Assessment of the Impact of Alternative Fixatives on HER2 Detection in Breast Cancer and Gastric Cancer Tumor Specimens.

The type of fixative used for preserving tumor specimens can significantly impact the performance of the immunohistochemistry and in situ hybridization assays used for assessing human epidermal growth factor receptor 2 (HER2) status. This study reports the prevalence of the use of alternative fixatives other than the guideline-recommended 10% neutral buffered formalin (NBF) during HER2 testing in a real-world setting. The effects of alternative fixatives [20% NBF and 10% unbuffered formalin (UBF) fixatives] on HER2 testing of breast cancer (BC) and gastric cancer (GC) cell lines and tissues are also assessed. Overall, 117,636 tumor samples received at a central laboratory from >8000 clinical trial sites across 60 countries were reviewed to determine the prevalence of alternative fixative usage. To investigate the impact of alternative fixatives, 27 cell lines (21 BC and 6 GC) and 76 tumor tissue samples (50 BC and 26 GC) were fixed in 10% NBF, 20% NBF, or 10% UBF, and evaluated for HER2 status by immunohistochemistry and in situ hybridization. Real-world data showed that 9195 (7.8%) tumor samples were preserved using an alternative fixative. In cell lines, overall percentage agreement, negative percentage agreement, and positive percentage agreement among the 3 fixatives were 100%. In tumor tissues, the agreement among 10% NBF, 20% NBF, and 10% UBF ranged between 94.7% and 96.6% for negative percentage agreement and 90.9% for overall percentage agreement compared with a range of 58.3% to 66.7% for positive percentage agreement. These results suggest that alternative fixatives may have the potential to convert HER2 status in tissues from positive to negative.

Do Environmental Cues to Discovery Influence the Likelihood to Rape?

Research on men's sexual exploitation of women has documented that men's psychology tracks cues associated with the ease of women's exploitability. In the current studies, we examined a different class of cues hypothesized to aid men's use of sexually exploitative strategies: environmental cues to the likelihood of discovery. We defined likelihood of discovery as the perceived probability of identification when engaging in exploitative behavior (e.g., presence of others). We test the hypothesis that men's likelihood to rape increases when their perception of the likelihood of discovery is low in three studies. In Study 1, we conducted a content analysis of individuals' responses (N = 1,881) when asked what one would do if they could stop time or be invisible. Besides the "other" category whereby there were no specific category for nominated behaviors, the most nominated category included sexually exploitative behavior-representing 15.3% of reported behaviors. Both Studies 2 (N = 672) and 3 (N = 614) were preregistered manipulations of likelihood of discovery surreptitiously testing men's rape likelihood to rape across varying levels of discovery. We found men, compared to women, reported a statistically higher likelihood to rape in both Studies 2 and 3: 48% compared to 39.7% and 19% compared to 6.8%, respectively. Across Studies 2 and 3, we found no statistical effect of the likelihood of discovery on participants' likelihood to rape. We discuss how the presence of one's peers may provide social protection against the costs of using an exploitative sexual strategy if a perpetrator is caught.

Regulation of ingestive behaviors in the rat by GSK1521498, a novel micro-opioid receptor-selective inverse agonist.

µ-Opioid receptor (MOR) agonism induces palatable food consumption principally through modulation of the rewarding properties of food. N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine (GSK1521498) is a novel opioid receptor inverse agonist that, on the basis of in vitro affinity assays, is greater than 10- or 50-fold selective for human or rat MOR, respectively, compared with κ-opioid receptors (KOR) and δ-opioid receptors (DOR). Likewise, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with µ receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats, which comprised fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption; thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates the hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.

Tetrahydroquinoline derivatives as opioid receptor antagonists.

Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the µ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications.

The evolutionary psychology of violence.

This paper reviews theory and research on the evolutionary psychology of violence. First, I examine evidence suggesting that humans have experienced an evolutionary history of violence. Next, I discuss violence as a context-sensitive strategy that might have provided benefits to our ancestors under certain circumstances. I then focus on the two most common forms of violence that plague humans -violence over status contests and intimate partner violence- outlining psychological mechanisms involved in each. Finally, I suggest that greater progress will be made by shifting the study from contexts to mechanisms.

