Malignant central nervous system (CNS) cancers are among the most difficult to treat, with low rates of survival and a high likelihood of recurrence. This is primarily due to their location within ...the CNS, hindering adequate drug delivery and tumour access via surgery. Furthermore, CNS cancer cells are highly plastic, an adaptive property that enables them to bypass targeted treatment strategies and develop drug resistance. Potassium ion channels have long been implicated in the progression of many cancers due to their integral role in several hallmarks of the disease. Here, we will explore this relationship further, with a focus on malignant CNS cancers, including high-grade glioma (HGG). HGG is the most lethal form of primary brain tumour in adults, with the majority of patient mortality attributed to drug-resistant secondary tumours. Hence, targeting proteins that are integral to cellular plasticity could reduce tumour recurrence, improving survival. This review summarises the role of potassium ion channels in malignant CNS cancers, specifically how they contribute to proliferation, invasion, metastasis, angiogenesis, and plasticity. We will also explore how specific modulation of these proteins may provide a novel way to overcome drug resistance and improve patient outcomes.
Movement is an essential behavior requiring the assembly and refinement of spinal motor circuits. However, the mechanisms responsible for circuit refinement and synapse maintenance are poorly ...understood. Similarly, the molecular mechanisms by which gene mutations cause dysfunction and elimination of synapses in neurodegenerative diseases that occur during development are unknown. Here, we demonstrate that the complement protein C1q is required for the refinement of sensory-motor circuits during normal development, as well as for synaptic dysfunction and elimination in spinal muscular atrophy (SMA). C1q tags vulnerable SMA synapses, which triggers activation of the classical complement pathway leading to microglia-mediated elimination. Pharmacological inhibition of C1q or depletion of microglia rescues the number and function of synapses, conferring significant behavioral benefit in SMA mice. Thus, the classical complement pathway plays critical roles in the refinement of developing motor circuits, while its aberrant activation contributes to motor neuron disease.
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•C1q refines spinal sensory-motor circuits during normal development•Upregulated C1q tags SMA synapses for elimination via classical cascade and microglia•Pharmacological inhibition of C1q or depletion of microglia confer benefit in SMA mice•C1q deletion results in an excessive number of synapses, leading to behavioral deficits
Vukojicic et al. show that complement protein C1q is required for the refinement of spinal sensory-motor circuits during normal development, as well as for synaptic elimination in spinal muscular atrophy (SMA). Pharmacological inhibition of C1q or depletion of microglia rescues vulnerable synapses, yielding significant behavioral benefit in SMA mice.
Bitcoin was created in 2008 to serve as an alternative payment mechanism for both the under-banked and un-banked, or those in regions where the formal financial system suffers from broad corruption ...and efficient regulation. However, criminals and terrorists quickly exploited Bitcoin's unique properties, namely its peer-to-peer nature and pseudo-anonymity, to facilitate extensive terrorist financing and money laundering schemes. Government reactions to safeguard national security interests have been extremely varied, ranging from outright bans to passive tolerance. This inconsistency stems from how to effectively classify Bitcoin. On one side are those who argue Bitcoin is a currency, and on the other are those who claim it is a type of asset. In the US alone, these discrepancies have led to a bureaucratic turf war between different regulatory bodies, namely the Financial Crimes Enforcement Network, the Commodity Futures Trading Association, the Securities and Exchange Commission, and the Internal Revenue Service. This study seeks to move beyond the existing legal frameworks, arguing that Bitcoin should be classified as a technology and regulation should rest with private sector technology companies.
In humans, many cases of congenital insensitivity to pain (CIP) are caused by mutations of components of the NGF/TrkA signaling pathway, which is required for survival and specification of ...nociceptors and plays a major role in pain processing. Mutations in PRDM12 have been identified in CIP patients that indicate a putative role for this transcriptional regulator in pain sensing. Here, we show that Prdm12 expression is restricted to developing and adult nociceptors and that its genetic ablation compromises their viability and maturation. Mechanistically, we find that Prdm12 is required for the initiation and maintenance of the expression of TrkA by acting as a modulator of Neurogenin1/2 transcription factor activity, in frogs, mice, and humans. Altogether, our results identify Prdm12 as an evolutionarily conserved key regulator of nociceptor specification and as an actionable target for new pain therapeutics.
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•In somatosensory ganglia, Prdm12 is specific to the nociceptive lineage•Prdm12 is necessary for the survival of developing nociceptors•Prdm12 initiates and maintains the expression of TrkA in developing nociceptors•Prdm12 acts in conjunction with bHLH proteins Ngn1/2 to promote a nociceptor fate
Desiderio et al. report that, in developing somatosensory neurons, Prdm12 is restricted to the nociceptors and that these are selectively eliminated from Prdm12 mutant mice. In Xenopus and human iPSCs, they show that Prdm12, in conjunction with bHLH proneural proteins, promotes the expression of the neurotrophin receptor TrkA.
