Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia

Identification of the signalling cascades that are differentially activated during prostatic tumourigenesis is a crucial step in the search for future molecular targets in this disease. The stress-activated protein kinase (SAPK) signalling cascade culminates in the phosphorylation of the JNK and p38 mitogen-activated protein kinases (MAPKs). Recently, the upstream activators of these proteins, the MAPK kinases (MKKs), have been implicated as inhibitors of tumour progression in a variety of clinical and experimental tumour models. This study evaluates MKK4, MKK6 and MKK7 expression during prostate cancer progression in humans and in the transgenic adenocarcinoma of a mouse prostate (TRAMP) model of prostate tumourigenesis. Benign prostate, prostatic intraepithelial neoplasia (PIN) lesions and tumour tissues were collected from 37 TRAMP mice. Additionally, six tissue microarrays were constructed with tumours from a matched group of 102 men who underwent radical prostatectomy. Tissues from 20 patients with extensive high-grade prostatic intraepithelial neoplasia (HGPIN) were also analysed. For all samples, immunohistochemical staining for MKK4, MKK6 and MKK7 was scored in normal and neoplastic glands. Staining intensities of MKK4, MKK6 and MKK7 were significantly increased in HGPIN and prostate cancer compared to surrounding normal glands in both the TRAMP and human samples (p < 0.0001 for all markers). Increased levels of MKK4 or MKK7 correlated with higher pathological stage at prostatectomy (p = 0.01 and p = 0.04). Using multivariate analysis, there was no association between protein levels and time to biochemical recurrence in the human samples. The up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression in both TRAMP and human tissues highlights an important role for the SAPK signalling cascade in prostatic neoplasia. The finding that higher MKK4 and MKK7 expression is associated with higher-stage prostatic tumours underscores the dynamic regulation of these proteins during prostatic tumourigenesis.     

Toxicological and ecotoxicological properties of gas-to-liquid (GTL) products. 2. Ecotoxicology

Gas-to-liquid (GTL) products are synthetic hydrocarbons produced from natural gas using a catalytic process known as the Fischer–Tropsch process. This process yields a synthetic crude oil that consists of saturated hydrocarbons which can subsequently be refined to a range of products analogous to those obtained from petroleum refining. However, in contrast to their petroleum-derived analogs, GTL products are essentially free of unsaturated or aromatic compounds and do not contain any sulfur-, oxygen-, or nitrogen-containing compounds. Under new chemical substance notification requirements, an extensive testing program covering the entire portfolio of GTL products has been undertaken to assess their hazardous properties to human health and environment. The results of these studies have been summarized in a two-part review. Part 1 provides an overview of the mammalian toxicity hazardous properties of the various GTL products. This second part of the review focuses on the aquatic, sediment, terrestrial, and avian toxicity studies which assess the ecotoxicological hazard profile of the GTL products. Many challenges were encountered during these tests relating to dosing, analysis and interpretation of results. These are discussed with the intent to share experiences to help inform and shape future regulatory mandates for testing of poorly soluble complex substances. As was the case with the mammalian toxicology review, there were a few cases where adverse effects were found, but overall the GTL products were found to exert minimal adverse ecotoxicological effects and these were less severe than effects observed with their conventional, petroleum-derived analogs.     

Research on hand dexterity and the practice of dentistry: reality and myth

A brief review of the literature finds that studies of digital dexterity fail to confirm that dental students or dentists possess aptitudes that are different from the general population or that those with higher aptitudes achieve superior levels of performance. It is suggested that the complex nature of modern dental practice requires such a broad range of skills that digital dexterity contributes only a small increment or that technical dental procedures are completely trainable in the course of dental education.     

Using mobile technology to overcome language barriers in medicine

Australia has a large migrant population with variable fluency in English. Interpreting services help ensure that healthcare services are delivered appropriately to these populations. However, the use of professional interpreters in hospitals is expensive. There are also issues with service availability and convenience. Mobile devices containing software with translating abilities have promising potential to improve communication between patients and hospital staff as an adjunct to professional interpreters. It is highly convenient and inexpensive. There are concerns about the accuracy of the interpretation done with such software and more research needs to be carried out to support or allay these concerns. For now, clinically important and medicolegal related interpretation should be undertaken by professional interpreters whereas less crucial tasks may be performed with the help of interpreting software on mobile devices.     