Is the Vertical-Horizontal Illusion a Byproduct of the Environmental Vertical Illusion?

The vertical-horizontal illusion is the overestimation of a vertical line compared to a horizontal line of the same length. Jackson and Cormack (2007) proposed that the vertical-horizontal illusion might be a byproduct of the mechanisms that generate the environmental vertical illusion, which is the tendency to overestimate vertical distances (i.e., heights) relative to horizontal distances the same length. In our study, 326 undergraduate participants stood atop an 18.6-meter parking structure and estimated both the height of the structure and the horizontal distance of a target placed 18.6 meters away, using a moveable horizontal target across the length of the structure. Participants also completed a vertical-horizontal illusion task by drawing a horizontal line below a 9.1 cm vertical line. We correlated vertical distance estimates with vertical line estimates to test Jackson and Cormack's byproduct hypothesis. This hypothesis was very weakly-if at all-supported by the data: Participants' overestimations in the vertical-horizontal illusion task explained 1% of the variance associated with their overestimations in the environmental vertical illusion task. Additionally, to test whether the environmental vertical illusion is impervious to explicit awareness, a random half of our participants were advised to be mindful that people tend to overestimate heights. The results supported our second hypothesis: Even when participants were made aware of the environmental vertical illusion, they still reliably overestimated heights. Discussion addressed implications for the robustness of the environmental vertical illusion (e.g., treatment of those with acrophobia).

Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors.

Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.

Sexual coercion in intimate relationships: a comparative analysis of the effects of women's infidelity and men's dominance and control.

Researchers studying the proximate (or immediate) causes of sexual coercion have proposed that partner rape is motivated by a man's attempt to dominate and control his partner and that this expression of power is the product of men's social roles. Researchers studying the ultimate (or evolutionary) causes, in contrast, have proposed that partner rape may function as an anti-cuckoldry tactic, with its occurrence related to a man's suspicions of his partner's sexual infidelity. In two studies, we collected data relevant to both perspectives to explore how these variables interact with men's sexual coercion in an intimate relationship. Regression analyses from Study 1 (self-reports from 256 men) and Study 2 (partner-reports from 290 women) indicated that men's sexual coercion of their partners was consistently predicted by female infidelity and men's controlling behavior, suggesting that both variables are necessary to explain men's sexual coercion. Discussion addressed limitations of the current research and highlighted the importance of integrating multiple levels of analysis when studying men's sexual coercion of their intimate partners.

Discovery of small molecule agonists for the bombesin receptor subtype 3 (BRS-3) based on an omeprazole lead.

Starting from a weak omeprazole screening hit, replacement of the pyridine with a 1,3-benzodioxole moiety, modification of the thioether linkage, and substitution of the benzimidazole pharmacophore led to the discovery of nanomolar BRS-3 agonists.

Absence makes the adaptations grow fonder: proportion of time apart from partner, male sexual psychology, and sperm competition in humans (Homo sapiens).

Sperm competition occurs when the sperm of multiple males concurrently occupy the reproductive tract of a female and compete to fertilize an egg. We used a questionnaire to investigate psychological responses to the risk of sperm competition for 237 men in committed, sexual relationships. As predicted, a man who spends a greater (relative to a man who spends a lesser) proportion of time apart from his partner since the couple's last copulation reported (a) greater sexual interest in his partner, (b) greater distress in response to his partner's sexual rejection, and (c) greater sexual persistence in response to his partner's sexual rejection. All effects were independent of total time since the couple's last copulation and the man's relationship satisfaction. Discussion addresses limitations of the current research and situates the current results within the broader comparative literature on adaptation to sperm competition.

Potent, selective, and orally efficacious antagonists of melanin-concentrating hormone receptor 1.

The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.

6-(4-chlorophenyl)-3-substituted-thieno[3,2-d]pyrimidin-4(3H)-one-based melanin-concentrating hormone receptor 1 antagonist.

Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.

Pharmacological regulation of insulin secretion in MIN6 cells through the fatty acid receptor GPR40: identification of agonist and antagonist small molecules.

