Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis.

Survival signaling is critical for the metastatic program of cancer cells. The current study investigated the role of Akt survival proteins in colorectal cancer (CRC) metastasis and explored potential mechanisms of Akt-mediated metastasis regulation. Using an orthotopic implantation model in mice, which uniquely recapitulates the entire multistep process of CRC metastasis, combined with an inducible system of short hairpin RNA-mediated Akt isoform knockdown in human CRC cells, our studies confirm a role of Akt2 in CRC cell dissemination to distant organs in vivo. Akt2 deficiency profoundly inhibited the development of liver lesions in mice, whereas Akt1 had no effect under the experimental conditions used in the study. Array analysis of human metastatic genes identified the scaffolding protein metastasis suppressor 1 (MTSS1) as a novel Akt2-regulated gene. Inducible loss of Akt2 in CRC cells robustly upregulated MTSS1 at the messenger RNA and protein level, and the accumulated protein was functionally active as shown by its ability to engage an MTSS1-Src-cortactin inhibitory axis. MTSS1 expression led to a marked reduction in levels of functional cortacin (pcortactin Y421), an actin nucleation-promoting factor that has a crucial role in cancer cell invasion and metastasis. MTSS1 was also shown to mediate suppressive effects of Akt2 deficiency on CRC cell viability, survival, migration and actin polymerization in vitro. The relevance of these findings to human CRC is supported by analysis of The Cancer Genome Atlas (TCGA) and NCBI GEO data sets, which demonstrated inverse changes in expression of Akt2 and MTSS1 during CRC progression. Taken together, the data identify MTSS1 as a new Akt2-regulated gene, and point to suppression of MTSS1 as a key step in the metastasis-promoting effects of Akt2 in CRC cells.

Eliciting public preferences for healthcare: a systematic review of techniques.

BACKGROUND: Limited resources coupled with unlimited demand for healthcare mean that decisions have to be made regarding the allocation of scarce resources across competing interventions. Policy documents have advocated the importance of public views as one such criterion. In principle, the elicitation of public values represents a big step forward. However, for the exercise to be worthwhile, useful information must be obtained that is scientifically defensible, whilst decision-makers must be able and willing to use it. AIMS AND OBJECTIVES: The aim was to identify techniques that could be reasonably used to elicit public views on the provision of healthcare. Hence, the objectives were: (1) to identify research methods with the potential to take account of public views on the delivery of healthcare; (2) to identify criteria for assessing these methods; (3) to assess the methods identified according to the predefined criteria; (4) to assess the importance of public views vis-à-vis other criteria for setting priorities, as judged by a sample of decision-makers; (5) to make recommendations regarding the use of methods and future research. METHODS: A systematic literature review was carried out to identify methods for eliciting public views. Criteria currently used to evaluate such methods were identified. The methods identified were then evaluated according to predefined criteria. A questionnaire-based survey assessed the relative importance of public views vis-à-vis five other criteria for setting priorities: potential health gain; evidence of clinical effectiveness; budgetary impact; equity of access and health status inequalities; and quality of service. Two techniques were used: choice-based conjoint analysis and allocation of points technique. The questionnaire was sent to 143 participants. A subsample was followed up with a telephone interview. RESULTS: The methods identified were classified as quantitative or qualitative. RESULTS - QUANTITATIVE TECHNIQUES: Quantitative techniques, classified as ranking, rating or choice-based approaches, were evaluated according to eight criteria: validity; reproducibility; internal consistency; acceptability to respondents; cost (financial and administrative); theoretical basis; whether the technique offered a constrained choice; and whether the technique provided a strength of preference measure. Regarding ranking exercises, simple ranking exercises have proved popular, but their results are of limited use. The qualitative discriminant process has not been used to date in healthcare, but may be useful. Conjoint analysis ranking exercises did well against the above criteria. A number of rating scales were identified. The visual analogue scale has proved popular within the quality-adjusted life-year paradigm, but lacks constrained choice and may not measure strength of preference. However, conjoint analysis rating scales performed well. Methods identified for eliciting attitudes include Likert scales, the semantic differential technique, and the Guttman scale. These methods provide useful information, but do not consider strength of preference or the importance of different components within a total score. Satisfaction surveys have been frequently used to elicit public opinion. Researchers should ensure that they construct sensitive techniques, despite their limited use, or else use generic techniques where validity has already been established. Service quality (SERVQUAL) appears to be a potentially useful technique and its application should be researched. Three choice-based techniques with a limited application in healthcare are measure of value, the analytical hierarchical process and the allocation of points technique, while those more widely used, and which did well against the predefined criteria, include standard gamble, time trade-off, discrete choice conjoint analysis and willingness to pay. Little methodological work is currently available on the person trade-off. RESULTS - QUALITATIVE TECHNIQUES: Qualitative techniques were classified as either individual or group-based approaches. Individual approaches included one-to-one interviews, dyadic interviews, case study analyses, the Delphi technique and complaints procedures. Group-based methods included focus groups, concept mapping, citizens' juries, consensus panels, public meetings and nominal group techniques. Six assessment criteria were identified: validity; reliability; generalisability; objectivity; acceptability to respondents; and cost. Whilst all the methods have distinct strengths and weaknesses, there is a lot of ambiguity in the literature. Whether to use individual or group methods depends on the specific topic being discussed and the people being asked, but for both it is crucial that the interviewer/moderator remains as objective as possible. The most popular and widely used such methods were one-to-one interviews and focus groups. (ABSTRACT TRUNCATED)

Re-organising emergency medical admitting: the Stobhill experience, 1992-1997.

