Advanced colorectal carcinoma: redefining the role of oral ftorafur

The therapeutic performance, effect on quality of life and cost effectiveness of an orally administered medication in a home care setting were examined prospectively in a group of 61 patients presenting with advanced colorectal carcinoma. A regimen of daily ftorafur capsules (370 mg/m2) and leucovorin tablets (20 mg/m2) was offered to 35 symptomatic patients with poor performance status; the standard in-hospital i.v. protocol of 5-fluouracil and leucovorin was given to the remaining 26 patients. Follow-up and survival analysis indicated that there was no compromise in survival associated with home care and oral chemotherapy. There were statistically significant advantages in terms of reduced toxicity and improved Karnofsky performance status in this group. Home care was approximately 70% less expensive. A home treatment program based on oral ftorafur may be the most desirable option for all patients with advanced colorectal carcinoma.     

Structure-activity of tetrad-forming oligonucleotides as a potent anti-HIV therapeutic drug

Recently, we have described the design and characterization of oligonucleotides containing only G and T bases, i.e. T30695 and T30177, that are potent inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in culture (Jing, N., Rando, R. F., Pommier, Y., and Hogan, M. E. (1997) Biochemistry 36, 12498-12505). To understand that observation and to rationalize the generally high thermal stability of oligonucleotide folding for these compounds, we have used NMR methods, coupled to molecular modeling, to obtain a high resolution structure model for T30695, which is the most potent of the integrase inhibitors that have been identified thus far. Modeling and NMR data obtained in the presence of Li+ ions show that T30695 assumes an intramolecular fold with a distorted G-octet core and a set of three open, partially disordered loops. This is referred to as Li+-form structure. The NMR-based model suggests that, upon coordination with three K+ equivalents, the central G-octet becomes more regular and that the loop domains become orderly and compact. This is referred to as K+-form structure. Based upon the assay of inhibition of HIV-1 integrase, T30695 demonstrated a strong inhibition of HIV-1 integrase activity as the K+-form structure, but a poor inhibition of HIV-1 integrase activity as the Li+-form structure. The structure/activity analysis suggests that the K+-induced conformation transition of the tetrad-forming oligonucleotides, such as T30695 and T30177, plays a key role in inhibition of HIV-1 integrase activity.     

Acquired equivalence and distinctiveness in matching to sample by pigeons: Mediation by reinforcer-specific expectancies.

Assessed the ability of a reinforcer to mediate an association between 2 stimuli that independently predict the occurrence of that reinforcer (acquired equivalence of cues). In Exp I, 12 male White Carneaux pigeons were trained on shape (plus and circle) and color (red and green) matching-to-sample tasks. Correct responses were systematically reinforced with corn on some trials and wheat on others to establish associations between 1 stimulus from each task and a "common" outcome. Following training, Ss were transferred to a symbolic matching-to-sample task wherein a stimulus from one training task was presented as the sample, and the stimuli from the other training task were presented as comparisons. In the 1st session, experimental Ss made significantly more correct responses than controls (i.e., Ss "matched" stimuli previously associated with a common outcome). Exp II with 18 Ss replicated this acquired equivalence effect and controlled for food preference. Delayed matching-to-sample training demonstrated enhanced memory performance for Ss exposed to different reinforcement contingencies, but this effect was confined to the shape task. Results indicate that a reinforcer can serve as the basis for organizing otherwise unpaired predictive cues in memory and that animals will selectively use differential expectancies as cues for solving complex discrimination tasks, depending on the difficulty of the discrimination. (29 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nuclear distribution of human DNA topoisomerase IIbeta: a nuclear targeting signal resides in the 116-residue C-terminal tail

Surgery is considered to be a standard therapy for stage III or the earlier stage of esophageal cancer. However, the standard therapy is changing because of the recent advances in the non-surgical approach, especially chemoradiotherapy. Various obstacles remain to estimate the outcomes of combined modality therapy, while the consensus of the treatment for such stage excluding T4 diseases are as follows: 1) Concurrent chemoradiotherapy has a superior outcome to radiation alone in patients with squamous cell carcinoma. 2) Recent chemoradiotherapy without surgery achieves results comparable to surgery alone. 3) Preoperative chemoradiotherapy can achieve better results than surgery alone in patients with adenocarcinoma. 4) Preoperative chemotherapy is still experimental. Our preliminary results of chemoradiotherapy for esophageal cancer also showed comparable data to extended surgery in terms of survival. Some significant points to be elucidated regarding combined modalities in stage III or earlier are: 1) the comparison of definitive chemoradiotherapy with Japanese extended surgery, and 2) evaluation of efficacy of surgery after chemoradiotherapy. However, these studies require randomized trials comparing surgery with non-surgical treatment, which appears to present significant obstacles. Critical estimation for each study should be recommended based on accurate clinical staging, biological behavior, and intention-to-treat.     

Correlation of the enzyme activities of Bacillus stearothermophilus lactate dehydrogenase on three substrates with the results of molecular dynamics/energy minimization conformational searching

Current methods for reengineering enzyme substrate specificities rely heavily on the use of static x-ray crystallographic models. In this article we detail the use of a molecular mechanics approach for suggesting regions of Bacillus stearothermophilus L-lactate dehydrogenase (EC 1.1.1.27) involved in substrate specificity, and hence areas of interest for protein engineers. The approach combines molecular dynamics with energy minimization (MD/EM) to search the conformational space available to a 15-A sphere of the ternary complex centered on the catalytic histidine. The search is carried out by calculating a 30-ps dynamics trajectory at 300 K and minimizing structures at 1-ps intervals. The protocol has been performed on 14 systems containing different combinations of substrate and mutant/wt LDH. In order to discover which interactions are important in defining substrate specificity, eight conformational parameters representing substrate-active site interactions were measured in each of the 420 minimized structures. These parameters were then compared to the measured catalytic activity of the protein-substrate combinations. These comparisons show that arginine 109 orientation is a major determining factor in LDH specificity. Using this methodology it is possible to estimate the catalytic activity of proteins of varied sequence by computer simulation before synthesis.     

Personality correlates of physical fitness.

In this article, I examine the relation between personality and physical fitness. One group (N?=?97) of male adults completed the Hogan Personality Inventory and five nationally recognized physical fitness batteries. A second group (N?=?35) completed the Minnesota Multiphasic Personality Inventory and a set of medical and physical performance assessments. Results indicate that physical fitness must be defined in multidimensional terms and that fitness is related to self-discipline. Measures of psychopathology were unrelated to measures of health and fitness. These data suggest that the personal qualities associated with fitness are also those that promote and extend health. (PsycINFO Database Record (c) 2010 APA, all rights reserved)