Different expression patterns of lysosomal proteins exposed to melanin in HeLa cells

As a high quantity of melanin can lead to hyperpig­mentation or skin cancer in humans and it can also activate lysosomal enzymes so in the present study the changes in lysosomal enzymes upon exposure of HeLa cells to melanin has been studied. The HeLa cells were exposed to 100 ppm melanin for 24 hours and lysosomal enzymes were extracted. The lysosomal enzymes were identified through two­dimensional polyacrylamide gel electrophoresis (2­DE) after exposure of HeLa cells to melanin. The results showed 12 up­ and 3­down regulation spots in relation to melanin exposure. It has been observed that lysosomal proteins are related to melanin to decrease the color and quantity through cellular activation of lysosomes.     

Thrombin causes subsecond changes in protein phosphorylation of platelets

We have developed a general quenched-flow approach to study platelet function as early as 0.3 seconds after stimulation. Phosphorylation of 20- and 40-kd proteins has been analyzed during the first five seconds of platelet response to thrombin from 0.1 to 5.0 U/mL and compared with the progress of aggregation and serotonin secretion. The onset time for aggregation and phosphorylation of both proteins was less than one second, although with lowest (less than 0.5 U/mL) thrombin levels, a lag of up to 0.6 seconds occurred before 40K phosphorylation increased. The thrombin sensitivity of aggregation and 20K phosphorylation was approximately twice that of 40K phosphorylation, with Ka values of 0.51 and 0.53 v 1.10 U/mL, respectively. External calcium was necessary for maximal 20K phosphorylation, since EDTA inhibited this by 30%. The 40K phosphorylation was not affected by EDTA. Platelet activation by thrombin thus induced biochemical changes well before one second. The quenched-flow approach may help to reveal relationships between phospholipase activation, calcium fluxes, and protein phosphorylation during these early periods of platelet function.     

Cigarette smoking: risk factor for premature facial wrinkling

OBJECTIVE: To determine if cigarette smoking is a risk factor for the development of premature facial wrinkling. DESIGN: Cross-sectional study. SETTING: Smoking cessation clinic and community. PATIENTS: Convenience sample of 132 adult smokers and non-smokers in 1988. MEASUREMENTS: A questionnaire was administered to quantify cigarette smoking and to obtain information about possibly confounding factors such as skin pigmentation, sun exposure, age, and sex. Wrinkling was assessed using photographs of the temple region, and a severity score based on predetermined criteria was assigned. A logistic regression model, which controlled for confounding variables, was developed to assess the risk for premature wrinkling in response to pack-years of smoking. MAIN RESULTS: The prevalence of premature wrinkling was independently associated with sun exposure and pack-years of smoking. After controlling for age, sex, and sun exposure, premature wrinkling increased with increased pack-years of smoking. Heavy cigarette smokers (greater than 50 pack-years) were 4.7 times more likely to be wrinkled than nonsmokers (95% CI, 1.0 to 22.6; P value for trend = 0.05). Sun exposure of more than 50,000 lifetime hours also increased the risk of being excessively wrinkled 3.1-fold (CI, 1.2 to 7.1). When excessive sun exposure and cigarette smoking occurred together, the risk for developing excessive wrinkling was multiplicative (prevalence ratio of 12.0; CI, 1.5 to 530). CONCLUSION: Cigarette smoking is an independent risk factor for the development of premature wrinkling.     

Molecular characterization of a high A2 beta thalassemia by direct sequencing of single strand enriched amplified genomic DNA

Two families, one of Anglo-Saxon-Dutch descent, and the other, West Indian black, have an atypical beta thalassemia characterized by an unusually high level of Hb A2 in the heterozygous state. Restriction endonuclease mapping showed a deletion of about 1.35 kilobase (kb) in the 5' region of the beta globin gene. Direct sequencing of a specific region of genomic DNA amplified by a new modification of the polymerase chain reaction defined the deletion to be 1,393 base pairs (bp) and to be the same in both families. The deletion extends from 485 bp 5' to the mRNA CAP site to the middle of the second intervening sequence. This deletion, together with three others previously described that remove the 5' end of the beta gene but leave the delta gene intact, are all associated with unusually high levels of Hb A2 in the heterozygous state.