Cobimetinib and trametinib inhibit platelet MEK but do not cause platelet dysfunction

The MEK inhibitors cobimetinib and trametinib are used in combination with BRAF inhibitors to treat metastatic melanoma but increase rates of hemorrhage relative to BRAF inhibitors alone. Platelets express several members of the MAPK signalling cascade including MEK1 and MEK2 and ERK1 and ERK2 but their role in platelet function and haemostasis is ambiguous as previous reports have been contradictory. It is therefore unclear if MEK inhibitors might be causing platelet dysfunction and contributing to increased hemorrhage. In the present study we performed pharmacological characterisation of cobimetinib and trametinib in vitro to investigate potential for MEK inhibitors to cause platelet dysfunction. We report that whilst both cobimetinib and trametinib are potent inhibitors of platelet MEK activity, treatment with trametinib did not alter platelet function. Treatment with cobimetinib results in inhibition of platelet aggregation, integrin activation, alpha-granule secretion and adhesion but only at suprapharmacological concentrations. We identified that the inhibitory effects of high concentrations of cobimetinib are associated with off-target inhibition on Akt and PKC. Neither inhibitor caused any alteration in thrombus formation on collagen under flow conditions in vitro. Our findings demonstrate that platelets are able to function normally when MEK activity is fully inhibited, indicating MEK activity is dispensable for normal platelet function. We conclude that the MEK inhibitors cobimetinib and trametinib do not induce platelet dysfunction and are therefore unlikely to contribute to increased incidence of bleeding reported during MEK inhibitor therapy

PPARγ agonists negatively regulate αIIbβ3 integrin outside-in signalling and platelet function through upregulation of protein kinase A activity

BACKGROUND: Agonists for the peroxisome proliferator activated receptor PPARγ, have been shown to have inhibitory effects on platelet activity following stimulation by GPVI and GPCR agonists. OBJECTIVES: Profound effects on thrombus formation led us to suspect a role for PPARγ agonists in the regulation of integrin αIIbβ3 mediated signalling. Both GPVI and GPCR signalling pathways lead to αIIbβ3 activation, and signalling through αIIbβ3 plays a critical role in platelet function and normal haemostasis. METHODS: The effects of PPARγ agonists on the regulation of αIIbβ3 outside-in signalling was determined by monitoring the ability of platelets to adhere and spread on fibrinogen and undergo clot retraction. Effects on signalling components downstream of αIIbβ3 activation were also determined following adhesion to fibrinogen by western blotting. RESULTS: Treatment of platelets with PPARγ agonists inhibited platelet adhesion and spreading on fibrinogen and diminished clot retraction. A reduction in phosphorylation of several components of αIIbβ3 signalling, including the integrin β3 subunit, Syk, PLCγ2, FAK and Akt was also observed as a result of reduced interaction of the integrin β3 subunit with Gα13. Studies of VASP phosphorylation revealed that this was a due to an increase in PKA activity following treatment with PPARγ receptor agonists. CONCLUSIONS: This study provides further evidence for anti-platelet actions of PPARγ agonists, identifies a negative regulatory role for PPARγ agonists in the control of integrin αIIbβ3 outside-in signalling, and provides a molecular basis by which the PPARγ agonists negatively regulate platelet activation and thrombus formation

Efficacy of cognitive remediation on activities of daily living in individuals with mild cognitive impairment or early-stage dementia : a systematic review and meta-analysis

