Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.

BackgroundIn melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.MethodsThe 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.ResultsSensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.ConclusionsCombining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors

Aortic valve imaging using 18F-sodium fluoride: impact of triple motion correction

BACKGROUND: Current (18)F-NaF assessments of aortic valve microcalcification using (18)F-NaF PET/CT are based on evaluations of end-diastolic or cardiac motion-corrected (ECG-MC) images, which are affected by both patient and respiratory motion. We aimed to test the impact of employing a triple motion correction technique (3 × MC), including cardiorespiratory and gross patient motion, on quantitative and qualitative measurements. MATERIALS AND METHODS: Fourteen patients with aortic stenosis underwent two repeat 30-min PET aortic valve scans within (29 ± 24) days. We considered three different image reconstruction protocols; an end-diastolic reconstruction protocol (standard) utilizing 25% of the acquired data, an ECG-gated (four ECG gates) reconstruction (ECG-MC), and a triple motion-corrected (3 × MC) dataset which corrects for both cardiorespiratory and patient motion. All datasets were compared to aortic valve calcification scores (AVCS), using the Agatston method, obtained from CT scans using correlation plots. We report SUV(max) values measured in the aortic valve and maximum target-to-background ratios (TBR(max)) values after correcting for blood pool activity. RESULTS: Compared to standard and ECG-MC reconstructions, increases in both SUV(max) and TBR(max) were observed following 3 × MC (SUV(max): Standard = 2.8 ± 0.7, ECG-MC = 2.6 ± 0.6, and 3 × MC = 3.3 ± 0.9; TBR(max): Standard = 2.7 ± 0.7, ECG-MC = 2.5 ± 0.6, and 3 × MC = 3.3 ± 1.2, all p values ≤ 0.05). 3 × MC had improved correlations (R(2) value) to the AVCS when compared to the standard methods (SUV(max): Standard = 0.10, ECG-MC = 0.10, and 3 × MC = 0.20; TBR(max): Standard = 0.20, ECG-MC = 0.28, and 3 × MC = 0.46). CONCLUSION: 3 × MC improves the correlation between the AVCS and SUV(max) and TBR(max) and should be considered in PET studies of aortic valves using (18)F-NaF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40658-022-00433-7

Revisiting the frequency domain: the multiple and partial coherence of cerebral blood flow velocity in the assessment of dynamic cerebral autoregulation

Despite advances in modelling dynamic autoregulation, only part of the variability of cerebral blood flow velocity (CBFV) in the low frequency range has been explained. We investigate whether a multivariate representation can be used for this purpose. Pseudorandom sequences were used to inflate thigh cuffs and to administer 5% CO2. Multiple and partial coherence were estimated, using arterial blood pressure (ABP), end-tidal CO2 (EtCO2) and resistance area product as input and CBFV as output variables. The inclusion of second and third input variables increased the amount of CBFV variability that can be accounted for (p  <  10−4 in both cases). Partial coherence estimates in the low frequency range (<0.07 Hz) were not influenced by the use of thigh cuffs, but CO2 administration had a statistically significant effect (p  <  10−4 in all cases). We conclude that the inclusion of additional inputs of a priori known physiological significance can help account for a greater amount of CBFV variability and may represent a viable alternative to more conventional non-linear modelling. The results of partial coherence analysis suggest that dynamic autoregulation and CO2 reactivity are likely to be the result of different physiological mechanisms

Triple-gated motion and blood pool clearance corrections improve reproducibility of coronary 18F-NaF PET

PurposeTo improve the test-retest reproducibility of coronary plaque 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) uptake measurements.MethodsWe recruited 20 patients with coronary artery disease who underwent repeated hybrid PET/CT angiography (CTA) imaging within 3&nbsp;weeks. All patients had 30-min PET acquisition and CTA during a single imaging session. Five PET image-sets with progressive motion correction were reconstructed: (i) a static dataset (no-MC), (ii) end-diastolic PET (standard), (iii) cardiac motion corrected (MC), (iv) combined cardiac and gross patient motion corrected (2 × MC) and, (v) cardiorespiratory and gross patient motion corrected (3 × MC). In addition to motion correction, all datasets were corrected for variations in the background activities which are introduced by variations in the injection-to-scan delays (background blood pool clearance correction, BC). Test-retest reproducibility of PET target-to-background ratio (TBR) was assessed by Bland-Altman analysis and coefficient of reproducibility.ResultsA total of 47 unique coronary lesions were identified on CTA. Motion correction in combination with BC improved the PET TBR test-retest reproducibility for all lesions (coefficient of reproducibility: standard = 0.437, no-MC = 0.345 (27% improvement), standard&nbsp;+&nbsp;BC = 0.365 (20% improvement), no-MC + BC = 0.341 (27% improvement), MC + BC = 0.288 (52% improvement), 2 × MC + BC = 0.278 (57% improvement) and 3 × C + BC = 0.254 (72% improvement), all p &lt; 0.001). Importantly, in a sub-analysis of 18F-NaF-avid lesions with gross patient motion &gt;&nbsp;10&nbsp;mm following corrections, reproducibility was improved by 133% (coefficient of reproducibility: standard = 0.745, 3 × MC = 0.320).ConclusionJoint corrections for cardiac, respiratory, and gross patient motion in combination with background blood pool corrections markedly improve test-retest reproducibility of coronary 18F-NaF PET

