Silencing of integrated human papillomavirus type 18 oncogene transcription in cells expressing SerpinB2

The serine protease inhibitor SerpinB2 (PAI-2), a major product of differentiating squamous epithelial cells, has recently been shown to bind and protect the retinoblastoma protein (Rb) from degradation. In human papillomavirus type 18 (HPV-18) -transformed epithelial cells the expression of the E6 and E7 oncoproteins is controlled by the HPV-18 upstream regulatory region (URR). Here we illustrate that PAI-2 expression in the HPV-18-transformed cervical carcinoma line HeLa resulted in the restoration of Rb expression, which led to the functional silencing of transcription from the HPV-18 URR. This caused loss of E7 protein expression and restoration of multiple E6- and E7-targeted host proteins, including p53, c-Myc, and c-Jun. Rb expression emerged as sufficient for the transcriptional repression of the URR, with repression mediated via the C/EB beta-YY1 binding site (URR 7709 to 7719). In contrast to HeLa cells, where the C/EBP beta-YY1 dimer binds this site, in PAI-2- and/or Rb-expressing cells the site was occupied by the dominant-negative C/EBP beta isoform liver-enriched transcriptional inhibitory protein (LIP). PAI-2 expression thus has a potent suppressive effect on HPV-18 oncogene transcription mediated by Rb and LIP, a finding with potential implications for prognosis and treatment of HPV-transformed lesions.

Differential motor speech outcomes in children treated for mid-line cerebellar tumour

Primary objective: To investigate the nature of the motor speech impairments and dysarthria that can arise subsequent to treatment for childhood mid-line cerebellar tumours (CMCT). Research design: The motor speech ability of six cases of children with CMCT was analysed using perceptual and physiological measures and compared with that of a group of non-neurologically impaired children matched for age and sex. Main outcome and results: Three of the children with CMCT were perceived to exhibit dysarthric speech, while the remaining three were judged to have normal speech. The speech disorder in three of the children with CMCT was marked by deviances in prosody, articulation and phonation. The underlying pathophysiology was linked to cerebellar damage and expressed as difficulty in co-ordinating the motor speech musculature as required for speech production. These deficits were not identified in the three non-dysarthric children with CMCT. Conclusion: Differential motor speech outcomes occur for children treated for CMCT and these are discussed within the realm of possible mechanisms responsible for these differences. The need for further investigation of the risk factors for development of motor speech impairment in children treated for CMCT is also highlighted.

Articulatory function following traumatic brain injury in childhood: A perceptual and instrumental analysis

Primary objective: To investigate the articulatory function of a group of children with traumatic brain injury (TBI), using both perceptual and instrumental techniques. Research design: The performance of 24 children with TBI was assessed on a battery of perceptual (Frenchay Dysarthria Assessment, Assessment of Intelligibility of Dysarthric Speech and speech sample analysis) and instrumental ( lip and tongue pressure transduction systems) assessments and compared with that of 24 non-neurologically impaired children matched for age and sex. Main outcomes: Perceptual assessment identified consonant and vowel imprecision, increased length of phonemes and overall reduction in speech intelligibility, while instrumental assessment revealed significant impairment in lip and tongue function in the TBI group, with rate and pressure in repetitive lip and tongue tasks particularly impaired. Significant negative correlations were identified between the degree of deviance of perceptual articulatory features and decreased function on many non-speech measures of lip function, as well as maximum tongue pressure and fine force tongue control at 20% of maximum tongue pressure. Additionally, sub-clinical articulatory deficits were identified in the children with TBI who were non-dysarthric. Conclusion: The results of the instrumental assessment of lip and tongue function support the finding of substantial articulatory dysfunction in this group of children following TBI. Hence, remediation of articulatory function should be a therapeutic priority in these children.

Long-term increase in sunscreen use in an Australian community after a skin cancer prevention trial

Background. Given the public health burden of skin cancer in white populations, an increase in sun protective behavior is needed. In a highrisk community, we assessed long-term Sunscreen use among people who had participated in a randomized trial of daily Sunscreen application for prevention of skin cancer. Methods. In 1992, 1621 residents of the subtropical Australian township of Nambour were randomly allocated to either daily or discretionary sunscreen use until 1996. From 1997 to 2002, we monitored by questionnaires their ongoing sunscreen use. Results. People who had never or irregularly used sunscreen when in summer sun before the trial were more likely (P < 0.0001) to be sustaining regular application especially to their face (20% vs. 11%) and forearms (14% vs. 5%) if they had been allocated to daily, not discretionary, use of sunscreen for 5 years. Conclusions. Regular voluntary sunscreen use for skin cancer prevention can be sustained by sun-sensitive people in the long term. Habit formation appears to be an important goal for sun protection programs among those living, or on vacation, in sunny places. (c) 2005 Elsevier Inc. All rights reserved.