1. Long chain fatty acids have recently been identified as agonists for the G protein-coupled receptors GPR40 and GPR120. Here, we present the first description of GW9508, a small-molecule agonist of the fatty acid receptors GPR40 and GPR120. In addition, we also describe the pharmacology of GW1100, a selective GPR40 antagonist. These molecules were used to further investigate the role of GPR40 in glucose-stimulated insulin secretion in the MIN6 mouse pancreatic beta-cell line. 2. GW9508 and linoleic acid both stimulated intracellular Ca2+ mobilization in human embryonic kidney (HEK)293 cells expressing GPR40 (pEC50 values of 7.32+/-0.03 and 5.65+/-0.06, respectively) or GPR120 (pEC50 values of 5.46+/-0.09 and 5.89+/-0.04, respectively), but not in the parent HEK-293 cell line. 3. GW1100 dose dependently inhibited GPR40-mediated Ca2+ elevations stimulated by GW9508 and linoleic acid (pIC50 values of 5.99+/-0.03 and 5.99+/-0.06, respectively). GW1100 had no effect on the GPR120-mediated stimulation of intracellular Ca2+ release produced by either GW9508 or linoleic acid. 4. GW9508 dose dependently potentiated glucose-stimulated insulin secretion in MIN6 cells, but not in primary rat or mouse islets. Furthermore, GW9508 was able to potentiate the KCl-mediated increase in insulin secretion in MIN6 cells. The effects of GW9508 on insulin secretion were reversed by GW1100, while linoleic acid-stimulated insulin secretion was partially attenuated by GW1100. 5. These results add further evidence to a link between GPR40 and the ability of fatty acids to acutely potentiate insulin secretion and demonstrate that small-molecule GPR40 agonists are glucose-sensitive insulin secretagogues.

Comparative evolutionary psychology of sperm competition.

A comparative evolutionary psychological perspective predicts that species that recurrently faced similar adaptive problems may have evolved similar psychological mechanisms to solve these problems. Sperm competition provides an arena in which to assess the heuristic value of such a comparative evolutionary perspective. The sperm competition that results from female infidelity and polyandry presents a similar class of adaptive problems for individuals across many species. The authors first describe mechanisms of sperm competition in insects and in birds. They suggest that the adaptive problems and evolved solutions in these species provide insight into human anatomy, physiology, psychology, and behavior. The authors then review recent theoretical and empirical arguments for the existence of sperm competition in humans and discuss proposed adaptations in humans that have analogs in insects or birds. The authors conclude by highlighting the heuristic value of a comparative evolutionary psychological approach in this field.

Sexual coercion and forced in-pair copulation as sperm competition tactics in humans.

Rape of women by men might be generated either by a specialized rape adaptation or as a by-product of other psychological adaptations. Although increasing number of sexual partners is a proposed benefit of rape according to the "rape as an adaptation" and the "rape as a by-product" hypotheses, neither hypothesis addresses directly why some men rape their long-term partners, to whom they already have sexual access. In two studies we tested specific hypotheses derived from the general hypothesis that sexual coercion in the context of an intimate relationship may function as a sperm competition tactic. We hypothesized that men's sexual coercion in the context of an intimate relationship is related positively to his partner's perceived infidelities and that men's sexual coercion is related positively to their mate retention behaviors (behaviors designed to prevent a partner's infidelity). The results from Study 1 (self-reports from 246 men) and Study 2 (partner-reports from 276 women) supported the hypotheses. The Discussion section addresses limitations of this research and highlights future directions for research on sexual coercion in intimate relationships.

Mate guarding and frequent in-pair copulation in humans : Concurrent or compensatory anti-cuckoldry tactics?

Cuckoldry is an adaptive problem faced by parentally investing males of socially monogamous species (e.g., humans and many avian species). Mate guarding and frequent in-pair copulation (IPC) may have evolved as anti-cuckoldry tactics in avian species and in humans. In some avian species, the tactics are used concurrently, with the result that mate guarding behaviors and IPC frequency are correlated positively. In other avian species, the tactics are compensatory, with the result that mate guarding behaviors and IPC frequency are correlated negatively. The relationship between mate guarding and IPC frequency in humans is unknown. Avian males that use these tactics concurrently share with human males an inability to guard a female partner continuously during her peak fertile period. We hypothesized, therefore, that men's mate guarding and IPC frequency function as concurrent anti-cuckoldry tactics, resulting in a positive correlation between them. Study 1 (n=305) secured men's self-reports of mate guarding and IPC frequency. Study 2 (n+367) secured women's reports of their partners' mate guarding and IPC frequency. The concurrent tactics hypothesis was supported in both studies: Men's mate guarding and IPC frequency are correlated positively, and this association is not attributable to male age, female age, relationship satisfaction, relationship length, or time that the couple spends together. The Discussion section addresses potential limitations of this research and future research directions.