Coherent averaging of pseudorandom binary stimuli: is the dynamic cerebral autoregulatory response symmetrical?

Objective: Previous studies on cerebral autoregulation have shown the existence of hemispheric symmetry, which may be altered in stroke and traumatic brain injury. There is a paucity of data however on whether the response is symmetrical between those disturbances that cause cerebral hyperperfusion, to those that cause hypoperfusion. Our aim was to investigate whether the responses of cerebral autoregulation to haemodynamic stimuli of different directions are symmetrical. &#13; Approach: Using a previously described assessment method, we employed coherent averaging of the cerebral blood flow velocity (CBFV) responses to thigh cuff inflation and deflation, as driven by pseudorandom binary sequences, whilst simultaneously altering the inspired CO2. The symmetry of the autoregulatory response was assessed with regards to two parameters, its speed and gain. Using the first harmonic method, critical closing pressure (CrCP) and resistance area product (RAP) were estimated, and the gain of the autoregulatory response was calculated by performing linear regression between the coherent averages of arterial blood pressure (ABP) and CBFV, ABP and CrCP and finally ABP and RAP. A two-way repeated measures ANOVA was used to assess for the effect of the direction of change in ABP and the method of CO2 administration. &#13; Main results: Our results suggest that whilst the direction of ABP change does not have a significant effect, the effect of CO2 administration method is highly significant (p&lt;10-4). &#13; Significance: This is the first report to report to demonstrate the symmetry of the autoregulatory response to stimuli of different directions as well as the short term dynamics of RAP and CrCP under intermittent and constant hypercapnia. As haemodynamic stimulus direction does not appear to have an influence, our findings validate previous work done using different assessment methods

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Erratum to : Antitumor activity of the ERK inhibitor SCH722984 against BRAF mutant, NRAS mutant and wild-type melanoma

Correcció d'errades de l'article: Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma. Mol Cancer. 2014 (doi: 10.1186/1476-4598-13-194.)After publication of this work [1], we noted that we repeatedly had a typo mistake across the manuscript. The compound we used to test our cell lines was SCH772984 and not SCH722984. The typo was found misspelled in 54 occasions, including the title. We also wanted to add an affiliation detail to the author's list, as noted above.We regret the mistake and upload this note to clarify it

Larotrectinib versus Prior Therapies in Tropomyosin Receptor Kinase Fusion Cancer: An Intra-Patient Comparative Analysis.

Randomized controlled basket trials investigating drugs targeting a rare molecular alteration are challenging. Using patients as their own control overcomes some of these challenges. Growth modulation index (GMI) is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the last prior line of therapy; GMI ≥ 1.33 is considered a threshold of meaningful clinical activity. In a retrospective, exploratory analysis among patients with advanced tropomyosin receptor kinase (TRK) fusion cancer treated with the selective TRK inhibitor larotrectinib who received ≥1 prior line of therapy for locally advanced/metastatic disease, we determined the proportion of patients with GMI ≥ 1.33; patients who had not progressed by data cut-off were censored for PFS. Among 72 eligible patients, median GMI was 2.68 (range 0.01-48.75). Forty-seven patients (65%) had GMI ≥ 1.33; 13/25 patients (52%) with GMI < 1.33 had not yet progressed on larotrectinib. Kaplan-Meier estimates showed a median GMI of 6.46. The probability of attaining GMI ≥ 1.33 was 0.75 (95% confidence interval (CI), 0.65-0.85). Median TTP on previous treatment was 3.0 months (95% CI, 2.6-4.4). Median PFS on larotrectinib was not estimable ((NE); 95% CI, NE; hazard ratio, 0.220 (95% CI, 0.146-0.332)). This analysis suggests larotrectinib improves PFS for patients with TRK fusion cancer compared with prior therapy