Purpose: One mechanism of tumor resistance to cytotoxic therapy is repair of damaged DNA.Poly(ADP-ribose) polymerase (PARP)-1is a nuclear enzyme involved in base excision repair, one of the five major repair pathways. PARP inhibitors are emerging as a new class of agents that can potentiate chemotherapy and radiotherapy. The article reports safety, efficacy, pharmacokinetic, and pharmacodynamic results of the first-in-class trial of a PARP inhibitor, AG014699, combined with temozolomide in adults with advanced malignancy. Experimental Design: Initially, patients with solid tumors received escalating doses of AG014699 with 100 mg/m 2 /d temozolomide  5 every 28 days to establish the PARP inhibitory dose (PID). Subsequently, AG014699 dose was fixed at PID and temozolomide escalated to maximum tolerated dose or 200 mg/m 2 in metastatic melanoma patients whose tumors were biopsied. AG014699 and temozolomide pharmacokinetics, PARP activity, DNA strand single-strand breaks, response, and toxicity were evaluated. Results: Thirty-three patients were enrolled. PARP inhibition was seen at all doses; PID was 12 mg/m 2 based on 74% to 97% inhibition of peripheral blood lymphocyte PARP activity. Recommended doses were 12 mg/m 2 AG014699 and 200 mg/m 2 temozolomide. Mean tumor PARP inhibition at 5 h was 92% (range, 46-97%). No toxicity attributable to AG014699 alone was observed. AG014699 showed linear pharmacokinetics with no interaction with temozolomide. All patients treated at PID showed increases in DNA single-strand breaks and encouraging evidence of activity was seen. Conclusions: The combination of AG014699 and temozolomide is well tolerated, pharmacodynamic assessments showing proof of principle of the mode of action of this new class of agents.Multiple pathways contribute to the repair of damaged DNA (1). Defects in these pathways are a cause of cancer susceptibility (2, 3), but, when intact, their activity is a factor in tumor resistance to widely used DNA-damaging cancer treatments (e.g., cytotoxic drugs and ionizing radiation; ref. 4). Several novel agents are being developed which target DNA repair in an attempt to improve cancer treatment (5), including agents that may exploit tumor DNA repair defects (e.g., BRCA1 and BRCA2) by inducing ''synthetic lethality'' (6, 7).Base excision repair is a complex process that repairs DNA single-strand breaks caused by endogenous reactive species and anticancer agents (8). Poly(ADP-ribose) polymerase-1 (PARP) is a key enzyme in this pathway, binding to and being activated by the DNA break, effectively acting as a molecular nick sensor (9), and recruiting additional repair factors. Preclinical evidence has shown that inhibiting PARP potentiates cytotoxics, particularly alkylating agents and topoisomerase I inhibitors, and radiotherapy (10 -12). Several PARP

Impulsivity is a colloquial term with which nearly everyone has some commerce. Although the term is sometimes used to describe socially appropriate actions (e.g., "She possessed an impulsive force to succeed in her job"), it more often refers to problematic behavior. For example, children are described as impulsive when they take a toy from a peer without considering the likely consequences of doing so (e.g., the peer crying and a reprimand from a caretaker). College students are said to be impulsive when they choose to attend a party with friends rather than study for an exam scheduled for the next day. And middle-aged adults might be similarly described if they repeatedly buy things on impulse without considering that payments (with interest) will come due at the end of the month. In this more frequent usage, impulsivity describes a tendency to act on a whim and, in so doing, disregard a more rational long-term strategy for success.

