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

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 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

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

Cross Adaptation - Heat and Cold Adaptation to Improve Physiological and Cellular Responses to Hypoxia

To prepare for extremes of heat, cold or low partial pressures of O2, humans can undertake a period of acclimation or acclimatization to induce environment specific adaptations e.g. heat acclimation (HA), cold acclimation (CA), or altitude training. Whilst these strategies are effective, they are not always feasible, due to logistical impracticalities. Cross adaptation is a term used to describe the phenomenon whereby alternative environmental interventions e.g. HA, or CA, may be a beneficial alternative to altitude interventions, providing physiological stress and inducing adaptations observable at altitude. HA can attenuate physiological strain at rest and during moderate intensity exercise at altitude via adaptations allied to improved oxygen delivery to metabolically active tissue, likely following increases in plasma volume and reductions in body temperature. CA appears to improve physiological responses to altitude by attenuating the autonomic response to altitude. While no cross acclimation-derived exercise performance/capacity data have been measured following CA, post-HA improvements in performance underpinned by aerobic metabolism, and therefore dependent on oxygen delivery at altitude, are likely. At a cellular level, heat shock protein responses to altitude are attenuated by prior HA suggesting that an attenuation of the cellular stress response and therefore a reduced disruption to homeostasis at altitude has occurred. This process is known as cross tolerance. The effects of CA on markers of cross tolerance is an area requiring further investigation. Because much of the evidence relating to cross adaptation to altitude has examined the benefits at moderate to high altitudes, future research examining responses at lower altitudes should be conducted given that these environments are more frequently visited by athletes and workers. Mechanistic work to identify the specific physiological and cellular pathways responsible for cross adaptation between heat and altitude, and between cold and altitude, is warranted, as is exploration of benefits across different populations and physical activity profiles