The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma

BACKGROUND: Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). METHODS: Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. RESULTS: The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. CONCLUSION: The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression

Sleep Physiology, Circadian Rhythms, Waking Performance and the Development of Sleep-Wake Therapeutics

Disturbances of the sleep-wake cycle are highly prevalent and diverse. The aetiology of some sleep disorders, such as circadian rhythm sleep-wake disorders, is understood at the conceptual level of the circadian and homeostatic regulation of sleep and in part at a mechanistic level. Other disorders such as insomnia are more difficult to relate to sleep regulatory mechanisms or sleep physiology. To further our understanding of sleep-wake disorders and the potential of novel therapeutics, we discuss recent findings on the neurobiology of sleep regulation and circadian rhythmicity and its relation with the subjective experience of sleep and the quality of wakefulness. Sleep continuity and to some extent REM sleep emerge as determinants of subjective sleep quality and waking performance. The effects of insufficient sleep primarily concern subjective and objective sleepiness as well as vigilant attention, whereas performance on higher cognitive functions appears to be better preserved albeit at the cost of increased effort. We discuss age-related, sex and other trait-like differences in sleep physiology and sleep need and compare the effects of existing pharmacological and non-pharmacological sleep- and wake-promoting treatments. Successful non-pharmacological approaches such as sleep restriction for insomnia and light and melatonin treatment for circadian rhythm sleep disorders target processes such as sleep homeostasis or circadian rhythmicity. Most pharmacological treatments of sleep disorders target specific signalling pathways with no well-established role in either sleep homeostasis or circadian rhythmicity. Pharmacological sleep therapeutics induce changes in sleep structure and the sleep EEG which are specific to the mechanism of action of the drug. Sleep- and wake-promoting therapeutics often induce residual effects on waking performance and sleep, respectively. The need for novel therapeutic approaches continues not at least because of the societal demand to sleep and be awake out of synchrony with the natural light-dark cycle, the high prevalence of sleep-wake disturbances in mental health disorders and in neurodegeneration. Novel approaches, which will provide a more comprehensive description of sleep and allow for large-scale sleep and circadian physiology studies in the home environment, hold promise for continued improvement of therapeutics for disturbances of sleep, circadian rhythms and waking performance

Nutrient Limitation on Phytoplankton Growth in the Upper Barataria Basin, Louisiana: Microcosm Bioassays

The Davis Pond Diversion (DPD) was constructed to divert Mississippi River (MR) water into the Barataria Basin to reduce the salinity in support of wetland restoration on the Louisiana coast. To assess the phytoplankton nutrient limitation in adjacent water systems and potential impacts of DPD, 12 seasonal nutrient-phytoplankton bioassay experiments were conducted from October 2003 to July 2004 using the natural phytoplankton assemblages from freshwater and brackish-water lakes, Cataouatche and Salvador, LA (USA), which receive Mississippi River water from the DPD, and from a nearby freshwater lake, Lac des Allemands, that does not. Dissolved inorganic nitrogen (N), phosphorus (P), and silicate (Si) were added with different combinations at Redfield ratios in 10-l microcosms. Nitrogen was found to be the sole or primary limiting nutrient in all 12 experiments. N and P colimitations were found in seven of 12 experiments, but N was always the stronger limiting factor. P limitation was never observed to be the sole limiting nutrient. The results showed that a low concentration of P and a relatively high concentration of N do not necessarily indicate only P limitation in these lakes. Lake Cataouatche and Lake Salvador were dominated by centric diatoms, and Anabaena spp. were detected at high levels, particularly in summer. Lac des Allemands was generally dominated by N-fixing Anabaena spp. and other cyanobacteria, and their biomass responded significantly to N addition but not to P addition, indicating that nitrogen fixation in Lac des Allemands may be inhibited by other factors such as iron. Our bioassay results demonstrate that whether a water body is N- or P-limited is the consequence of the nutrient status and not the salinity regime. The results suggest that the addition of nutrient-rich waters via diversions of Mississippi River water into these lakes might increase the frequency of algal blooms, including noxious and toxic freshwater cyanobacteria