Synthesis and immunological evaluation of M protein targeted tetra-valent and tri-valent group A streptococcal vaccine candidates based on the lipid-core peptide system

Group A streptococcus (GAS) is responsible for causing many clinical complications including the relatively benign streptococcal pharyngitis and impetigo. However. if left untreated. these conditions may lead to more severe diseases such as rheumatic fever (RF) and rheumatic heart disease (RHD). These diseases exhibit high morbidity and mortality, Particularly in developing countries and in indigenous populations of affluent countries. Only ever occur following GAS infection, a vaccine offers Promise for their Prevention. As stich, we have investigated the Use of the lipid-core peptide (LCP) system for the development of multi-valent Prophylactic GAS vaccines. The current study has investigated the capacity of this system to adjuvant LIP to four different GAS peptide epitopes. Presented are the synthesis and immunological assessment of tetra-valent and tri-valent GAS LCP systems. We demonstrated their capacity to elicit systemic IgG antibody responses in B10.BR mice to all GAS peptide epitopes. The data also showed that the LCP systems Were self-adjuvanting. These findings are particularly encouraging for the development of multi-valent LCP-based GAS vaccines.

Head and neck cancer: past, present and future

Head and neck cancer consists of a diverse group of cancers that ranges from cutaneous, lip, salivary glands, sinuses, oral cavity, pharynx and larynx. Each group dictates different management. In this review, the primary focus is on head and neck squamous cell carcinoma (HNSCC) arising from the mucosal lining of the oral cavity and pharynx, excluding nasopharyngeal cancer. Presently, HNSCC is the sixth most prevalent neoplasm in the world, with approximately 900,000 cases diagnosed worldwide. Prognosis has improved little in the past 30 years. In those who have survived, pain, disfigurement and physical disability from treatment have had an enormous psychosocial impact on their lives. Management of these patients remains a challenge, especially in developing countries where this disease is most common. Of all human cancers, HNSCC is the most distressing since the head and neck is the site of the most complex functional anatomy in the human body. Its areas of responsibility include breathing, the CNS, vision, hearing, balance, olfaction, taste, swallowing, voice, endocrine and cosmesis. Cancers that occur in this area impact on these important human functions. Consequently, in treating cancers of the head and neck, the effects of the treatment on the functional outcome of the patient need the most serious consideration. In assessing the success of HNSCC treatment, consideration of both the survival and functional deficits that the patient may suffer as a consequence of their treatment are of paramount importance. For this reason, the modern-day management of head and neck patients should be carried out in a multidisciplinary head and neck clinic.

EAAT2 splice variants in Alzheimer disease

Regional atrophy caused by neuronal loss is a characteristic of Alzheimer Disease (AD). Excitatory amino acid transporter-2 (EAAT2) is the major carrier responsible for clearing glutamate from the synaptic cleft in mammalian CNS. A localized attenuation of glutamate transport via reduced expression of functional forms of EAAT2 might contribute to regional excitotoxicity. The EAAT2 gene spans over 100 kb and encodes a 12-kb message. Several groups have identified alternative splice variants of EAAT2 in human brain tissue. These variants can affect transport by altering wild-type EAAT2 protein expression, localization, or transport efficiency. Alternative EAAT2 mRNA transcripts reportedly elicit a dominant-negative effect on glutamate uptake in cell culture. A 50% reduction in the expression in AD cortex of the truncated EAAT2 C-terminal isoform, EAAT2b, has been reported. We obtained cerebral cortex tissue, under informed written consent from the next of kin, from pathologically confirmed control, AD, and non-AD dementia cases. We aimed to determine the distribution and expression patterns of EAAT2 subtypes in susceptible and spared brain regions. We detected five alternate transcripts of EAAT2, two of which had not previously been reported. The relative contributions of novel variants, wild-type EAAT2, and previously discovered splice variants was investigated using Real-time PCR in AD, non-AD dementia, and age-matched control cortex. Our aim is to survey the relationship between these expression patterns and those of markers such as tau, GFAP, and b-amyloid, and to assess the correlation between variant-transporter expression and the level of cell loss.