Voltage-gated Na+ Channel Activity Increases Colon Cancer Transcriptional Activity and Invasion Via Persistent MAPK Signaling

Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes

Prevention of mood disorder after stroke : a randomised controlled trial of problem solving therapy versus volunteer support

Background: Mood disorder after stroke is common but drug and psychosocial treatments have been assessed with disappointing results. Preventing mood disorder from developing in the first place could be a better approach and might reduce the need for pharmacotherapy in this predominantly older patient group. We used a brief problem-solving therapy and evaluated its effect in reducing mood disorder in the 12 months after stroke. Methods: A 3-group, parallel, randomised controlled trial. Four hundred fifty patients with stroke were randomised within 1 month of hospital admission to problem-solving therapy from a psychiatric nurse, non-specific support given by volunteers or treatment-as-usual. Follow up took place at 6 and 12 months after stroke. Standardised measures of mood (Present State Examination, GHQ-28), cognitive state (mini-mental state examination) and function (Barthel ADL index, Frenchay Activities Index) were taken at baseline, 6 and 12 months after randomisation. Satisfaction with care was recorded at follow up. Results: At 6 months, all psychological and activity measures favoured problem-solving therapy. At 12 months, patients in the problem-solving therapy group had significantly lower GHQ-28 scores and lower median Present State Examination symptom scores. There were no statistically significant differences in activity. The problem-solving therapy group were more satisfied with some aspects of care. Conclusions: The results are encouraging and suggest it is possible to prevent mood disorder in stroke patients using a psychological intervention. The differences between the groups at 12 months may indicate a sustained impact of psychological therapies, by comparison with non-specific support

Epizootic Hemorrhagic Disease in Cattle, Western Turkey

In 2007, an outbreak of epizootic hemorrhagic disease (EHD) occurred in Turkey. On the basis of clinical investigation, 41 cattle were suspected to have EHD. Reverse transcription–PCR and sequence analyses indicated that the virus belonged to EHD virus serotype 6, thus confirming EHD virus infection of cattle in Turkey

Anabolic androgenic steroid abuse in the United Kingdom: An update

© 2020 The British Pharmacological Society. This is the peer reviewed version of the following article: Mullen, C, Whalley, BJ, Schifano, F, Baker, JS. Anabolic Androgenic Steroid Abuse in the United Kingdom; An Update The increasing popularity of anabolic androgenic steroids. Br J Pharmacol. 2020, which has been published in final form at https://doi.org/10.1111/bph.14995. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Anabolic androgenic steroids (AASs) are prescribed for medical conditions related to low testosterone. Abuse of AASs has surged as they become recognised as potent image enhancement drugs. The primary goal of most abusers is to obtain a more attractive outward appearance. Abuse is complex. There are a vast range of AAS substances illegally available, the nature of their true composition is difficult to evaluate. Users follow dosing patterns which incorporate a number of different AASs, in addition to other pharmaceutical substances believed to complement the desired physical effects or manage unwanted effects. Animal work and medical case reports suggest potential to cause serious hepatotoxicity, plus possible neurotoxicity, nephrotoxicity and damage to the cardiovascular and reproductive systems. As the long-term AASs users reach maturity, further controlled experimentation, with larger sample sizes, is required. Data gathering should be directed towards the most vulnerable group of AAS users, females and adolescent boys.Peer reviewedFinal Accepted Versio

A Factor Graph Nested Effects Model To Identify Networks from Genetic Perturbations

Complex phenotypes such as the transformation of a normal population of cells into cancerous tissue result from a series of molecular triggers gone awry. We describe a method that searches for a genetic network consistent with expression changes observed under the knock-down of a set of genes that share a common role in the cell, such as a disease phenotype. The method extends the Nested Effects Model of Markowetz et al. (2005) by using a probabilistic factor graph to search for a network representing interactions among these silenced genes. The method also expands the network by attaching new genes at specific downstream points, providing candidates for subsequent perturbations to further characterize the pathway. We investigated an extension provided by the factor graph approach in which the model distinguishes between inhibitory and stimulatory interactions. We found that the extension yielded significant improvements in recovering the structure of simulated and Saccharomyces cerevisae networks. We applied the approach to discover a signaling network among genes involved in a human colon cancer cell invasiveness pathway. The method predicts several genes with new roles in the invasiveness process. We knocked down two genes identified by our approach and found that both knock-downs produce loss of invasive potential in a colon cancer cell line. Nested effects models may be a powerful tool for inferring regulatory connections and genes that operate in normal and disease-related processes

Multi-institutional analysis of pancreatic adenocarcinoma demonstrating the effect of diabetes status on survival after resection

The effect of diabetes on survival after resection pancreatic ductal carcinoma (PDAC) is unclear. The present study was undertaken to determine whether pre-operative diabetes has any predictive value for survival

Role of Voltage-gated Sodium Ion Channels in the Metastatic Potential of Colon Cancer Cells

An interesting new field in cancer research is the role of voltage-gated Na+ channels (VGSCs) in cancer cell invasion. Expression of these ion channels is normally restricted to excitable cells; however functional expression has been demonstrated in multiple cancer cell types where channel activity leads to changes in invasion potential in vitro. This study investigated the consequences of functional expression of Na v1.5, a protein encoded by SCN5A, in colon cancer cell lines. Pharmacological inhibition of channel activity led to a decrease in invasion potential, whereas activation led to an increase in invasion potential. Moreover, upon examination of patient samples we found that protein expression was restricted to malignant tissue. What has remained largely uncharacterized is the mechanism by which these channels promote oncogenic behavior. We explored the mechanism of VGSC-mediated invasion potential on the basis of reported links between VGSC activity and gene expression in excitable cells. Probabilistic modeling of loss-of-function screens and microarray data established a clear role of VGSC SCN5A as a key regulator of a colon cancer invasion network. Coincidentally, many genes regulated by SCN5A have binding sites for transcription factors phosphorylated by ERK1/2. We hypothesized that VGSC activity promotes MAPK activation, a pathway activated during neurogenesis and deregulated in cancer. Using pharmacological inhibition of MAPK, we demonstrated the requirement of this molecule for colon cancer invasion in vitro. Furthermore, we showed that MAPK activity is reduced when colon cancer cells are treated with the VGSC blocker, lidocaine, and persistently enhanced when treated with the VGSC activator, veratridine. This persistent activation and the increase in invasion potential were lost when veratridine was used in the presence of a PKA inhibitor or with a siRNA directed against Rap1. Lastly, we demonstrated increased Src activity after treatment with veratridine. Taken together our data suggest that VGSC activation increases MAPK activity through activation of PKA, Rap1 and Src in colon cancer cells. This is the first study demonstrating functional expression of VGSCs in colon cancer cells and the first to illustrate both genomic and molecular signaling pathways activated in response to VGSC activity to promote oncogenesis in colon cancer cells