p53 and thymidylate synthase expression in untreated stage II colon cancer: associations with recurrence, survival, and site

We initiated a retrospective study to determine whether p53 status and thymidylate synthase (TS) protein expression in primary colon tumors influence recurrence and survival for patients with stage II colon cancer. Tumor specimens from 45 consecutive untreated patients with stage II colon cancer were examined for p53 and TS protein expression using immunohistochemistry. The median follow-up was 5.1 years. Eighteen patients had left-sided tumors, and 27 had right-sided tumors. Fourteen of 45 patients (31%) developed recurrence. p53 overexpression was detected in the tumors of 18 patients (40%); 10 patients (55%) with p53 overexpression recurred; and 4 of 27 (15%) without evidence of p53 overexpression recurred (P = 0.002). High TS expression was detected in the tumors of 16 patients (36%): 8 patients (50%) with high TS expression recurred, and 6 patients (21%) with low TS expression recurred (P = 0.027). Patients with p53 overexpression had a significantly poorer survival than did those patients without p53 overexpression (P < 0.001). High TS expression was associated with poor survival (P = 0.004). p53 overexpression and high TS expression were significantly associated with left-sided tumors (P = 0.003 and P = 0.022). Thirteen of 16 patients (81%) with high TS expression also overexpressed p53, and 24 of 29 patients (81%) with low TS expression did not manifest p53 overexpression (P < 0.001). p53 and TS expression in primary stage II colon cancer are associated and appear to influence recurrence and survival. In this pilot study, left-sided tumors demonstrate significantly more p53 overexpression and significantly higher TS expression than do right-sided tumors, which may explain the significantly poorer survival for patients with left-sided tumors.     

Estimating the number of errors in a system using a martingaleapproach

A new, efficient procedure estimates the number of errors in a system. A known number of seeded errors are inserted into a system. The failure intensities of the seeded and real errors are allowed to be different and time dependent. When an error is detected during the test, it is removed from the system. The testing process is observed for a fixed amount of time τ. Martingale theory is used to derive a class of estimators for the number of seeded errors in a continuous time setting. Some of the estimators and their associated standard deviations have explicit expressions. An optimal estimator among the class of estimators is obtained. A simulation study assesses the performance of the proposed estimators     

X-linked exudative vitreoretinopathy caused by an arginine to leucine substitution (R121L) in the Norrie disease protein

We report the cosegregation of an arginine to leucine substitution at position 121 of the Norrie disease protein in a large kindred where exudative vitreoretinopathy segregates as an X-linked recessive trait. The clinical phenotype and rate of disease progression were extremely variable, with progression to total retinal detachment from less than age 2 years to more than 21 years. To date, all mutations in X-linked vitreoretinopathy have been missense mutations, presumably not affecting the three-dimensional structure of the NDP gene product, and clustered around residues 121-126 of the Norrie protein. This contrasts with the diversity of mutations seen in the more severe, allelic Norrie disease.     

The genetics of age-related macular degeneration

Age-related macular degeneration (ARM) is a progressive, chronic condition that results when the macula degenerates and central vision is lost. ARM is the leading cause of vision loss in Americans over age 50 and is a major public health concern. Very little is known about the etiology of ARM. Deciphering the genetic susceptibility associated with ARM holds great promise for gaining a better understanding of the disease, identifying at-risk individuals, and developing interventions and treatments.     

An epidemiological profile of elderly suicides in Hong Kong

Suicide rates in Hong Kong increased with age, and the highest suicide rate occurred among the oldest age groups. Hong Kong has one of the highest elderly suicide rates in the world. The elderly suicide rate was four to five times above the average. Furthermore, gender differences were observed among different marital status groups. For example, single males had a much higher rate than single females and married males had a higher rate than their widowed counterparts. The suicide rate for an economically inactive person was six times higher than for an active one. Jumping has become increasingly common and seems to substitute for other methods of suicide. Winter months and the Chinese New Year period had the lowest suicide occurrence. Some explanations are given.     

Highly potent, selective, and low cost bis-tetrahydroaminacrine inhibitors of acetylcholinesterase. Steps toward novel drugs for treating Alzheimer's disease

We report highly potent, selective, and low cost bifunctional acetylcholinesterase (AChE) inhibitors developed by our two-step prototype optimization strategy utilizing computer modeling of ligand docking with target proteins: 1) identify low affinity sites normally missed by x-ray crystallography; and 2) design bifunctional analogs capable of simultaneous binding at the computer-determined low affinity site and the x-ray-identified high affinity site. Applying this strategy to 9-amino-1,2,3,4-tetrahydroacridine (THA), a drug for Alzheimer's disease, we obtained alkylene linked bis-THA analogs. These analogs were up to 10,000-fold more selective and 1,000-fold more potent than THA in inhibiting rat AChE and yet required one simple reaction to synthesize. Additionally, alkylene linked benzyl-THA analogs were developed to examine the specificity of the docking-derived low affinity THA peripheral site in AChE. The present work and our previous computational studies strongly suggest that a low affinity THA peripheral site exists in AChE. This peripheral site provides a structural basis for design of improved cholinesterase ligands for treating Alzheimer's disease and for other health-related purposes.