Diagnostic performance of early increase in S100B or LDH as outcome predictor for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma

As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.</p

Seasonal variation of anti-PD-1 outcome in melanoma—Results from a Dutch patient cohort

Despite the improved survival rates of patients with advanced stage melanoma since the introduction of ICIs, many patients do not have (long-term) benefit from these treatments. There is evidence that the exposome, an accumulation of host-extrinsic factors including environmental influences, could impact ICI response. Recently, a survival benefit was observed in patients with BRAF wild-type melanoma living in Denmark who initiated immunotherapy in summer as compared to winter. As the Netherlands lies in close geographical proximity to Denmark and has comparable seasonal differences, a Dutch validation cohort was established using data from our nationwide melanoma registry. In this study, we did not observe a similar seasonal difference in overall survival and are therefore unable to confirm the Danish findings. Validation of either the Dutch or Danish findings in (combined) patient cohorts from other countries would be necessary to determine whether this host-extrinsic factor influences the response to ICI-treatment. Analysis and support of clinical decision makin

Discontinuation of anti-PD-1 antibody therapy in the absence of disease progression or treatment limiting toxicity : clinical outcomes in advanced melanoma

Background Programmed cell death protein 1 (PD-1) blocking monoclonal antibodies improve the overall survival of patients with advanced melanoma but the optimal duration of treatment has not been established. Patients and Methods This academic real-world cohort study investigated the outcome of 185 advanced melanoma patients who electively discontinued anti-PD-1 therapy with pembrolizumab (N=167) or nivolumab (N=18) in the absence of disease progression (PD) or treatment limiting toxicity (TLT) at 14 medical centres across Europe and Australia. Results Median time on treatment was 12months (range 0.7-43). The best objective tumour response at the time of treatment discontinuation was complete response (CR) in 117 (63%) patients, partial response (PR) in 44 (24%) patients and stable disease (SD) in 16 (9%) patients; 8 (4%) patients had no evaluable disease (NE). After a median follow-up of 18months (range 0.7-48) after treatment discontinuation, 78% of patients remained free of progression. Median time to progression was 12months (range 2-23). PD was less frequent in patients with CR (14%) compared with patients with PR (32%) and SD (50%). Six out of 19 (32%) patients who were retreated with an anti-PD-1 at the time of PD obtained a new antitumour response. Conclusions In this real-world cohort of advanced melanoma patients discontinuing anti-PD-1 therapy in the absence of TLT or PD, the duration of anti-PD-1 therapy was shorter when compared with clinical trials. In patients obtaining a CR, and being treated for >6months, the risk of relapse after treatment discontinuation was low. Patients achieving a PR or SD as best tumour response were at higher risk for progression after discontinuing therapy, and defining optimal treatment duration in such patients deserves further study. Retreatment with an anti-PD-1 at the time of progression may lead to renewed antitumour activity in some patients. Clinical trial registration NCT02673970 (https://clinicaltrials.gov/ct2/show/NCT02673970?cond=melanoma&cntry=BE&city=Jette&rank=3)Peer reviewe

Spreading continents kick-started plate tectonics

International audienceStresses acting on cold, thick and negatively buoyant oceanic litho- sphere are thought to be crucial to the initiation of subduction and the operation of plate tectonics, which characterizes the present- day geodynamics of the Earth. Because the Earth’s interior was hotter in the Archaean eon, the oceanic crust may have been thicker, thereby making the oceanic lithosphere more buoyant than at present, and whether subduction and plate tectonics occurred during this time is ambiguous, both in the geological record and in geodynamic models. Here we show that because the oceanic crust was thick and buoyant5, early continents may have produced intra-lithospheric gravitational stresses large enough to drive their gravitational spreading, to initiate subduction at their margins and to trigger episodes of subduction. Our model predicts the co-occurrence of deep to progressively shallower mafic volcanics and arc magmatism within continents in a self-consistent geodynamic framework, explaining the enigmatic multimodal volcanism and tectonic record of Archaean cratons. Moreover, our model predicts a petrological stratification and tectonic structure of the sub-continental lithospheric mantle, two predictions that are consistent with xenolith and seismic studies, respectively, and consistent with the existence of a mid-lithospheric seismic discontinuity. The slow gravitational collapse of early continents could have kick-started transient episodes of plate tectonics until, as the Earth’s interior cooled and oceanic lithosphere became heavier, plate tectonics became self-sustaining

