Targeting mTOR network in colorectal cancer therapy

The mechanistic target of rapamycin(mTOR)integrates growth factor signals with cellular nutrient and energy levels and coordinates cell growth,proliferation and survival.A regulatory network with multiple feedback loops has evolved to ensure the exquisite regulation of cell growth and division.Colorectal cancer is the most intensively studied cancer because of its high incidence and mortality rate.Multiple genetic alterations are involved in colorectal carcinogenesis,including oncogenic Ras activation,phosphatidylinositol 3-kinase pathway hyperactivation,p 53 mutation,and dysregulation of wnt pathway.Many oncogenic pathways activate the mTOR pathway.mTOR has emerged as an effective target for colorectal cancer therapy.In vitro and preclinical studies targeting the mTOR pathway for colorectal cancer chemotherapy have provided promising perspectives.However,the overall objective response rates in major solid tumors achieved with single-agent rapalog therapy have been modest,especially in advanced metastatic colorectal cancer.Combination regimens of mTOR inhibitor with agents such as cytotoxic chemotherapy,inhibitors of vascular endothelial growth factor,epidermal growth factor receptor and Mitogen-activated protein kinase kinase(MEK)inhibitors are being intensively studied and appear to be promising.Further understanding of the molecular mechanism in mTOR signaling network is needed to develop optimized therapeutic regimens.In this paper,oncogenic gene alterations in colorectal cancer,as well as their interaction with the mTOR pathway,are systematically summarized.The most recent preclinical and clinical anticancer therapeutic endeavors are reviewed.New players in mTOR signaling pathway,such as nonsteroidal anti-inflammatory drug and metformin with therapeutic potentials are also discussed here.     

H pylori receptor MHC classⅡcontributes to the dynamic gastric epithelial apoptotic response

AIM: To investigate the role of MHC classⅡin the modulation of gastric epithelial cell apoptosis induced by H pylon infection. METHODS: After stimulating a human gastric epithelial cell line with bacteria or agonist antibodies specific for MHC classⅡand CD95, the quantitation of apoptotic and anti-apoptotic events, including caspase activation, BCL-2 activation, and FADD recruitment, was performed with a fluorometric assay, a cytometric bead array, and confocal microscopy, respectively. RESULTS: Pretreatment of N87 cells with the anti-MHC classⅡIgM antibody RFD1 resulted in a reduction in global caspase activation at 24 h of H pylori infection. When caspase 3 activation was specifically measured, crosslinking of MHC class n resulted in markedly reduced caspase activation, while simple ligation of MHC classⅡdid not. Crosslinking of MHC class n also resulted in an increased activation of the anti-apoptosis molecule BCL-2 compared to simple ligation. Confocal microscope analysis demonstrated that the pretreatment of gastric epithelial cells with a crosslinking anti-MHC classⅡIgM blocked the recruitment of FADD to the cell surface. CONCLUSION: The ability of MHC class n to modulate gastric epithelial apoptosis is at least partially dependent on its crosslinking. The crosslinking of this molecule has anti-apoptotic effects during the earlier time points of H pylori infection. This effect is possibly mediated by the ability of MHC classⅡto modulate the activation of the pro-apoptotic receptor Fas by blocking the recruitment of the accessory molecule FADD, and this delay in apoptosis induction could allow for prolonged cytokine secretion by H pylori-infected gastric epithelial cells.     

Budget [Restrictions on abortion funding,summary. 21 March 1990

The West Virginia Budget for 1990-1991 prohibits the state funding of abortions except in cases of threat to life; threat of permanent, catastrophic physical injuries; fetal defect; rape; and incest.     

Fatal injuries caused by underarm use of shoulder belts

Safety belt use has dramatically increased in the past decade in North America because of safety belt use laws. Underarm use of shoulder belts is a means of relieving neck irritation and other complaints from shoulder belts but may result in serious or fatal injuries. Loads far in excess of the injury tolerance of the lower chest and upper abdomen are imposed by the shoulder belt in the underarm position. Six recent cases are presented in which fatal injury was caused by underarm use of shoulder belts. Lacerations of the liver, spleen, intestines, mesentery, diaphragm, and aorta, and spine injury have occurred in accidents, most of which should have been survivable. The motoring public must be warned that underarm use of shoulder belts is hazardous and may cause fatal injuries in otherwise survivable accidents.     

Abdominal aortic reconstruction in infected fields: early results of the United States cryopreserved aortic allograft registry

OBJECTIVE: Aortic reconstructions for primary graft infection (PGI), mycotic aneurysm (MA), and aortic graft-enteric erosion (AEE) bear high morbidity and mortality rates, and current treatment options are not ideal. Cryopreserved grafts have been implanted successfully in infected fields and may be suitable for abdominal aortic reconstructions. Registry data from several institutions were compiled to examine results of cryopreserved aortic allograft (CAA) placement. METHODS: The experience of 31 institutions was reviewed for CAAs inserted from March 4, 1999, to August 23, 2001. Indications for CAA, organisms, mortality, and complications were identified. RESULTS: Fifty-six patients, 43 men and 13 women, with a mean age of 66 years (range, 44 to 90 years) had in situ aortic replacement with CAA. Indications for CAA placement were PGI in 43 patients (77%), MA in seven (14%), AEE in four (7%), and aortic reconstruction with concomitant bowel resection in two (4%). Infectious organisms were identified in 33 patients (59%); the most frequent organism was Staphylococcus aureus in 17 (52%). Thirty-one patients (55%) needed an additional cryopreserved segment for reconstruction. The mean follow-up period was 5.3 months (range, 1 to 22 months). One patient died in the operating room, and the 30-day surgical mortality rate was 13% (7/56). Seven additional patients died during the follow-up period, yielding an overall mortality rate of 25% (14 patients). Two patients (4%) had graft-related mortality as the result of hemorrhage from the CAA and persistent infection. Graft-related complications included persistent infection with perianastomotic hemorrhage in five patients (9%), graft limb occlusion in five (9%), and pseudoaneurysm in one (2%). Three patients (5%) needed amputation. CONCLUSION: In situ aortic reconstruction with CAA in infected fields carries a high mortality rate, but most deaths are not the result of allograft failure. However, CAA infection and lethal hemorrhage caused by graft rupture occurs and is concerning. Early reinfection was not reported. Late graft-related complications, such as reinfection, thrombosis, or aneurysmal changes, are unknown. Preliminary data from this registry fail to justify the preferential use of CAA for PGI, MA, or AEE. A multicenter, randomized study is needed to compare results with established techniques.     

An approach to coordinate efforts to reduce the public health burden of stroke: the Delta States Stroke Consortium

Stroke is the third leading cause of death and a leading cause of disability in the United States, with a particularly high burden on the residents of the southeastern states, a region dubbed the "Stroke Belt." These five states — Alabama, Arkansas, Louisiana, Mississippi, and Tennessee — have formed the Delta States Stroke Consortium to direct efforts to reduce this burden. The consortium is proposing an approach to identify domains where interventions may be instituted and an array of activities that can be implemented in each of the domains. Specific domains include 1) risk factor prevention and control; 2) identification of stroke signs and symptoms and encouragement of appropriate responses; 3) transportation, Emergency Medical Services care, and acute care; 4) secondary prevention; and 5) recovery and rehabilitation management. The array of activities includes 1) education of lay public; 2) education of health professionals; 3) general advocacy and legislative actions; 4) modification of the general environment; and 5) modification of the health care environment. The Delta States Stroke Consortium members propose that together these domains and activities define a structure to guide interventions to reduce the public health burden of stroke in this region.