OBJECTIVE: To examine patterns of acute medical emergency admissions and the effect of reorganisation on their management. DESIGN: Examination of statistics for emergency medical admissions from 1992 to 1997, a period that included a major reorganisation of the emergency admitting system within the hospital. SETTING: General hospital in a Scottish conurbation. RESULTS: There was a slow annual increase in numbers of admissions during the period of study with very considerable variations in daily and weekly numbers of admissions. Reorganisation achieved a reduction in average length of stay from seven to 4.5 days permitting reduction of the bed complement from 223 to 161. Following reorganisation, 31% of admissions were discharged home within 48 hours directly from the acute medical receiving ward, 18% of admissions were transferred directly to care of the elderly, and 33% of admissions were transferred to medical wards. Patient and staff satisfaction surveys indicated preference for the new system over the old. Admission peaks over the winter months of the last three years occurred at different weeks in the year. CONCLUSIONS: Reorganisation of the medical admitting system can improve efficiency and allow reductions in staffed beds. The considerable [table: see text] variation in daily demands in the system makes it important to retain flexibility. There may be scope for dealing with the large numbers of short-term admissions in other ways.

Structure-activity, theoretical, and X-ray studies on the intramolecular interactions in a series of novel histamine H2 receptor antagonists.

The furan ring of the histamine H2 receptor antagonist 3-amino-4-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]-methyl] thio]ethyl]amino]-1,2,5-thiadiazole 1-oxide (1a) was replaced by thiophene, pyridine, benzene, and pyrrole. The relative receptor affinities of these analogues were estimated by in vitro and in vivo techniques. A theoretical model for the stacking interaction, observed by single crystal X-ray analysis of 1a, was developed, and the ability to enter into this type of interaction was estimated. The X-ray analysis of the pyridine analogue of 1a revealed no intramolecular stacking interaction. The theoretical studies were evaluated in light of the observed receptor affinities, and the relevance of the solid-state geometry of 1a to the receptor-bound geometry was assessed. It is suggested that the stacked geometry found in the X-ray structure of 1a does not represent a conformation that is relevant to that bound at the histamine H2 receptor.

Prostaglandin isosteres. 2. Chain-modified thiazolidinone prostaglandin analogues as renal vasodilators.

Chain modification of a thiazolidinone prostaglandin isostere has led to the production of 4-[3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl] benzoic acid (5b) which at 1 mg/kg po in the conscious dog causes a 70% increase in renal blood flow over control values with a duration of action exceeding 5 h. Preliminary testing indicates that 5b has a relatively specific action on the vasculature of the kidney. The enantiomers of 5b have been separated and the renal vasodilatory activity has been found to be entirely a property of the R-(+) enantiomer.

11,12-Secoprostaglandins. 3. 8-Alkylthio(sulfinyl and sulfonyl)-12-hydroxyalkanoic acids and related compounds.

A series of 8-alkylthio(sulfinyl and sulfonyl)-12-hydroxyalkanoic acids which embody structural features of 11,12-secoprostaglandins was synthesized and evaluated for their ability to mimic the E series prostaglandins in stimulating cAMP formation in the mouse ovary and in binding to the rat lipocyte prostaglandin receptor. A key member of the series, 8-methylsulfonyl-12-hydroxyheptadecanoic acid, markedly stimulated cAMP formation at reasonable pharmacological concentrations, shows significant affinity for a prostaglandin receptor, and effectively inhibits antigen-induced lymphocyte transformation. In contrast, this compound is not a substrate for 15-hydroxyprostaglandin dehydrogenase, the major prostaglandin-metabolizing enzyme.

11,12-Secoprostaglandins. 1. Acylhydroxyalkanoic acids and related compounds.

The synthesis is described of a series of acylhydroxyalkanoic acids which embody structural modifications of that class of secoprostaglandins which are formally derived from the natural substances by scission of the cyclopentane ring between carbon atoms 11 and 12. These analogues have been tested for their ability to stimulate cAMP formation in the mouse ovary, a characteristic action of the (E)-prostaglandins, and for their ability to bind to the rat lipocyte prostaglandin receptor. Certain members of the series that most closely resemble the prostaglandins in structure (e.g., 8-acetyl-12-hydroxyheptadecanoic acid) markedly stimulate cAMP formation at concentrations in the pharmacological range and show a significant affinity for the prostaglandin receptor. Conversely, these compounds are not substrates for prostaglandin 15-hydroxydehydrogenase which catalyzes a major reaction in the biological deactivation of the prostaglandins.

(Vinylaryloxy)acetic acids. A new class of diuretic agents. 4. Various ((2-substituted and 2,2-disubstituted vinyl)aryloxy)acetic acids.

A variety of [(2-substituted and 2,2-disubstituted vinyl)aryloxy]acetic acids was synthesized in which the substituents were primarily electron-withdrawing groups. These compounds were tested in dogs for their saluretic and diuretic properties. Many of the compounds exhibited significant activity; however, they were generally less potent than those reported in the three earlier papers in this series.

(Vinylaryloxy)acetic acids. A new class of diuretic agents. 2. (4-(3-Oxo-1-alkenyl)phenoxy)acetic acids.

A series of (E)-[4-(3-oxo-1-alkenyl)phenoxy]acetic acids was synthesized and tested in dogs for saluretic and diuretic properties. Several compounds exhibited noteworthy activity, e.g., (E)-[2,3-dichloro-4-(3-oxo-1-butenyl)phenoxy]acetic acid (3a). While possessing only half of the dose potency of ethacrynic acid (2), the active compounds act similarly to this diuretic in causing a prompt increase in the excretion of water and in the excretion of sodium and chloride ions in approximately equimolar amounts. Potassium ion excretion is increased but less markedly than sodium excretion.