Experimentally induced pain does not influence updating of peripersonal space and body representations following tool-use

This is the final version. Available from the publisher via the DOI in this record.The data is available on the Open Science Framework. URL: https://osf.io/4v938/. DOI: 10.17605/OSF.IO/4V938.Representations of the body and peripersonal space can be distorted for people with some chronic pain conditions. Experimental pain induction can give rise to similar, but transient distortions in healthy individuals. However, spatial and bodily representations are dynamic, and constantly update as we interact with objects in our environment. It is unclear whether induced pain disrupts the mechanisms involved in updating these representations. In the present study, we sought to investigate the effect of induced pain on the updating of peripersonal space and body representations during and following tool-use. We compared performance under three conditions (pain, active placebo, neutral) on a visuotactile crossmodal congruency task and a tactile distance judgement task to measure updating of peripersonal space and body representations, respectively. Consistent with previous findings, the difference in crossmodal interference from visual distractors in the same compared to opposite visual field to the tactile target was less when tools were crossed than uncrossed. This suggests an extension of peripersonal space to incorporate the tips of the tools. Also consistent with previous findings, estimates of the felt tactile distance judgements decreased after active tool-use. In contrast to our predictions, however, we found no evidence that pain interfered with performance on either task when compared to the control conditions. Our findings suggest that the updating of peripersonal space and body representations is not disrupted by induced pain. That is, experiencing acute pain does not give rise to distorted representations of the body and peripersonal space that can be present in people with chronic pain conditions.Medical Research Council (MRC

Upregulation of PDL1 Expression by Resveratrol and Piceatannol in Breast and Colorectal Cancer Cells Occurs Via HDAC3/p300-Mediated NFkappaB Signaling

Programmed cell death ligand 1 (PDL1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD1/PDL1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PDL1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PDL1 in tumor cells may help to improve the response to PDL1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PDL1 in breast and colorectal cancer cells. The surface expression of PDL1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PDL1 and when used in combination, elicited a synergistic upregulation of PDL1 in some cell lines. The induction of PDL1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PDL1 was transcriptionally mediated by nuclear factor (NF)-kappaB, as shown by NFkappaB reporter assays, the nuclear accumulation of the p65 subunit of NFkappaB, inhibition by the IKK inhibitor, BMS345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, gammaH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/cMyc, and G1-to-S cell cycle arrest

Designing a broad-spectrum integrative approach for cancer prevention and treatment

Targeted therapies and the consequent adoption of "personalized" oncology have achieved notablesuccesses in some cancers; however, significant problems remain with this approach. Many targetedtherapies are highly toxic, costs are extremely high, and most patients experience relapse after a fewdisease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistantimmortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are notreliant upon the same mechanisms as those which have been targeted). To address these limitations, aninternational task force of 180 scientists was assembled to explore the concept of a low-toxicity "broad-spectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspectsof relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a widerange of high-priority targets (74 in total) that could be modified to improve patient outcomes. For thesetargets, corresponding low-toxicity therapeutic approaches were then suggested, many of which werephytochemicals. Proposed actions on each target and all of the approaches were further reviewed forknown effects on other hallmark areas and the tumor microenvironment. Potential contrary or procar-cinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixedevidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of therelationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. Thisnovel approach has potential to be relatively inexpensive, it should help us address stages and types ofcancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for futureresearch is offered

Altered updating of bodily and spatial representations following tool-use in complex regional pain syndrome

This is the author accepted manuscript. The final version is available from Lippincott, Williams & Wilkins via the DOI in this record.  Distorted representations of the body and peripersonal space are common in Complex Regional Pain Syndrome (CRPS), and might modulate its symptoms (e.g. asymmetric limb temperature). In pain-free people, such representations are malleable, and update when we interact with objects in our environment (e.g. during tool-use). Distortions are also common after immobilisation, but quickly normalise once movement is regained. We tested the hypothesis that people with CRPS have problems updating bodily and spatial representations, which contributes to the maintenance of their distorted representations by preventing normalization. We also explored spatially defined modulations of hand temperature asymmetries, and any influence of updating bodily and spatial representations on this effect. Thirty-six people with unilateral CRPS (18 upper limb, 18 lower limb) and 36 pain-free controls completed tool-use tasks considered to alter body and peripersonal space representations (measured using tactile distance judgements and a visuotactile crossmodal congruency task, respectively). We also tested how the arrangement (crossed, uncrossed) of the hands and tools affected hand temperature. In upper limb CRPS the non-affected arm representation updated normally, but the affected arm representation updated in the opposite to normal direction. A similar pattern was seen in lower limbs CRPS, although not significant. Furthermore, people with CRPS showed more pronounced updating of peripersonal space than the controls. We did not observe any modulation of hand temperature asymmetries by the arrangement of hands or tools. Our findings show enhanced malleability of bodily and spatial representations in CRPS, which may suggest that central mechanisms are altered in this condition.Medical Research Counci