Effect of β-alanine supplementation on 20 km cycling time trial performance

The effects of β-alanine supplementation on high-intensity cycling performance and capacity have been evaluated, although the effects on longer duration cycling performance are unclear. Nineteen UK category 1 male cyclists completed four 20 km cycling time trials, two before and two after supplementation with either 6.4 g•d -1 β-alanine (n = 10; BA) or a matched placebo (n = 9; P). Performance time for the 20 km time trial and 1 km split times were recorded. There was no significant effect of β-alanine supplementation on 20 km time trial performance (BA-pre 1943 ± 129 s; BA-post 1950 ± 147 s; P-pre 1989 ± 106 s; P-post 1986 ± 115 s) or on the performance of each 1 km split. The effect of β-alanine on 20 km time trial performance was deemed unclear as determined by magnitude based inferences. Supplementation with 6.4 g•d -1 of β-alanine for 4 weeks did not affect 20 km cycling time trial performance in well trained male cyclists

Influence of training status on high-intensity intermittent performance in response to β-alanine supplementation

Recent investigations have suggested that highly trained athletes may be less responsive to the ergogenic effects of β-alanine (BA) supplementation than recreationally active individuals due to their elevated muscle buffering capacity. We investigated whether training status influences the effect of BA on repeated Wingate performance. Forty young males were divided into two groups according to their training status (trained: T, and non-trained: NT cyclists) and were randomly allocated to BA and a dextrose-based placebo (PL) groups, providing four experimental conditions: NTPL, NTBA, TPL, TBA. BA (6.4 g day-1 ) or PL was ingested for 4 weeks, with participants completing four 30-s lower-body Wingate bouts, separated by 3 min, before and after supplementation. Total work done was significantly increased following supplementation in both NTBA (p = 0.03) and TBA (p = 0.002), and it was significantly reduced in NTPL (p = 0.03) with no difference for TPL (p = 0.73). BA supplementation increased mean power output (MPO) in bout 4 for the NTBA group (p = 0.0004) and in bouts 1, 2 and 4 for the TBA group (p ≤ 0.05). No differences were observed in MPO for NTPL and TPL. BA supplementation was effective at improving repeated high-intensity cycling performance in both trained and non-trained individuals, highlighting the efficacy of BA as an ergogenic aid for high-intensity exercise regardless of the training status of the individual

Effects of β-alanine supplementation on exercise performance: a meta-analysis

Due to the well-defined role of β-alanine as a substrate of carnosine (a major contributor to H+ buffering during high-intensity exercise), β-alanine is fast becoming a popular ergogenic aid to sports performance. There have been several recent qualitative review articles published on the topic, and here we present a preliminary quantitative review of the literature through a meta-analysis. A comprehensive search of the literature was employed to identify all studies suitable for inclusion in the analysis; strict exclusion criteria were also applied. Fifteen published manuscripts were included in the analysis, which reported the results of 57 measures within 23 exercise tests, using 18 supplementation regimes and a total of 360 participants [174, β-alanine supplementation group (BA) and 186, placebo supplementation group (Pla)]. BA improved (P = 0.002) the outcome of exercise measures to a greater extent than Pla [median effect size (IQR): BA 0.374 (0.140–0.747), Pla 0.108 (−0.019 to 0.487)]. Some of that effect might be explained by the improvement (P = 0.013) in exercise capacity with BA compared to Pla; no improvement was seen for exercise performance (P = 0.204). In line with the purported mechanisms for an ergogenic effect of β-alanine supplementation, exercise lasting 60–240 s was improved (P = 0.001) in BA compared to Pla, as was exercise of >240 s (P = 0.046). In contrast, there was no benefit of β-alanine on exercise lasting <60 s (P = 0.312). The median effect of β-alanine supplementation is a 2.85% (−0.37 to 10.49%) improvement in the outcome of an exercise measure, when a median total of 179 g of β-alanine is supplemented

The Shear Stress-Induced Transcription Factor KLF2 Affects Dynamics and Angiopoietin-2 Content of Weibel-Palade Bodies

