26 research outputs found
Harnessing the immunomodulatory effects of exercise to enhance the efficacy of monoclonal antibody therapies against B-cell haematological cancers: a narrative review
Get PDFTherapeutic monoclonal antibodies (mAbs) are standard care for many B-cell haematological cancers. The modes of action for these mAbs include: induction of cancer cell lysis by activating FcÎł-receptors on innate immune cells; opsonising target cells for antibody-dependent cellular cytotoxicity or phagocytosis, and/or triggering the classical complement pathway; the simultaneous binding of cancer cells with T-cells to create an immune synapse and activate perforin-mediated T-cell cytotoxicity against cancer cells; blockade of immune checkpoints to facilitate T-cell cytotoxicity against immunogenic cancer cell clones; and direct delivery of cytotoxic agents via internalisation of mAbs by target cells. While treatment regimens comprising mAb therapy can lead to durable anti-cancer responses, disease relapse is common due to failure of mAb therapy to eradicate minimal residual disease. Factors that limit mAb efficacy include: suboptimal effector cell frequencies, overt immune exhaustion and/or immune anergy, and survival of diffusely spread tumour cells in different stromal niches. In this review, we discuss how immunomodulatory changes arising from exposure to structured bouts of acute exercise might improve mAb treatment efficacy by augmenting (i) antibody-dependent cellular cytotoxicity, (ii) antibody-dependent cellular phagocytosis, (iii) complement-dependent cytotoxicity, (iv) T-cell cytotoxicity, and (v) direct delivery of cytotoxic agents
Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy in vitro
Get PDFMultiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for âŒ30-minutes, with blood samples collected pre-, immediately post-, and 30-minutes post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively (p < 0.001), owing to an increased frequency of CD3âCD56+CD16+ NK-cells (+348%), HLA-DR+CD14dimCD16+ monocytes (+125%), and HLA-DR+CD14+CD32+ monocytes (+41%) in blood (p < 0.01). However, overall, total plasma cells (CD38+CD138+) nor clonal plasma cells (CD38brightCD138+CD45â/dimCD19â with light-chain restriction) increased in blood (p > 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide â whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro. However, plasma cells were largely unchanged, and NK-cells expressing CD38 â the daratumumab target antigen â increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis
The effects of sleep deprivation, acute hypoxia, and exercise on cognitive performance: A multi-experiment combined stressors study
Get PDFIntroduction: Both sleep deprivation and hypoxia have been shown to impair executive function. Conversely, moderate intensity exercise is known to improve executive function. In a multi-experiment study, we tested the hypotheses that moderate intensity exercise would ameliorate any decline in executive function after i) three consecutive nights of partial sleep deprivation (PSD) (Experiment 1) and ii) the isolated and combined effects of a single night of total sleep deprivation (TSD) and acute hypoxia (Experiment 2).
Methods: Using a rigorous randomised controlled crossover design, 12 healthy participants volunteered in each experiment (24 total, 5 females). In both experiments seven executive function tasks (2-choice reaction time, logical relations, manikin, mathematical processing, 1-back, 2-back, 3-back) were completed at rest and during 20Â min semi-recumbent, moderate intensity cycling. Tasks were completed in the following conditions: before and after three consecutive nights of PSD and habitual sleep (Experiment 1) and in normoxia and acute hypoxia (FIO2Â =Â 0.12) following one night of habitual sleep and one night of TSD (Experiment 2).
Results: Although the effects of three nights of PSD on executive functions were inconsistent, one night of TSD (regardless of hypoxic status) reduced executive functions. Significantly, regardless of sleep or hypoxic status, executive functions are improved during an acute bout of moderate intensity exercise.
Conclusion: These novel data indicate that moderate intensity exercise improves executive function performance after both PSD and TSD, regardless of hypoxic status. The key determinants and/or mechanism(s) responsible for this improvement still need to be elucidated. Future work should seek to identify these mechanisms and translate these significant findings into occupational and skilled performance settings
Uncertainties in breakup markers along the Iberia-Newfoundland margins illustrated by new seismic data
Get PDFPlate tectonic modellers often rely on the identification of âbreak-upâ markers to reconstruct the early stages
of continental separation. Along the Iberian-Newfoundland
margin, so-called break-up markers include interpretations
of old magnetic anomalies from the M series, as well as the
âJ anomalyâ. These have been used as the basis for plate
tectonic reconstructions are based on the concept that these
anomalies pinpoint the location of first oceanic lithosphere.
However, uncertainties in the location and interpretation of
break-up markers, as well as the difficulty in dating them
precisely, has led to plate models that differ in both the timing and relative palaeo-positions of Iberia and Newfoundland
during separation.