Reduced Visuospatial Attention in Personal Space is Not Limited to the Affected Limb in Complex Regional Pain Syndrome

Monika Halicka,1– 3 Olivia Rose Cousins,3 Antonia F Ten Brink,2– 4 Axel D Vittersø,2,3,5 Michael J Proulx,3 Janet H Bultitude2,3 1Institute of Neuroscience, Universite catholique de Louvain, Brussels, Belgium; 2Centre for Pain Research, University of Bath, Bath, UK; 3Department of Psychology, University of Bath, Bath, UK; 4Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, the Netherlands; 5Division of Mental Health Services, Akershus University Hospital, Lørenskog, NorwayCorrespondence: Monika Halicka, Institute of Neuroscience (IoNS), Université catholique de Louvain, Avenue Mounier 53, B1.53.04, 1200 Woluwe-Saint-Lambert, Brussels, Belgium, Email [email protected]: Alterations in spatial attention have been reported in people with chronic pain and may be relevant to understanding its cortical mechanisms and developing novel treatments. There is conflicting evidence as to whether people with Complex Regional Pain Syndrome (CRPS) have reduced visuospatial attention to their affected limb and/or its surrounding space, with some evidence that these deficits may be greater in personal (bodily) space. We aimed to test the competing hypotheses of whether the visuospatial attentional bias is specific to the personal space of the affected limb or generalizes to the personal space of other parts of the affected side of the body.Patients and Methods: Using visual Temporal Order Judgement tasks, we measured spatial attention in the personal space of the hands and feet of patients with upper (n=14) or lower (n=14) limb CRPS and pain-free controls (n=17). Participants judged the order of two light flashes presented at different temporal offsets on each of their hands or feet. Slower processing of the flash on one side relative to the other reflects reduced attention to that side of space.Results: Controls prioritized stimuli on the non-dominant (left) relative to dominant side, consistent with the well-documented normal leftward bias of attention (ie “pseudoneglect”). Regardless of the location (upper or lower limb) of the pain or visual stimuli, people with CRPS showed no such asymmetry, representing reduced attention to the affected side (compared to the greater attention of controls to their non-dominant side). More severe CRPS symptoms were associated with a greater tendency to deprioritize stimuli on the affected side.Conclusion: Our findings suggest that relative visuospatial bias in CRPS is generalized to the personal space of the affected side of the body, rather than being specific to the personal space of the CRPS-affected limb.Keywords: complex regional pain syndrome, spatial attention, personal space, pseudoneglect, temporal order judgement, chronic pai

Characterising sensorimotor adaptation in Complex Regional Pain Syndrome

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData availability: Materials and data from this study are available at https://osf.io/6jpfg/files/It has been suggested that sensorimotor conflict contributes to the maintenance of some pathological pain conditions, implying that there are problems with the adaptation processes that normally resolve such conflict. We tested whether sensorimotor adaptation is impaired in people with Complex Regional Pain Syndrome (CRPS) by characterising their adaption to lateral prismatic shifts in vision. People with unilateral upper-limb CRPS Type I (n = 17), and pain-free individuals (n = 18; matched for age, sex, and handedness) completed prism adaptation with their affected/non-dominant and non-affected/dominant arms. We examined 1) the rate at which participants compensated for the optical shift during prism exposure (i.e., strategic recalibration), 2) endpoint errors made directly after prism adaptation (sensorimotor realignment) and the retention of these errors, and 3) kinematic markers associated with strategic control. Direct comparisons between people with CRPS and controls revealed no evidence of any differences in strategic recalibration, including no evidence for differences in a kinematic marker associated with trial-by-trial changes in movement plans during prism exposure. All participants made significant endpoint errors after prism adaptation exposure, indicative of sensorimotor realignment. Overall, the magnitude of this realignment did not differ between people with CRPS and pain-free controls. However, when endpoint errors were considered separately for each hand, people with CRPS made greater errors (indicating more rather than less realignment) when using their affected hand than their non-affected hand. No such difference was seen in controls. Taken together, these findings provide no evidence of impaired strategic control or sensorimotor realignment in people with CRPS. In contrast, they provide some indication that there could be a greater propensity for sensorimotor realignment in the CRPS-affected arm, consistent with more flexible representations of the body and peripersonal space. Our study challenges an implicit assumption of the theory that sensorimotor conflict might underlie some pathological pain conditions.GW4 BioMed Medical Research Council Doctoral Training PartnershipNetherlands Organisation for Scientific Research (NWO