Introduction: Instrumental activities of daily living are essential for ageing well and independent living. Little is known about the effectiveness of cognitive remediation on instrumental activities of daily living performance for individuals with mild cognitive impairment or early-stage dementia. The objective of this study was to evaluate the immediate and long-term carryover effects of cognitive remediation on improving or maintaining instrumental activities of daily living performance in older adults with mild cognitive impairment and early-stage dementia. Methods: Randomized controlled trials published from 2009 to 2022 were identified in OvidSP versions of MEDLINE and Embase, EBSCO versions of CINAHL and PsycINFO, and the Cochrane Central Register of Controlled Trials. A narrative synthesis of the findings was reported on the outcomes of the included studies. Relevant data was extracted and analysed using R software’s ‘metafor’ package with a random effect model with 95% CI. Results: Thirteen studies, totalling 1414 participants, were identified in the narrative analysis. The results of meta-analysis, inclusive of 11 studies, showed that cognitive remediation elicited a significant improvement in the instrumental activities of daily living performance (SMD: 0.17, 95% CI 0.03–0.31). There was insufficient evidence of any lasting effect. Discussion: Cognitive remediation is effective in improving instrumental activities of daily living performance immediately post-intervention in older adults with mild cognitive impairment and early-stage dementia. It appears that individualized interventions with a short duration, such as 10 hours, might be beneficial. Systematic review registration: PROSPERO CRD4201604236

A Transiting Planet of a Sun-like Star

A planet transits an 11th magnitude, G1V star in the constellation Corona Borealis. We designate the planet XO-1b, and the star, XO-1, also known as GSC 02041-01657. XO-1 lacks a trigonometric distance; we estimate it to be 200+-20 pc. Of the ten stars currently known to host extrasolar transiting planets, the star XO-1 is the most similar to the Sun in its physical characteristics: its radius is 1.0+-0.08 R_Sun, its mass is 1.0+-0.03 M_Sun, V sini < 3 km/s, and its metallicity [Fe/H] is 0.015+-0.04. The orbital period of the planet XO-1b is 3.941534+-0.000027 days, one of the longer ones known. The planetary mass is 0.90+-0.07 M_Jupiter, which is marginally larger than that of other transiting planets with periods between 3 and 4 days. Both the planetary radius and the inclination are functions of the spectroscopically determined stellar radius. If the stellar radius is 1.0+-0.08 R_Sun, then the planetary radius is 1.30+-0.11 R_Jupiter and the inclination of the orbit is 87.7+-1.2 degrees. We have demonstrated a productive international collaboration between professional and amateur astronomers that was important to distinguishing this planet from many other similar candidates.Comment: 31 pages, 9 figures, accepted for part 1 of Ap

A semantic-based cognitive training programme on everyday activities : a feasibility and acceptability study among cognitively healthy older adults

Background. During the normal ageing process, a person’s cognitive functions and memory gradually decline, which can affect their ability to perform everyday activities including cooking, cleaning, managing finances, and shopping. Semantic memory encoding strategies benefit older adults’ cognitive and functional performance. Such strategies can be taught by an accessible, cost-effective, and flexible app-based programme. Currently, no studies examine such an app-based programme focussed on everyday activities. Objectives. To determine if an app-based programme constructed on the principles of semantic memory encoding strategies, targeted towards older adults, called Enhancing Memory in Daily Life (E-MinD Life) is (1) feasible by examining acceptance, engagement, and attendance and (2) acceptable by examining the perceived effectiveness, relevancy, clarity, and convenience. Methods. Eleven participants were recruited to a nine-week (18 sessions) programme using E-MinD Life. Feasibility was measured by collecting data on recruitment and retention rates, attendance, and duration of sessions. Acceptability was measured via a Likert scale questionnaire and free comments. Likert scale responses were analysed using descriptive statistics; open-ended responses were categorised qualitatively via constant comparative approach. Results. Nine participants completed the programme. Overall, most participants found the programme relevant, convenient, logical, and easy to understand and perceived it to be effective to address functional cognitive problems impacting performance of everyday activities. The results from the qualitative analysis showed that participants found the programme enjoyable and the interaction with the research team throughout the intervention beneficial. Conclusion. E-MinD Life shows promise as the focus of further research to determine the effectiveness of the programme and sematic-based cognitive strategies in maintaining cognition and performance in everyday activities among older adults with and without cognitive impairment

The feasibility and acceptability of an app-based cognitive strategy training programme for older people

