has decreased survival in an ex vivo primary human ectocervical epithelial assay.

The relationship of cervical joint position error to balance and eye movement disturbances in persistent whiplash

Cervical joint position error (JPE) has been used as a measure of cervical afferent input to detect disturbances in sensori-motor control as a possible contributor to a neck pain syndrome. This study aimed to investigate the relationship between cervical JPE, balance and eye movement control. It was of particular interest whether assessment of cervical ME alone was sufficient to signal the presence of disturbances in the two other tests. One hundred subjects with persistent whiplash-associated disorders (WADs) and 40 healthy controls subjects were assessed on measures of cervical JPE, standing balance and the smooth pursuit neck torsion test (SPNT). The results indicated that over all subjects, significant but weak-to-moderate correlations existed between all comfortable stance balance tests and both the SPNT and rotation cervical ME tests. A weak correlation was found between the SPNT and right rotation cervical JPE. An abnormal rotation cervical JPE score had a high positive prediction value (88%) but low sensitivity (60%) and specificity (54%) to determine abnormality in balance and or SPNT test. The results suggest that in patients with persistent WAD, it is not sufficient to measure ME alone. All three measures are required to identify disturbances in the postural control system. (C) 2005 Elsevier Ltd. All rights reserved.

An endurance-strength training regime is effective in reducing myoelectric manifestations of cervical flexor muscle fatigue in females with chronic neck pain

Objective: The purpose of this study was to investigate whether an endurance-strength training program is effective in reducing myoelectric manifestations of sternocleidomastoid (SCM) and anterior scalene (AS) muscle fatigue which have been found to be greater in people with chronic neck pain. Methods: Fifty-eight female patients with chronic non-severe neck pain were randomized into one of two 6-week exercise intervention groups: an endurance-strength training regime for the cervical flexor muscles or a referent exercise intervention involving low load retraining of the cranio-cervical flexor muscles. The primary outcomes were a change in maximum voluntary contraction (MVC) force and change of the initial value and rate of change of the mean frequency, average rectified value and conduction velocity detected from the SCM and AS muscles during sub-maximal isometric cervical flexion contractions at 50, 25 and 10% MVC. Results: At the 7th week follow-up assessment, the endurance-strength training group revealed a significant increase in MVC force and a reduction in the estimates of the initial value and rate of change of the mean frequency for both the SCM and AS muscles (P < 0.05). Both exercise groups reported a reduced average intensity of neck pain and reduced neck disability index score (P < 0.05). Conclusions: An endurance-strength exercise regime for the cervical flexor muscles is effective in reducing myoelectric manifestations of superficial cervical flexor muscle fatigue as well as increasing cervical flexion strength in a group of patients with chronic non-severe neck pain. Significance: Provision of load to challenge the neck flexor muscles is required to reduce the fatigability of the SCM and AS muscles in people with neck pain. Improvements in cervical muscle strength and reduced fatigability may be responsible for the reported efficacy with this type of exercise program. (c) 2006 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All fights reserved.

Characteristics of speech following cervical spinal cord injury

The present study examined 24 individuals with either complete or incomplete injuries to the cervical spinal cord through the use of standardized assessments of dysarthria and a perceptual rating scale. Perceptual assessment revealed predominantly prosodic and phonatory disturbances, while physical impairments were common in the respiratory and laryngeal subsystems of speech production. A reduction in intelligibility and speaking rate resulted in a diminished communicative effectiveness ratio for most participants. Individuals showed a high degree of variation, with no clear relationship between lesion type and impairments present. Further investigation is required to verify the physiological nature of the respiratory and laryngeal impairments found in the present investigation and to determine the relative contributions of these to the overall presentation of speech and voice post cervical spinal cord injury (CSI).

Serologic response to human papillomavirus 16 among Australian women with high-grade cervical intraepithelial neoplasia

This study evaluated the detection of human papillomavirus (HPV) 16 antibody in HPV 16-associated cervical intraepithelial neoplasia (CIN) in Australian women. Seroreactivity to HPV 16 L1 virus-like particles was assessed in patients with CIN 2 (n = 169) and CIN 3 (n = 229) lesions previously tested for the presence of HPV DNA. Seropositivity was significantly commoner in women with HPV 16 DNA-positive lesions (98/184) than in women with no HPV DNA in the lesion (15/47) or with HPV of types other than 16 in the lesion (43/167) (P = 0.0004). In addition, seropositivity was observed in 33% (55/169) of women with CIN 2 and 46% (106/229) of women with CIN 3, in keeping with the lower fraction of CIN 2 (57/169) than CIN 3 (127/229) biopsies positive for HPV 16 DNA. HPV 16 seropositivity is most common in women with HPV 16-associated CIN, but many patients with HPV-associated CIN 3 are seronegative, and HPV 16 seropositivity is common in women with CIN associated with other HPV types. Overall, HPV 16 serology is a poor predictor of presence of HPV 16-associated CIN 3 in patient population studied.