Simvastatin and purine analogs have a synergic effect on apoptosis of chronic lymphocytic leukemia cells

Despite many therapeutic regimens introduced recently, chronic lymphocytic leukemia (CLL) is still an incurable disorder. Thus, there is an urgent need to discover novel, less toxic and more effective drugs for CLL patients. In this study, we attempted to assess simvastatin, widely used as a cholesterol-lowering drug, both as a single agent and in combination with purine analogs—fludarabine and cladribine—in terms of its effect on apoptosis and DNA damage of CLL cells. The experiments were done in ex vivo short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (named γH2AX) and activated ATM kinase (ataxia telangiectasia mutated kinase), reporters of DNA damage. Results of our study revealed that simvastatin induced apoptosis of CLL cells concurrently with lowering of BCL-2/BAX ratio, and its pro-apoptotic effect is tumor-specific, not affecting normal lymphocytes. We observed that combinations of simvastatin+fludarabine and simvastatin+cladribine had a synergic effect in inducing apoptosis. Interestingly, the rate of apoptosis caused by simvastatin alone and in combination was independent of markers of disease progression like ZAP-70 and CD38 expression or clinical stage according to Rai classification. We have also seen an increase in γH2AX expression in parallel with activation of ATM in most of the analyzed samples. The results suggest that simvastatin can be used in the treatment of CLL patients as a single agent as well as in combination with purine analogs, being equally effective both in high-risk and good-prognosis patients. One of the mechanisms of simvastatin action is inducing DNA damage that ultimately leads to apoptosis

Resveratrol increases rate of apoptosis caused by purine analogues in malignant lymphocytes of chronic lymphocytic leukemia

In this study, we attempted to assess the interactions of resveratrol, a natural compound present in various plant species, with the purine analogues fludarabine and cladribine in terms of their effects on DNA damage and apoptosis in chronic lymphocytic leukemia (CLL) cells. The experiments were performed ex vivo using short-term cell cultures of blood and bone marrow cells from newly diagnosed untreated patients. We analyzed the expression of active caspase-3 and the BCL-2/BAX ratio as markers of apoptosis and the expression of phosphorylated histone H2AX (γH2AX) and activated ATM kinase, which are reporters of DNA damage. The results of our study revealed that resveratrol induced apoptosis in CLL cells in a tumor-specific manner but did not affect non-leukemic cells, and apoptosis was associated with a decreased BCL2/BAX ratio. Here, we report for the first time that both resveratrol + fludarabine and resveratrol + cladribine caused a higher rate of apoptosis in comparison to the rate caused by a single drug. The percentage of apoptotic cells induced by resveratrol alone was higher in the group of patients with better prognostic markers than in those with worse prognostic markers. However, the rates of apoptosis caused by resveratrol combined with purine analogues were independent of ZAP-70 and CD38 expression and the clinical state of the disease; they were only dependent on the presence of high-risk cytogenetic abnormalities. We also observed an increase in γH2AX expression together with a rise in activated ATM in most of the analyzed samples. The obtained results indicate that resveratrol might warrant further study as a new therapeutic option for CLL patients. This naturally occurring substance may be used as a single agent, especially in older persons for whom there are some limitations for the use of aggressive treatment. On the other hand, a lower purine analogue dose could potentially be used in combination with resveratrol because of their combined effect. One of the mechanisms of action of resveratrol is the induction of DNA damage, which ultimately leads to apoptosis