Staging of non-small cell lung cancer (NSCLC): a review.

Lung cancer remains the most common cause of cancer-related mortality in Scotland, accounting for 28.9% of all cancer deaths in 2007. (1) Current guidelines recommend assessment of patient fitness and operability by a multi-disciplinary team when selecting management options. (2-6) Two of the most important prognostic markers are the stage of disease and ECOG performance status. The most commonly used cancer staging system is the tumour, node, metastasis (TNM) staging system, which is maintained by the American Joint Committee on Cancer (AJCC) and the International Union Against Cancer (UICC). In 1998, the International Association for the Study of Lung Cancer (IASLC) established The Lung Cancer Staging Project, collecting data on over 100,000 patients diagnosed with lung cancer between 1990-2000 worldwide, in order to revise the 6th edition TNM staging system for non-small cell lung cancer (NSCLC).(7) The 7th edition was published in late 2009. This review of staging in NSCLC, includes a summary of the different staging techniques currently available and the 7th edition TNM staging system for NSCLC.(8).

Investigation of outbreaks of highly pathogenic H5N1 avian influenza in waterfowl and wild birds in Hong Kong in late 2002.

Outbreaks of highly pathogenic H5N1 avian influenza have occurred in Hong Kong in chickens and other gallinaceous poultry in 1997, 2001, twice in 2002 and 2003. High mortality rates were seen in gallinaceous birds but not in domestic or wild waterfowl or other wild birds until late 2002 when highly pathogenic H5N1 avian influenza occurred in waterfowl (geese, ducks and swans), captive Greater Flamingo (Phoenicopterus ruber) and other wild birds (Little Egret Egretta garzetta) at two waterfowl parks and from two dead wild Grey Heron (Ardea cinerea) and a Black-headed Gull (Larus ridibundus) in Hong Kong. H5N1 avian influenza virus was also isolated from a dead feral pigeon (Columba livia) and a dead tree sparrow (Passer montanus) during the second outbreak. The first waterfowl outbreak was controlled by immediate strict quarantine and depopulation 1 week before the second outbreak commenced. Control measures implemented for the second outbreak included strict isolation, culling, increased sanitation and vaccination. Outbreaks in gallinaceous birds occurred in some live poultry markets concurrently with the second waterfowl outbreak, and infection on a chicken farm was detected 1 week after the second waterfowl park outbreak was detected, on the same day the second grey heron case was detected. Subsequent virus surveillance showed the outbreaks had been contained.

Regulation of cell proliferation by G proteins.

G Proteins provide signal transduction mechanisms to seven transmembrane receptors. Recent studies have indicated that the alpha-subunits as well as the betagamma-subunits of these proteins regulate several critical signaling pathways involved in cell proliferation, differentiation and apoptosis. Of the 17 alpha-subunits that have been cloned, at least ten of them have been shown to couple mitogenic signaling in fibroblast cells. Activating mutations in G alpha(s), G alpha(i)2, and G alpha12 have been correlated with different types of tumors. In addition, the ability of the betagamma-subunits to activate mitogenic pathways in different cell-types has been defined. The present review briefly summarizes the diverse and novel signaling pathways regulated by the alpha- as well as the betagamma-subunits of G proteins in regulating cell proliferation.

Regulation of calcium influx and phospholipase C activity by indoleamines in dinoflagellate Crypthecodinium cohnii.

Exogenous indoleamines such as melatonin and 5-methoxytryptamine have been shown to induce cyst formation (encystment) in many species of dinoflagellate. Induction of inositol phosphates formation by indoleamine has previously been demonstrated in Crypthecodinium cohnii. In addition, depletion of extracellular Ca2+ blocks the indoleamine-induced encystment. In the present study, 12 indoleamines (including melatonin and related compounds) were examined for their abilities to induce Ca2+ influx, inositol phosphates formation, and encystment in C. cohnii. The results showed that melatonin, 5-methoxytryptamine, and the peptide toxin mastoparan stimulated 45Ca2+ influxes in dose- and time-dependent manners. The EC50 values of 5-methoxytrypramine and mastoparan to stimulate 45Ca2+ uptake were 2 mM and 35 microM, respectively. The 5-methoxytryptamine- and mastoparan-induced 45Ca2+ influx were partially attenuated by the calcium channel blockers, verapamil and ruthenium red. A series of indoleamines were examined for their structure-activity relationship on the induction of encystment and formation of inositol phosphates. Melatonin-induced inositol phosphates formation was completely blocked by U73122, indicating the possible involvement of phospholipase C. Taken together, we conclude that indoleamines may induce encystment of the dinoflagellate C. cohnii via parallel activation of phospholipase C and Ca2+ influx signaling pathways. However, activation of phospholipase C and Ca2+ influx are not always necessary or sufficient for inducing encystment. Also, these data provided the first direct evidence of a Ca2+ influx regulating mechanism in dinoflagellate C. cohnii.