Summary Background Depression is a common, debilitating, and costly disorder. Many patients request psychological therapy, but the best-evidenced therapy—cognitive behavioural therapy (CBT)—is ...complex and costly. A simpler therapy—behavioural activation (BA)—might be as effective and cheaper than is CBT. We aimed to establish the clinical efficacy and cost-effectiveness of BA compared with CBT for adults with depression. Methods In this randomised, controlled, non-inferiority trial, we recruited adults aged 18 years or older meeting Diagnostic and Statistical Manual of Mental Disorders IV criteria for major depressive disorder from primary care and psychological therapy services in Devon, Durham, and Leeds (UK). We excluded people who were receiving psychological therapy, were alcohol or drug dependent, were acutely suicidal or had attempted suicide in the previous 2 months, or were cognitively impaired, or who had bipolar disorder or psychosis or psychotic symptoms. We randomly assigned participants (1:1) remotely using computer-generated allocation (minimisation used; stratified by depression severity Patient Health Questionnaire 9 (PHQ-9) score of <19 vs ≥19, antidepressant use, and recruitment site) to BA from junior mental health workers or CBT from psychological therapists. Randomisation done at the Peninsula Clinical Trials Unit was concealed from investigators. Treatment was given open label, but outcome assessors were masked. The primary outcome was depression symptoms according to the PHQ-9 at 12 months. We analysed all those who were randomly allocated and had complete data (modified intention to treat mITT) and also all those who were randomly allocated, had complete data, and received at least eight treatment sessions (per protocol PP). We analysed safety in the mITT population. The non-inferiority margin was 1·9 PHQ-9 points. This trial is registered with the ISCRTN registry, number ISRCTN27473954. Findings Between Sept 26, 2012, and April 3, 2014, we randomly allocated 221 (50%) participants to BA and 219 (50%) to CBT. 175 (79%) participants were assessable for the primary outcome in the mITT population in the BA group compared with 189 (86%) in the CBT group, whereas 135 (61%) were assessable in the PP population in the BA group compared with 151 (69%) in the CBT group. BA was non-inferior to CBT (mITT: CBT 8·4 PHQ-9 points SD 7·5, BA 8·4 PHQ-9 points 7·0, mean difference 0·1 PHQ-9 points 95% CI −1·3 to 1·5, p=0·89; PP: CBT 7·9 PHQ-9 points 7·3; BA 7·8 6·5, mean difference 0·0 PHQ-9 points –1·5 to 1·6, p=0·99). Two (1%) non-trial-related deaths (one 1% multidrug toxicity in the BA group and one 1% cancer in the CBT group) and 15 depression-related, but not treatment-related, serious adverse events (three in the BA group and 12 in the CBT group) occurred in three 2% participants in the BA group (two 1% patients who overdosed and one 1% who self-harmed) and eight (4%) participants in the CBT group (seven 4% who overdosed and one 1% who self-harmed). Interpretation We found that BA, a simpler psychological treatment than CBT, can be delivered by junior mental health workers with less intensive and costly training, with no lesser effect than CBT. Effective psychological therapy for depression can be delivered without the need for costly and highly trained professionals. Funding National Institute for Health Research.
Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma ...treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.
Caffeine in doses <400 mg is typically not considered arrhythmogenic, but little is known about the additional ingredients in energy drinks. We evaluated the ECG and blood pressure (BP) effects of ...high-volume energy drink consumption compared with caffeine alone.
This was a randomized, double-blind, controlled, crossover study in 18 young, healthy volunteers. Participants consumed either 946 mL (32 ounces) of energy drink or caffeinated control drink, both of which contained 320 mg of caffeine, separated by a 6-day washout period. ECG, peripheral BP, and central BP measurements were obtained at baseline and 1, 2, 4, 6, and 24 hours post study drink consumption. The time-matched, baseline-adjusted changes were compared. The change in corrected QT interval from baseline in the energy drink arm was significantly higher than the caffeine arm at 2 hours (0.44±18.4 ms versus -10.4±14.8 ms, respectively;
=0.02). The QTc changes were not different at other time points. While both the energy drink and caffeine arms raised systolic BP in a similar fashion initially, the systolic BP was significantly higher at 6 hours when compared with the caffeine arm (4.72±4.67 mm Hg versus 0.83±6.09 mm Hg, respectively;
=0.01). Heart rate, diastolic BP, central systolic BP, and central diastolic BP showed no evidence of a difference between groups at any time point. Post energy drink, augmentation index was lower at 6 hours.
The corrected QT interval and systolic BP were significantly higher post high-volume energy drink consumption when compared with caffeine alone. Larger clinical trials validating these findings and evaluation of noncaffeine ingredients within energy drinks are warranted.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT02023723.
BACKGROUND
New evidence suggests that central systolic blood pressure (cSBP) and augmentation index (AI) are superior predictors of adverse cardiovascular outcomes compared to peripheral systolic BP ...(pSBP). We performed a meta-analysis assessing the impact of antihypertensives on cSBP and AI.
METHODS
PubMed, Cochrane Library, and CINAHL were searched until September 2014 to identify eligible articles. A DerSimonian and Laird random-effects model was used to calculate the weighted mean difference (WMD) and its 95% confidence interval (CI). Fifty-two and 58 studies incorporating 4,381 and 3,716 unique subjects were included for cSBP and AI analysis, respectively.
RESULTS
Overall, antihypertensives reduced pSBP more than cSBP (WMD 2.52mm Hg, 95% CI 1.35 to 3.69; I
2 = 21.9%). β-Blockers (BBs) posed a significantly greater reduction in pSBP as compared to cSBP (WMD 5.19mm Hg, 95% CI 3.21 to 7.18). α-Blockers, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, renin-angiotensin aldosterone system inhibitors and nicorandil reduced cSBP and pSBP in a similar manner. The overall reduction in AI from baseline was 3.09% (95% CI 2.28 to 3.90; I
2 = 84.5%). A significant reduction in AI was seen with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, diuretics, renin-angiotensin aldosterone system inhibitors, BBs, α-blockers (ABs), nicorandil, and moxonidine reduced AI nonsignificantly.
CONCLUSIONS
BBs are not as beneficial as the other antihypertensives in reducing cSBP and AI.
Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by ...oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 μm, mean ± 95% CI) than non-responders (3.5 ± 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity.
ClinicalTrials.gov NCT01014052.
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