N-acetyl-l-cysteine sensitizes pancreatic cancers to gemcitabine by targeting the NFκB pathway

First-line therapy for pancreatic cancer is gemcitabine. Although tumors may initially respond to the gemcitabine treatment, soon tumor resistance develops leading to treatment failure. Previously, we demonstrated in human MIA PaCa-2 pancreatic cancer cells that N-acetyl-l-cysteine (NAC), a glutathione (GSH) precursor, prevents NFκB activation via S-glutathionylation of p65-NFκB, thereby blunting expression of survival genes. In this study, we documented the molecular sites of S-glutathionylation of p65, and we investigated whether NAC can suppress NFκB signaling and augment a therapeutic response to gemcitabine in vivo. Mass spectrometric analysis of S-glutathionylated p65-NFκB protein in vitro showed post-translational modifications of cysteines 38, 105, 120, 160 and 216 following oxidative and nitrosative stress. Circular dichroism revealed that S-glutathionylation of p65-NFκB did not change secondary structure of the protein, but increased tryptophan fluorescence revealed altered tertiary structure. Gemcitabine and NAC individually were not effective in decreasing MIA PaCa-2 tumor growth in vivo. However, combination treatment with NAC and gemcitabine decreased tumor growth by approximately 50%. NAC treatment also markedly enhanced tumor apoptosis in gemcitabine-treated mice. Compared to untreated tumors, gemcitabine treatment alone increased p65-NFκB nuclear translocation (3.7-fold) and DNA binding (2.5-fold), and these effects were blunted by NAC. In addition, NAC plus gemcitabine treatment decreased anti-apoptotic XIAP protein expression compared to gemcitabine alone. None of the treatments, however, affected extent of tumor hypoxia, as assessed by EF5 staining. Together, these results indicate that adjunct therapy with NAC prevents NFκB activation and improves gemcitabine chemotherapeutic efficacy.     

Validity of an eyetracking method for capturing auditory–visual cross-format semantic priming

Introduction: Semantic priming paradigms are important for understanding lexical–semantic processing and the nature of linguistic deficits accompanying language performance in neurologically impaired individuals such as people with aphasia. Reaction-time-(RT)-based traditional semantic priming tasks entail potential confounds, especially problematic when applied to people with aphasia, who may have concomitant neurocognitive challenges that limit task performance. Some of these confounds include requirements of following complex instructions, making metalinguistic judgments, and using speech or limb-based motor actions to indicate overt responses. Eyetracking methods have great potential for avoiding some of these confounds. We tested the validity of an eyetracking method in capturing semantic priming in an auditory–visual cross-format priming paradigm (auditory word prime–visual image target).

Method: A total of 72 neurologically unimpaired adults participated in two phases: a stimulus development phase using traditional priming (n = 32) and an experimental eyetracking phase (n = 40). Each phase included two conditions, representing distinct levels of prime–target semantic relatedness: unrelated and related. Mean RT data from the traditional priming (stimuli development) phase guided image selection for the eyetracking experiment. Eyetracking indices of fixation duration and latency of fixation were recorded to capture semantic priming in the eyetracking experiment.

Results: Eye fixation data indicated that images related to auditory primes were attended to earlier and attracted significantly greater visual attention than unrelated images. These results mirrored RT data from the traditional priming method, which showed faster RT latencies and more accurate naming performance for related images than for unrelated images.

Conclusions: Results support the validity of eyetracking indices of semantic priming and offer a robust testing protocol for future studies in this line of research. Current clinical relevance for people with aphasia is highlighted. Further empirical testing of the psychometric properties of the eyetracking measures in various semantic priming contexts is recommended.     

Ontogeny of prosocial behavior across diverse societies

Humans are an exceptionally cooperative species, but there is substantial variation in the extent of cooperation across societies. Understanding the sources of this variability may provide insights about the forces that sustain cooperation. We examined the ontogeny of prosocial behavior by studying 326 children 3–14 y of age and 120 adults from six societies (age distributions varied across societies). These six societies span a wide range of extant human variation in culture, geography, and subsistence strategies, including foragers, herders, horticulturalists, and urban dwellers across the Americas, Oceania, and Africa. When delivering benefits to others was personally costly, rates of prosocial behavior dropped across all six societies as children approached middle childhood and then rates of prosociality diverged as children tracked toward the behavior of adults in their own societies. When prosocial acts did not require personal sacrifice, prosocial responses increased steadily as children matured with little variation in behavior across societies. Our results are consistent with theories emphasizing the importance of acquired cultural norms in shaping costly forms of cooperation and creating cross-cultural diversity.