We use newly available seismic data from the Southern
Newfoundland Basin (SNB) to assess the suitability of commonly used break-up markers along the Newfoundland margin for plate kinematic reconstructions. Our data show that
basement associated with the younger M-series magnetic
anomalies is comprised of exhumed mantle and magmatic
additions and most likely represents transitional domains
and not true oceanic lithosphere. Because rifting propagated
northward, we argue that M-series anomaly identifications
further north, although in a region not imaged by our seismic, are also unlikely to be diagnostic of true oceanic crust
beneath the SNB. Similarly, our data also allow us to show
that the high amplitude of the J Anomaly is associated with a
zone of exhumed mantle punctuated by significant volcanic
additions and at times characterized by interbedded volcanics
and sediments. Magmatic activity in the SNB at a time coinciding with M4 (128 Ma) and the presence of SDR packages
onlapping onto a basement fault suggest that, at this time,
plate divergence was still being accommodated by tectonic
faulting.
We illustrate the differences in the relative positions of
Iberia and Newfoundland across published plate reconstructions and discuss how these are a direct consequence of the
uncertainties introduced into the modelling procedure by the
use of extended continental margin data (dubious magnetic
anomaly identifications, break-up unconformity interpretations). We conclude that a different approach is needed for
constraining plate kinematics of the Iberian plate pre-M0
times.</p
Heat acclimation improves sweat gland function and lowers sweat sodium concentration in an adult with cystic fibrosis
Get PDFWe present novel data concerning the time-course of adaptations and potential benefits of heat acclimation for people with cystic fibrosis (pwCF), who are at greater risk of exertional heat illness. A 25-year-old male (genotype: delta-F508 and RH117, forced expiratory volume in 1-second: 77% predicted and baseline sweat [Na+]: 70 mmol·L â 1), who had previously experienced muscle cramping during exercise in ambient heat, underwent 10-sessions of heat acclimation (90-min at 40°C and in 40% relative humidity). Adaptations included; lower resting core temperature (-0.40°C) and heart rate (-6 beats·minâ1), plasma volume expansion (+6.0%) and, importantly, increased sweat loss (+370 mL) and sweat gland activity (+12 glands·cm2) with decreased sweat [Na+] (-18 mmol·L â 1). Adaptations were maintained for at least 7-days, with no evidence of cramping during follow-up exercise-heat stress testing. These data suggest pwCF may benefit from heat acclimation to induce sudomotor function improvements, particularly reductions in sweat [Na+], however, further research is required
A single bout of vigorous intensity exercise enhances the efficacy of rituximab against autologous human chronic lymphocytic leukaemia B-cells ex vivo
No full textChronic lymphocytic leukaemia (CLL) is characterised by the clonal proliferation and accumulation of mature B-cells and is often treated with rituximab, an anti-CD20 monoclonal antibody immunotherapy. Rituximab often fails to induce stringent disease eradication, due in part to failure of antibody-dependent cellular cytotoxicity which relies on natural killer (NK)-cells binding to rituximab-bound CD20 on B-cells. CLL cells are diffusely spread across lymphoid and other bodily tissues, and ADCC resistance in survival niches may be due to several factors including low NK-cell frequency and a suppressive stromal environment that promotes CLL cell survival. It is well established that exercise bouts induce a transient relocation of NK-cells and B-cells into peripheral blood, which could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab in blood. In this pilot study, nâŻ=âŻ20 patients with treatment-naĂŻve CLL completed a bout of cycling 15âŻ% above their anaerobic threshold forâŻâŒâŻ30-minutes, with blood samples collected pre-, immediately post-, and 1-hour post-exercise. Flow cytometry revealed that exercise evoked a 254âŻ% increase in effector (CD3âCD56+CD16+) NK-cells in blood, respectively, and a 67âŻ% increase in CD5+CD19+CD20+ CLL cells in blood (all pâŻ<âŻ0.005). NK-cells were isolated from blood samples pre-, and immediately post-exercise and incubated with primary isolated CLL cells with or without the presence of rituximab to determine specific lysis using a calcein-release assay. Rituximab-mediated cell lysis increased by 129âŻ% following exercise (pâŻ<âŻ0.001). Direct NK-cell lysis of CLL cells â independent of rituximab â was unchanged following exercise (pâŻ=âŻ0.25). We conclude that exercise improved the efficacy of rituximab-mediated antibody-dependent cellular cytotoxicity against autologous CLL cells ex vivo and propose that exercise should be explored as a means of enhancing clinical responses in patients receiving anti-CD20 immunotherapy