Background Increasing numbers of people are living with mild cognitive impairment in later life and seeking therapy to maintain cognition to remain as independent as possible in daily life. Based on a review of the literature, an app-based programme using perceptual-encoding strategies called Enhancing Memory in Daily Life (E-MinD Life) was developed. An expert panel reviewed the programme’s appropriateness for older people with and without mild cognitive impairment. As part of the design process, the feasibility and acceptability of the E-MinD Life programme were then assessed in relation to its use by healthy older adults, with fndings informing the application of the programme to older people with mild cognitive impairment in the future. Methods Phase 1: The E-MinD Life programme was reviewed by an expert panel of occupational therapists. Experts rated the programme on a Likert scale and answered open-ended questions in relation to feasibility, clarity, and relevancy. Phase 2 involved feld-testing the 9-week programme with a sample of nine healthy older people. Participants rated the acceptability of the programme on a Likert scale questionnaire. Data on recruitment rates and retention, and adherence and duration of sessions were collected to determine the feasibility of the programme. Responses to the Likert scale were analysed using descriptive statistics. Open-ended responses were categorised qualitatively using a constant comparative approach. Results Phase 1: Experts indicated that the E-MinD Life programme was feasible and included relevant activities for community living. Although experts felt that an older user with mild NCD would be able to independently complete the programme, the qualitative analysis suggests formatting changes in future iterations of the programme to enhance visual clarity. Phase 2: All participants completed the 9-week programme. The average number of selfadministered sessions attempted over the 9-week period was 13.44 (SD=6.73) out of 18 scheduled sessions. Overall, most participants found the programme relevant, logical and easy to understand, and perceived it to be efective for functional cognitive problems. Conclusion The E-MinD Life programme shows promise for inclusion into trial designs to determine the efectiveness of the cognitive strategy programme for older people with and without cognitive impairment. Trial registration ClinicalTrials.gov, NCT03430401. Registered 1 February 2018

Ibrutinib inhibits platelet integrin αIIbβ3 outside-in signaling and thrombus stability but not adhesion to collagen

OBJECTIVE: Ibrutinib is an irreversible Bruton tyrosine kinase inhibitor approved for treatment of Waldenstrom macroglobulinemia, chronic lymphocytic leukemia, and mantle cell lymphoma that increases the risk of bleeding among patients. Platelets from ibrutinib-treated patients exhibit deficiencies in collagen-evoked signaling in suspension; however, the significance of this observation and how it relates to bleeding risk is unclear, as platelets encounter immobile collagen in vivo. We sought to clarify the effects of ibrutinib on platelet function to better understand the mechanism underlying bleeding risk. APPROACH AND RESULTS: By comparing signaling in suspension and during adhesion to immobilized ligands, we found that the collagen signaling deficiency caused by ibrutinib is milder during adhesion to immobilized collagen. We also found that platelets in whole blood treated with ibrutinib adhered to collagen under arterial shear but formed unstable thrombi, suggesting that the collagen signaling deficiency caused by ibrutinib may not be the predominant cause of bleeding in vivo. However, clot retraction and signaling evoked by platelet adhesion to immobilized fibrinogen were also inhibited by ibrutinib, indicating that integrin αIIbβ3 outside-in signaling is also effected in addition to GPVI signaling. When ibrutinib was combined with the P2Y12 inhibitor, cangrelor, thrombus formation under arterial shear was inhibited additively. CONCLUSIONS: These findings suggest that (1) ibrutinib causes GPVI and integrin αIIbβ3 platelet signaling deficiencies that result in formation of unstable thrombi and may contribute toward bleeding observed in vivo and (2) combining ibrutinib with P2Y12 antagonists, which also inhibit thrombus stability, may have a detrimental effect on hemostasis

Deep brain stimulation can suppress pathological synchronisation in parkinsonian patients

