Do Stress Responses Promote Leukemia Progression? An Animal Study Suggesting a Role for Epinephrine and Prostaglandin-E2 through Reduced NK Activity

In leukemia patients, stress and anxiety were suggested to predict poorer prognosis. Oncological patients experience ample physiological and psychological stress, potentially leading to increased secretion of stress factors, including epinephrine, corticosteroids, and prostaglandins. Here we tested whether environmental stress and these stress factors impact survival of leukemia-challenged rats, and studied mediating mechanisms. F344 rats were administered with a miniscule dose of 60 CRNK-16 leukemia cells, and were subjected to intermittent forced swim stress or to administration of physiologically relevant doses of epinephrine, prostaglandin-E2 or corticosterone. Stress and each stress factor, and/or their combinations, doubled mortality rates when acutely applied simultaneously with, or two or six days after tumor challenge. Acute administration of the β-adrenergic blocker nadolol diminished the effects of environmental stress, without affecting baseline survival rates. Prolonged β-adrenergic blockade or COX inhibition (using etodolac) also increased baseline survival rates, possibly by blocking tumor-related or normal levels of catecholamines and prostaglandins. Searching for mediating mechanisms, we found that each of the stress factors transiently suppressed NK activity against CRNK-16 and YAC-1 lines on a per NK basis. In contrast, the direct effects of stress factors on CRNK-16 proliferation, vitality, and VEGF secretion could not explain or even contradicted the in vivo survival findings. Overall, it seems that environmental stress, epinephrine, and prostaglandins promote leukemia progression in rats, potentially through suppressing cell mediated immunity. Thus, patients with hematological malignancies, which often exhibit diminished NK activity, may benefit from extended β-blockade and COX inhibition

Regulation of T Cell Priming by Lymphoid Stroma

The priming of immune T cells by their interaction with dendritic cells (DCs) in lymph nodes (LN), one of the early events in productive adaptive immune responses, occurs on a scaffold of lymphoid stromal cells, which have largely been seen as support cells or sources of chemokines and homeostatic growth factors. Here we show that murine fibroblastic reticular cells (FRCs), isolated from LN of B6 mice, play a more direct role in the immune response by sensing and modulating T cell activation through their upregulation of inducible nitric oxide synthase (iNOS) in response to early T cell IFNγ production. Stromal iNOS, which only functions in very close proximity, attenuates responses to inflammatory DC immunization but not to other priming regimens and preferentially affects Th1 cells rather than Th2. The resultant nitric oxide production does not affect T cell-DC coupling or initial calcium signaling, but restricts homotypic T cell clustering, cell cycle progression, and proliferation. Stromal feedback inhibition thus provides basal attenuation of T cell responses, particularly those characterized by strong local inflammatory cues

Dispositional free riders do not free ride on punishment

Strong reciprocity explains prosocial cooperation by the presence of individuals who incur costs to help those who helped them (‘strong positive reciprocity’) and to punish those who wronged them (‘strong negative reciprocity’). Theories of social preferences predict that in contrast to ‘strong reciprocators’, self-regarding people cooperate and punish only if there are sufficient future benefits. Here, we test this prediction in a two-stage design. First, participants are classified according to their disposition towards strong positive reciprocity as either dispositional conditional cooperators (DCC) or dispositional free riders (DFR). Participants then play a one-shot public goods game, either with or without punishment. As expected, DFR cooperate only when punishment is possible, whereas DCC cooperate without punishment. Surprisingly, dispositions towards strong positive reciprocity are unrelated to strong negative reciprocity: punishment by DCC and DFR is practically identical. The ‘burden of cooperation’ is thus carried by a larger set of individuals than previously assumed

The impact of intolerance of uncertainty and cognitive behavioural instructions on safety learning

Background Difficulty updating threat associations to safe associations has been observed in individuals who score high in self-reported Intolerance of Uncertainty (IU). Here we sought to determine whether an instruction based on fundamental principles of Cognitive Behavioural Therapy could promote safety learning in individuals with higher levels of IU, whilst controlling for self-reported trait anxiety (STICSA). Methods We measured skin conductance response, pupil dilation and expectancy ratings during an associative threat learning task in which participants either received a cognitive behavioural instruction or no instruction prior to threat extinction (n = 92). Results Analyses revealed that both self-reported IU and STICSA similarly predicted differences in skin conductance response. Only individuals with lower IU/STICSA in the cognitive behavioural instruction condition displayed successful safety learning via skin conductance response. Conclusions These initial results provide some insight into how simple cognitive behavioural instructions combined with exposure are applied differently in individuals with varying levels of self-reported anxiety. The results further our understanding of the role of basic cognitive behavioural principles and self-reported anxiety in safety learning

What do I do now? Intolerance of uncertainty is associated with discrete patterns of anticipatory physiological responding to different contexts

Heightened physiological responses to uncertainty are a common hallmark of anxiety disorders. Many separate studies have examined the relationship between individual differences in intolerance of uncertainty (IU) and physiological responses to uncertainty during different contexts. Despite this there is a scarcity of research examining the extent to which individual differences in IU are related to shared or discrete patterns of anticipatory physiological responding across different contexts. Anticipatory physiological responses to uncertainty were assessed in three different contexts (associative threat learning and extinction, threat uncertainty, decision-making) within the same sample (n = 45). During these tasks, behavioural responses (i.e. reaction times, choices), skin conductance and corrugator supercilli activity were recorded. In addition, self-reported IU and trait anxiety were measured. IU was related to both skin conductance and corrugator supercilii activity for the associative threat learning and extinction context, and decision-making context. However, trait anxiety was related to corrugator supercilii activity during the threat uncertainty context. Ultimately, this research helps us further tease apart the role of IU on different aspects of anticipation (i.e. valence and arousal) across contexts, which will be relevant for future IU-related models of psychopathology

17β-Oestradiol treatment modulates nitric oxide synthase activity in MDA231 tumour with implications on growth and radiation response

The putative oestrogen receptor negative human breast cancer cell line MDA231, when grown as tumours in mice continually receiving 17β-oestradiol, showed substantially increased growth rate when compared to control animals. Further, we observed that 17β-oestradiol treatment could both increase the growth rate of established MDA231 tumours as well as decreasing the time taken for initiating tumour growth. We have also demonstrated that this increase in growth rate is accompanied by a four-fold increase in nitric oxide synthase activity, which was predominantly the inducible form. Inducible-nitric oxide synthase expression in these tumours was confirmed by immunohistochemical analysis and appeared localized primarily in areas between viable and necrotic regions of the tumour (an area that is presumably hypoxic). Prophylactic treatment with the nitric oxide synthase inhibitor nitro-L-arginine methyl ester resulted in significant reduction in this apparent 17β-oestradiol-mediated growth promoting effect. Tumours derived from mice receiving 17β-oestradiol-treatment were characterized by a significantly lower fraction of perfused blood vessels and an indication of an increased hypoxic fraction. Consistent with these observations, 17β-oestradiol-treated tumours were less radio-responsive compared to control tumours when treated with a single radiation dose of 15 Gy. Our data suggests that long-term treatment with oestrogen could significantly alter the tumour oxygenation status during breast tumour progression, thus affecting response to radiotherapy