Calcium ion dependency and the role of inositol phosphates in melatonin-induced encystment of dinoflagellates.

The unicellular eukaryotic dinoflagellates shed their flagella and form a new pellicle cyst wall in response to environmental stress. This encystment process can also be induced by indoleamines such as melatonin and 5-methoxytryptamine. To decipher the complex signaling events which lead to encystment, we have investigated the functional roles of Ca2+ and inositol phosphates in indoleamine-induced encystment of the dinoflagellates Alexandrium catenella and Crypthecodinium cohnii. Pretreatment with EGTA, but not with EDTA, effectively blocked the indoleamine-induced encystment of A. catenella in a dose-dependent manner. Conversely, agents that facilitate the influx of Ca2+ (Bay K 8644, A23187 and ionomycin) dose-dependently induced encystment of A. catenella. Endoplasmic Ca2+-ATPase inhibitors such as thapsigargin and the peptide toxin melittin also induced encystment of A. catenella. These results suggest that an elevation of intracellular [Ca2+] may be involved in the encystment response. In terms of the regulation of phospholipase C, melatonin dose- and time-dependently stimulated the formation of inositol phosphates in C. cohnii. The rank order of potency for several indoleamines to stimulate inositol phosphates formation was 2-iodomelatonin > 5-methoxytryptamine > or = melatonin >> N-acetylserotonin > 5-hydroxytryptamine. This rank order was the same as for the indoleamine-induced encystment of C. cohnii as previously reported. Our results indicate that indoleamine-induced activation of phospholipase C and elevation of intracellular [Ca2+] may be proximal steps in the signal transduction pathway leading to encystment in dinoflagellates. Moreover, this is the first demonstration of the possible involvement of Ca2+ and inositol phosphates as second messengers in dinoflagellates.

Effects of dibutyryl cAMP and bacterial toxins on indoleamine-induced encystment of dinoflagellates.

Dinoflagellates are the causative agents of red tides with worldwide occurrence and can be induced to encyst by in doleamines such as melatonin and 5-methoxytryptamine (5-MOT). This biological response may be mediated via indoleamine-binding proteins or receptors. Here we report the initial characterization of the signal transduction mechanisms by which indoleamines induce encystment of dinoflagellates. In particular, we explored the possible involvement of G proteins and cAMP in cyst formation. Both melatonin and 5-MOT promoted the encystment of Gonyaulax tamarensis and Crypthecodinium cohnii. Exposure of dinoflagellates to dibutyryl cAMP, which directly activates cAMP-dependent pathways, did not affect the ability of indoleamines to promote encystment. However, dibutyryl cAMP dose-dependently diminished the indoleamine-induced suppression of cell growth. Exposure of dinoflagellates to the bacterial toxins from Vibrio cholerae and Bordetella pertussis had no effect on the indoleamine-induced encystment response, indicating the lack of involvement of Gs or Gi-like proteins. Moreover, [32P]ADP ribosylation of dinoflagellate membranes by either toxin failed to identify substrate proteins. These results suggest that although the indoleamine-induced encystment of dinoflagellates may involve a G-protein-coupled signal transduction pathway, the identity of the G protein concerned may be distinct from those that regulate adenylyl cyclases in mammalian cells.

Stimulation of cAMP accumulation by the cloned Xenopus melatonin receptor through Gi and Gz proteins.

The Xenopus melatonin receptor was expressed in human embryonic kidney 293 cells and assayed for cAMP accumulation. In transfected 293 cells expressing the melatonin receptor, melatonin dose-dependently inhibited the endogenous adenylyl cyclases. In contrast, melatonin stimulated the accumulation of cAMP in cells co-expressing the type II adenylyl cyclase. Both the inhibitory and stimulatory responses to melatonin were mediated via Gi-like proteins as they were blocked by pertussis toxin. Upon co-transfection with the alpha subunit of Gz, the ability of melatonin to regulate both type II and the endogenous adenylyl cyclases became refractory to pertussis toxin, indicating that the melatonin receptor can also couple to Gz. However, other pertussis toxin-insensitive G proteins such as Gq, G12 and G13 were unable to interact with the melatonin receptor.