Background Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a highly effective therapeutic intervention in severe Parkinson's disease, its mechanism of action remains unclear. One possibility is that DBS suppresses local pathologically synchronised oscillatory activity.Methods To explore this, the authors recorded from DBS electrodes implanted in the STN of 16 patients with Parkinson's disease during simultaneous stimulation (pulse width 60 mu s; frequency 130 Hz) of the same target using a specially designed amplifier. The authors analysed data from 25 sides.Results The authors found that DBS progressively suppressed peaks in local field potential activity at frequencies between 11 and 30 Hz as voltage was increased beyond a stimulation threshold of 1.5 V. Median peak power had fallen to 54% of baseline values by a stimulation intensity of 3.0 V.Conclusion The findings suggest that DBS can suppress pathological 11-30 Hz activity in the vicinity of stimulation in patients with Parkinson's disease. This suppression occurs at stimulation voltages that are clinically effective

The metabolites of the dietary flavonoid quercetin possess potent antithrombotic activity, and interact with aspirin to enhance antiplatelet effects

Quercetin, a dietary flavonoid, has been reported to possess antiplatelet activity. However, its extensive metabolism following ingestion has resulted in difficulty elucidating precise mechanisms of action. In this study, we aimed to characterize the antiplatelet mechanisms of two methylated metabolites of quercetin—isorhamnetin and tamarixetin—and explore potential interactions with aspirin. Isorhamnetin and tamarixetin inhibited human platelet aggregation, and suppressed activatory processes including granule secretion, integrin αIIbβ3 function, calcium mobilization, and spleen tyrosine kinase (Syk)/linker for activation of T cells (LAT) phosphorylation downstream of glycoprotein VI with similar potency to quercetin. All three flavonoids attenuated thrombus formation in an in vitro microfluidic model, and isoquercetin, a 3-O-glucoside of quercetin, inhibited thrombosis in a murine laser injury model. Isorhamnetin, tamarixetin, and quercetin enhanced the antiplatelet effects of aspirin more-than-additively in a plate-based aggregometry assay, reducing aspirin IC50 values by an order of magnitude, with this synergy maintained in a whole blood test of platelet function. Our data provide mechanistic evidence for the antiplatelet activity of two quercetin metabolites, isorhamnetin and tamarixetin, and suggest a potential antithrombotic role for these flavonoids. In combination with their interactions with aspirin, this may represent a novel avenue of investigation for the development of new antithrombotic strategies and management of current therapies

Insulin signaling inhibits the 5-HT(2C )receptor in choroid plexus via MAP kinase

BACKGROUND: G protein-coupled receptors (GPCRs) interact with heterotrimeric GTP-binding proteins (G proteins) to modulate acute changes in intracellular messenger levels and ion channel activity. In contrast, long-term changes in cellular growth, proliferation and differentiation are often mediated by tyrosine kinase receptors and certain GPCRs by activation of mitogen-activated protein (MAP) kinases. Complex interactions occur between these signaling pathways, but the specific mechanisms of such regulatory events are not well-understood. In particular it is not clear whether GPCRs are modulated by tyrosine kinase receptor-MAP kinase pathways. RESULTS: Here we describe tyrosine kinase receptor regulation of a GPCR via MAP kinase. Insulin reduced the activity of the 5-HT(2C )receptor in choroid plexus cells which was blocked by the MAP kinase kinase (MEK) inhibitor, PD 098059. We demonstrate that the inhibitory effect of insulin and insulin-like growth factor type 1 (IGF-1) on the 5-HT(2C )receptor is dependent on tyrosine kinase, RAS and MAP kinase. The effect may be receptor-specific: insulin had no effect on another GPCR that shares the same G protein signaling pathway as the 5-HT(2C )receptor. This effect is also direct: activated MAP kinase mimicked the effect of insulin, and removing a putative MAP kinase site from the 5-HT(2C )receptor abolished the effect of insulin. CONCLUSION: These results show that insulin signaling can inhibit 5-HT(2C )receptor activity and suggest that MAP kinase may play a direct role in regulating the function of a specific GPCR