Nineteen treatment-seeking men meeting DSM-IV diagnostic criteria for pathological gambling and 19 demographic-matched controls participated. Participants provided demographic information, information about their recent drug-use and gambling activities, and biological samples (to confirm drug abstinence). They also completed the Eysenck Personality Questionnaire, the South Oaks Gambling Screen (SOGS), and two questionnaires designed to separately quantify probability and delay discounting. Pathological gamblers discounted probabilistic rewards significantly less steeply than matched controls. A significant correlation revealed that more shallow probability discounting was associated with higher SOGS scores. Across groups, there was no significant difference in delay discounting, although this difference approached significance when education and ethnicity were included as covariates. These findings, collected for the first time with pathological gamblers, are consistent with previous reports that problem-gambling college students discount probabilistic rewards less steeply than controls. The nature of the relation between probability discounting and severity of problem gambling is deserving of further study. Keywords probability discounting; pathological gambling; delay discounting; SOGS Within a behavioral economic framework, discounting refers to the devaluation of an outcome when the outcome is either delayed (delay discounting) or obtained probabilistically (probability discounting). This tendency to discount delayed or probabilistic outcomes has been studied by examining the behavior of humans and animals as they choose between immediate and delayed or between certain and probabilistic real or hypothetical outcomes. In what might be viewed as a striking example of either homologous behavior or convergent evolution, a single equation well describes the choices of humans and animals in these experiments, and typically accounts for over 90% of the behavioral variance (see review by Green & Myerson, 2004). Applied to delay discounting, the equation holds that the subjective value (V) of an outcome of amount A, obtained following delay D, declines hyperbolically (Mazur, 1987):Corresponding Author Address: Gregory J. Madden, Ph.D., Department of Applied Behavioral Science, University of Kansas, 1000 Sunnyside Ave., Lawrence, KS 66045. Publisher's Disclaimer: The following manuscript is the final accepted manuscript. It has not been subjected to the final copyediting, fact-checking, and proofreading required for formal publication. It is not the definitive, publisher-authenticated version. The American Psychological Association and its Council of Editors disclaim any responsibility or liabilities for errors or omissions of this manuscript version, any version derived from this manuscript by NIH, or other third parties. The published version is available at www.apa.org/pubs/journals/pha. NIH Public AccessEquations 1 and 2 each contain a single free parameter which is straightforwardly interpreted as degree...

Humans are reported to discount delayed rewards at lower rates than nonhumans. However, nonhumans are studied in tasks that restrict reinforcement during delays, whereas humans are typically studied in tasks that do not restrict reinforcement during delays. In nonhuman tasks, the opportunity cost of restricted reinforcement during delays may increase delay discounting rates. The present within-subjects study used online crowdsourcing (Amazon Mechanical Turk, or MTurk) to assess the discounting of hypothetical delayed money (and cigarettes in smokers) under four hypothetical framing conditions differing in the availability of reinforcement during delays. At one extreme, participants were free to leave their computer without returning, and engage in any behavior during reward delays (modeling typical human tasks). At the opposite extreme, participants were required to stay at their computer and engage in little other behavior during reward delays (modeling typical nonhuman tasks). Discounting rates increased as an orderly function of opportunity cost. Results also indicated predominantly hyperbolic discounting, the “magnitude effect,” steeper discounting of cigarettes than money, and positive correlations between discounting rates of these commodities. This is the first study to test the effects of opportunity costs on discounting, and suggests that procedural differences may partially account for observed species differences in discounting.

Preliminary information has suggested that megestrol acetate leads to appetite stimulation and nonfluid weight gain in patients with breast cancer, other cancers, and AIDS. Pursuant to this, we developed a randomized, double-blind, placebo-controlled trial of megestrol acetate in patients with cancer-associated anorexia and cachexia. We randomly assigned 133 eligible patients to receive 800 mg of megestrol acetate per day or a placebo. Patients assigned to megestrol acetate more frequently reported improved appetite (P = .003) and food intake (P = .009) when compared with patients receiving the placebo. A weight gain of 15 lb or more over baseline was seen in 11 of 67 (16%) patients receiving megestrol acetate compared with one of 66 (2%) given the placebo (P = .003). Patients receiving megestrol acetate reported significantly less nausea (13% vs. 38%; P = .001) and emesis (8% vs. 25%, P = .009). No clinically or statistically significant toxic reactions were ascribed to megestrol acetate, with the exception of mild edema. This study convincingly demonstrated that megestrol acetate can stimulate appetite and food intake in patients with anorexia and cachexia associated with cancer, leading to significant weight gain in a proportion of such patients.