Modern application of evolutionary theory to psychology: key concepts and clarifications.

Darwinian selection has become the centerpiece of biology, and in the past few decades many psychologists and anthropologists have recognized the value of using an evolutionary perspective to guide their work. With a focus on evolved psychological mechanisms and associated information processing features, evolutionary psychology has risen as a compelling and fruitful approach to the study of human psychology and behavior. In this article we review the instrument of evolution: natural selection, the products of evolution, and the impact of evolutionary thinking on modern psychological science. We conclude that as prejudicial barriers are overcome, as more evolutionary psychological work is conducted, and as hypothesized psychological mechanisms are substantiated in other disciplines, evolutionary psychology will emerge as the metatheory for psychology.

Adding insult to injury: development and initial validation of the Partner-Directed Insults Scale.

Women who are verbally abused by their intimate male partners suffer serious mental health consequences and often experience physical violence in their relationship. Despite the importance of studying verbal abuse, no previous research has investigated the specific content of the insults men use to derogate their partners. We present the development and initial validation of a new measure designed to assess the specific content of insults used by men against their intimate partners. In a preliminary study, we used feedback from battered women, along with a review of the relevant literature, to identify specific insults for inclusion in the Partner-Directed Insults Scale (PDIS). We administered the PDIS to a sample of United States participants (Study 1) and a sample of New Zealand participants (Study 2), allowing for a cross-national investigation of the specific insults that men use to derogate their partners. The results demonstrate the practical need for such a scale and provide evidence for the discriminant validity of the PDIS by documenting that men's use of insults predicts their use of controlling behaviors and physical violence.

A Phenotypic High-Throughput Screen with RSV-Infected Primary Human Small Airway Epithelial Cells (SAECs).

Respiratory syncytial virus (RSV) is a commonly occurring pathogen that can cause severe disease in children, the elderly, and immunocompromised individuals with a large, unmet clinical need. We developed a high-throughput, primary cell-based antiviral RSV assay to enable identification of small molecules using cytopathic effect (CPE) as a phenotypic end point. To provide increased biological relevance, we developed our assay with primary human small airway epithelial cells (SAECs), which originate from known sites of RSV infection and replication instead of a more traditional immortalized cell line. Using purchased low-passage cells, cost-effective large-scale culture methods were developed to provide assay-ready frozen SAECs. A high-throughput screening campaign using the GSK Screening Collection was performed. The screen was executed in 384-well plates over a 12-week period with an average Z' of 0.5. The screen yielded 17 post-entry hits with activity in the primary cells, which were not active in immortalized cells. Potencies for this class of compounds were equal between the primary and immortalize cell lines. For entry inhibitors, the number was much lower, with increased potency observed in immortalized cells. This is the first known use of frozen primary human cells for an RSV high-throughput screening phenotypic campaign.

Men's sexual coercion in intimate relationships: development and initial validation of the Sexual Coercion in Intimate Relationships scale.

We report the development and initial validation of the Sexual Coercion in Intimate Relationships Scale (SCIRS), a measure designed to assess the prevalence and severity of sexual coercion in committed intimate relationships. We review existing measures of sexual coercion and discuss their limitations, describe the identification of the SCIRS items, perform a principal components analysis and describe the resulting three components, and present evidence for the convergent and discriminative validity of the SCIRS. Because sexual coercion in intimate relationships often takes the form of subtle tactics, the SCIRS items assess communicative tactics such as hinting and subtle manipulations in addition to tactics such as the use of physical force. The SCIRS provides researchers and clinicians with a valid, reliable, and comprehensive measure with which to study the dynamics of sexual coercion in intimate relationships.