BACKGROUND: The shear-stress induced transcription factor KLF2 has been shown to induce an atheroprotective phenotype in endothelial cells (EC) that are exposed to prolonged laminar shear. In this study we characterized the effect of the shear stress-induced transcription factor KLF2 on regulation and composition of Weibel-Palade bodies (WPBs) using peripheral blood derived ECs. METHODOLOGY AND PRINCIPAL FINDINGS: Lentiviral expression of KLF2 resulted in a 4.5 fold increase in the number of WPBs per cell when compared to mock-transduced endothelial cells. Unexpectedly, the average length of WPBs was significantly reduced: in mock-transduced endothelial cells WPBs had an average length of 1.7 µm versus 1.3 µm in KLF2 expressing cells. Expression of KLF2 abolished the perinuclear clustering of WPBs observed following stimulation with cAMP-raising agonists such as epinephrine. Immunocytochemistry revealed that WPBs of KLF2 expressing ECs were positive for IL-6 and IL-8 (after their upregulation with IL-1β) but lacked angiopoietin-2 (Ang2), a regular component of WPBs. Stimulus-induced secretion of Ang2 in KLF2 expressing ECs was greatly reduced and IL-8 secretion was significantly lower. CONCLUSIONS AND SIGNIFICANCE: These data suggest that KLF2 expression leads to a change in size and composition of the regulated secretory compartment of endothelial cells and alters its response to physiological stimuli

The effect of two β-alanine dosing strategies on 30-minute rowing performance: a randomized, controlled trial

Background: β-alanine (βA) supplementation has been shown to increase intramuscular carnosine content and subsequent high-intensity performance in events lasting <4 minutes, which may be dependent on total, as opposed to daily, dose. The ergogenic effect of βA has also been demonstrated for 2000-m rowing performance prompting interest in whether βA may be beneficial for sustained aerobic exercise. This study therefore investigated the effect of two βA dosing strategies on 30-minute rowing and subsequent sprint performance. Methods: Following University Ethics approval, twenty-seven healthy, male rowers (age: 24±2 years; body-height: 1.81±0.02m; body-mass: 82.3±2.5kg; body-fat: 14.2±1.0%) were randomised in a double-blind manner to 4 weeks of: i) βA (2.4 g·d-1, βA1); ii) matched total βA (4.8g on alternate days, βA2); or iii) cornflour placebo (2.4 g·d-1, PL). Participants completed a laboratory 30-minute rowing time-trial, followed by 3x30s maximal sprint efforts at days 0, 14 and 28 (T1-T3). Total distance (m), average power (W), relative average power (W·kg-1), cardio-respiratory measures and perceived exertion were assessed for each 10-minute split. Blood lactate ([La-]b mmol·L-1) was monitored pre-post time-trial and following maximal sprint efforts. A 3-way repeated measures ANOVA was employed for main analyses, with Bonferonni post-hoc assessment (P≤0.05). Results: Total 30-minute time-trial distance significantly increased from T1-T3 within βA1 only (7397±195m to 7580±171m, P=0.002, ƞp2 = 0.196), including absolute average power (194.8±18.3W to 204.2±15.5W, P=0.04, ƞp2=0.115) and relative average power output (2.28±0.15W·kg-1 to 2.41±0.12W·kg-1, P=0.031, ƞp2= 0.122). These findings were potentially explained by within-group significance for the same variables for the first 10 minute split (P≤0.01), and for distance covered (P=0.01) in the second 10-minute split. However, no condition x time interactions were observed. No significant effects were found for sprint variables (P>0.05) with comparable values at T3 for mean distance (βA1: 163.9±3.8m; βA2: 161.2±3.5m; PL: 162.7±3.6m), average power (βA1: 352.7±14.5W; βA2: 342.2±13.5W; PL: 348.2±13.9W) and lactate (βA1: 10.0±0.9mmol·L-1; βA2: 9.2±1.1mmol·L-1; PL: 8.7±0.9mmol·L-1). Conclusions: Whilst daily βA may confer individual benefits, these results demonstrate limited impact of βA (irrespective of dosing strategy) on 30-minute rowing or subsequent sprint performance. Further investigation of βA dosage > 2.4 g·d-1 and/or chronic intervention periods (>4-8 weeks) may be warranted based on within-group observations