Kliem MA, Maidment NT, Ackerson LC, Chen S, Smith Y, Wichmann T. Activation of nigral and pallidal dopamine D1-like receptors modulates basal ganglia outflow in monkeys. J Neurophysiol 98: 1489-1500, 2007. First published July 18, 2007; doi:10.1152/jn.00171.2007. Studies of the effects of dopamine in the basal ganglia have focused on the striatum, whereas the functions of dopamine released in the internal pallidal segment (GPi) or in the substantia nigra pars reticulata (SNr) have received less attention. Anatomic and biochemical investigations have demonstrated the presence of dopamine D1-like receptors (D1LRs) in GPi and SNr, which are primarily located on axons and axon terminals of the GABAergic striatopallidal and striatonigral afferents. Our experiments assessed the effects of D1LR ligands in GPi and SNr on local ␥-aminobutyric acid (GABA) levels and neuronal activity in these nuclei in rhesus monkeys. Microinjections of the D1LR receptor agonist SKF82958 into GPi and SNr significantly reduced discharge rates in GPi and SNr, whereas injections of the D1LR antagonist SCH23390 increased firing in the majority of GPi neurons. D1LR activation also increased bursting and oscillations in neuronal discharge in the 3-to 15-Hz band in both structures, whereas D1LR blockade had the opposite effects in GPi. Microdialysis measurements of GABA concentrations in GPi and SNr showed that the D1LR agonist increased the level of the transmitter. Both findings are compatible with the hypothesis that D1LR activation leads to GABA release from striatopallidal or striatonigral afferents, which may secondarily reduce firing of basal ganglia output neurons. The antagonist experiments suggest that a dopaminergic "tone" exists in GPi. Our results support the finding that D1LR activation may have powerful effects on GPi and SNr neurons and may mediate some of the effects of dopamine replacement therapies in Parkinson's disease.

In sporadic colon cancer, colon cancer stem cells (CCSCs) initiate tumorigenesis and may contribute to late disease recurrences and metastases. We previously showed that aldehyde dehydrogenase (ALDH) activity (as indicated by the ALDEFLUOR® assay) is an effective marker for highly enriching CCSCs for further evaluation. Here, we used comparative transcriptome and proteome approaches to identify signaling pathways overrepresented in the CCSC population. We found overexpression of several components of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway, including PI3KR2, a regulatory subunit of PI3K. LY294002, a PI3K inhibitor, defined the contribution of the PI3K/Akt/mTOR signaling pathway in CCSCs. LY294002-treated CCSCs showed decreases in proliferation, sphere formation and self-renewal, in phosphorylation-dependent activation of Akt, and in expression of cyclin D1. Inhibition of PI3K in vivo reduced tumorigenicity, increased detection of cleaved caspase 3, an indicator of apoptosis, and elevated expression of the inflammatory chemokine, CXCL8. Collectively, these results indicate that PI3K/Akt/mTOR signaling controls CCSC proliferation and CCSC survival, and suggests that it would be useful to develop therapeutic agents that target this signaling pathway.

Background Colorectal cancer remains the most common gastrointestinal cancer. While screening combined with effective surgical treatment has reduced its mortality, we still do not have effective means to prevent recurrence nor to treat metastatic disease. What we know about cancer biology has gone through revolutionary changes in recent decades. The advent of the cancer stem cell theory has accelerated our understanding of the cancer cell. However, there is increasing evidence that cancer cells are influenced by their surrounding microenvironment. Purpose This review divides the tumor microenvironment into four functional components—the stem cell niche, cancer stroma, immune cells, and vascular endothelia—and examines their individual and collective influence on the growth and metastasis of the colon cancer stem cell. The discussion will highlight the need to fully exploit the tumor microenvironment when designing future prognostic tools and therapies.

Dysfunctional inflammatory pathways are associated with an increased risk of cancer, including colorectal cancer. We have previously identified and enriched for a self-renewing, colon cancer stem cell (CCSC) subpopulation in primary sporadic colorectal cancers (CRC) and a related subpopulation in ulcerative colitis (UC) patients defined by the stem cell marker, aldehyde dehydrogenase (ALDH). Subsequent work demonstrated that CCSC-initiated tumors are dependent on the inflammatory chemokine, CXCL8, a known inducer of tumor proliferation, angiogenesis and invasion. Here, we use RNA interference to target CXCL8 and its receptor, CXCR1, to establish the existence of a functional signaling pathway promoting tumor growth initiated by sporadic and colitis CCSCs. Knocking down either CXCL8 or CXCR1 had a dramatic effect on inhibiting both in vitro proliferation and angiogenesis. Likewise, tumorigenicity was significantly inhibited due to reduced levels of proliferation and angiogenesis. Decreased expression of cycle cell regulators cyclins D1 and B1 along with increased p21 levels suggested that the reduction in tumor growth is due to dysregulation of cell cycle progression. Therapeutically targeting the CXCL8-CXCR1 signaling pathway has the potential to block sustained tumorigenesis by inhibiting both CCSC- and pCCSC-induced proliferation and angiogenesis.

The emergence of pay-for-performance systems pose a risk to an academic medical center's (AMC) mission to provide care for interhospital surgical transfer patients. This study examines quality metrics and resource consumption for a sample of these patients from the University Health System Consortium (UHC) and our Department of Surgery (DOS). Standard benchmarks, including mortality rate, length of stay (LOS), and cost, were used to evaluate the impact of inter-hospital surgical transfers versus direct admission (DA) patients from January 2010 to December 2012. For 1,423,893 patients, the case mix index for transfer patients was 38 per cent (UHC) and 21 per cent (DOS) greater than DA patients. Mortality rates were 5.70 per cent (UHC) and 6.93 per cent (DOS) in transferred patients compared with 1.79 per cent (UHC) and 2.93 per cent (DOS) for DA patients. Mean LOS for DA patients was 4 days shorter. Mean total costs for transferred patients were greater $13,613 (UHC) and $13,356 (DOS). Transfer patients have poorer outcomes and consume more resources than DA patients. Early recognition and transfer of complex surgical patients may improve patient rescue and decrease resource consumption. Surgeons at AMCs and in the community should develop collaborative programs that permit collective assessment and decision-making for complicated surgical patients.