A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma.

A mutated cyclin-dependent kinase 4 (CDK4) was identified as a tumor-specific antigen recognized by HLA-A2. 1-restricted autologous cytolytic T lymphocytes (CTLs) in a human melanoma. The mutated CDK4 allele was present in autologous cultured melanoma cells and metastasis tissue, but not in the patient's lymphocytes. The mutation, an arginine-to-cysteine exchange at residue 24, was part of the CDK4 peptide recognized by CTLs and prevented binding of the CDK4 inhibitor p16INK4a, but not of p21 or of p27KIP1. The same mutation was found in one additional melanoma among 28 melanomas analyzed. These results suggest that mutation of CDK4 can create a tumor-specific antigen and can disrupt the cell-cycle regulation exerted by the tumor suppressor p16INK4a.

Hypnotic efficacy of lorazepam and flurazepam.

In a double-blind crossover study involving 15 insomniac subjects, the hypnotic efficacy of lorazepam, 2 and 4 mg, was compared with flurazepam, 15 and 30 mg, and placebo. Five subjective measures were used: onset, length, and depth of sleep, number of times awakened, and satisfaction with the hypnotic. Lorazepam in 2- and 4-mg doses was comparable in hypnotic efficacy to flurazepam, 30 mg, according to most parameters of measurement. Side effects were minor, although relatively numerous at the 4-mg doses.

A method for evaluating anxiolytic sedatives.

Although anxiolytic sedatives are widely used in clinical practice, the methodology for assessing treatment effect of these compounds has not been well developed. The present double-blind study was designed to refine methodology for evaluating anxiolytics. Choice of rating scale, patient selection, maintenance of the double-blind status, the subjects' environment during the study, and the subjects' understanding of the study are discussed as considerations in reducing sources of variability and bias in the study of anxiolytics. After placebo prescreening, 14 subjects with diagnoses of anxiety recieved 3 to 6 mg lorazepam daily for four weeks, while 14 control subjects received placebo. The Hamilton Anxiety Rating Scale (HARS) and the Wang Anxiety Rating Scale (WARS), with its Anxiolytic Adjunct Scale (AAS), were used to assess changes in anxiety. The Wang and Hamilton ratings correlated well at both comparison periods. Lorazepam demonstrated significant superiority to placebo and produced no serious adverse effects. Anxiolytic efficacy did not differ significantly among the four weekly ratings.

Determining optimum dose and acute tolerance of triazolam.

The present two-phase study was designed to determine the optimum hynotic dose of triazolam and to assess any evidence of acute tolerance. Subjective and objective data were used to assess hypnotic efficacy. In the dose-titration phase, the dose of triazolam was increased in 0-5 mg increments to the highest level tolerated by each individual patient. Maximum tolerable doses ranged between 0-5 and 3-0 mg; however, all subjects experienced maximum therapeutic effect at 1-5 mg triazolam. During the 4-night acute tolerance portion of the study no clear evidence of tolerance was found.

Characteristics of drug abuse patients at a Veterans Administration Hospital.

A total of 308 patients were treated at the Wood VAC Drug Treatment Center during its first 2 years of operation (November 1, 1971-October 318 1973). They completed confidential questionnaires upon admission. Personal information and data concerning drug usage were obtained. Significant findings include the following: 1. A wide variety of opiate and nonopiate drugs were available in the military. 2. Although most patients had experienced illicit drugs prior to service, over 60% tried heroin for the first time while in the military; 83% of these men were subsequently treated for opiate dependence. 3. High rates of unemployment, marital instability, and convictions for illegal activities were revealed. A significant proportion of first convictions occurred prior to major drug usage. Data suggest that a flexible and multimodal approach to drug abuse therapy may have the best potential for success. Problems in evaluating and coordinating drug treatment programs are discussed briefly.