Individuals with cocaine use disorders are disproportionately affected by HIV/AIDS, partly due to higher rates of unprotected sex. Recent research suggests delay discounting of condom use is a factor in sexual HIV risk. Delay discounting is a behavioral economic concept describing how delaying an event reduces that event’s value or impact on behavior. Probability discounting is a related concept describing how the uncertainty of an event decreases its impact on behavior. Individuals with cocaine use disorders (n = 23) and matched non-cocaine-using controls (n = 24) were compared in decision-making tasks involving hypothetical outcomes: delay discounting of condom-protected sex (Sexual Delay Discounting Task), delay discounting of money, the effect of sexually transmitted infection (STI) risk on likelihood of condom use (Sexual Probability Discounting Task), and probability discounting of money. The Cocaine group discounted delayed condom-protected sex (i.e., were more likely to have unprotected sex vs. wait for a condom) significantly more than controls in two of four Sexual Delay Discounting Task partner conditions. The Cocaine group also discounted delayed money (i.e., preferred smaller immediate amounts over larger delayed amounts) significantly more than controls. In the Sexual Probability Discounting Task, both groups showed sensitivity to STI risk, however the groups did not differ. The Cocaine group did not consistently discount probabilistic money more or less than controls. Steeper discounting of delayed, but not probabilistic, sexual outcomes may contribute to greater rates of sexual HIV risk among individuals with cocaine use disorders. Probability discounting of sexual outcomes may contribute to risk of unprotected sex in both groups. Correlations showed sexual and monetary results were unrelated, for both delay and probability discounting. The results highlight the importance of studying specific behavioral processes (e.g., delay and probability discounting) with respect to specific outcomes (e.g., monetary and sexual) to understand decision making in problematic behavior.

Awareness and use of electronic cigarettes (e-cigarettes) is increasing. Questions regarding positive (e.g., smoking reduction/cessation) and negative (e.g., delay of cessation) potential public health consequences of e-cigarettes may be informed by studying dual users of e-cigarettes and tobacco cigarettes. A cross-sectional online survey assessed demographics, product use patterns, and beliefs about relative product benefits and harms among dual users (n = 350) in the United States using the website Amazon Mechanical Turk (MTurk). Compared to tobacco cigarettes, e-cigarettes were used less often and were associated with lower dependence. Participants reported a 30% reduction in self-reported tobacco cigarette smoking since beginning to use e-cigarettes. Reported primary reasons for e-cigarette use were harm reduction and smoking cessation. E-cigarette use was reported as more likely in settings with smoking restrictions and when others’ health could be adversely affected. Conversely, participants reported having used tobacco cigarettes more often than e-cigarettes in hedonic situations (e.g., after eating, drinking coffee or alcohol, or having sex), outdoors, or when stressed. Participants were twice as likely to report wanting to quit tobacco cigarettes compared to e-cigarettes in the next year and intended to quit tobacco cigarettes sooner. Tobacco cigarettes were described as more harmful and addictive, but also more enjoyable than e-cigarettes. Participants provided evidence consistent with both positive and negative public health consequences of e-cigarettes, highlighting the need for experimental research, including laboratory studies and clinical trials. Policies should consider potential public health benefits of e-cigarettes, in addition to potential harms.

Naturally occurring impulsive choice has been found to positively predict alcohol consumption in rats. However, the extent to which experimental manipulation of impulsive choice may modify alcohol consumption remains unclear. In the present study, we sought to: (a) train low levels of impulsive choice in rats using early, prolonged exposure to reward delay, and (b) determine the effects of this manipulation on subsequent alcohol consumption. During a prolonged training regimen, three groups of male, adolescent Long-Evans rats (21-22 days old at intake) responded on a single lever for food rewards delivered after either a progressively increasing delay, a fixed delay, or no delay. Post-tests of impulsive choice were conducted, as was an evaluation of alcohol consumption using a limited-access, two-bottle test. Following delay-exposure training, both groups of delay-exposed rats made significantly fewer impulsive choices than did rats in the no-delay group. In addition, fixed-delay rats consumed significantly more alcohol during daily, 30-min sessions than no-delay rats. Possible mechanisms of these effects are discussed, as is the significance of these findings to nonhuman models of addiction.