30 research outputs found
Reframing How Physical Activity Reduces The Incidence of Clinically-Diagnosed Cancers: Appraising Exercise-Induced Immuno-Modulation As An Integral Mechanism
Get PDFUndertaking a high volume of physical activity is associated with reduced risk of a broad range of clinically diagnosed cancers. These findings, which imply that physical activity induces physiological changes that avert or suppress neoplastic activity, are supported by preclinical intervention studies in rodents demonstrating that structured regular exercise commonly represses tumour growth. In Part 1 of this review, we summarise epidemiology and preclinical evidence linking physical activity or regular structured exercise with reduced cancer risk or tumour growth. Despite abundant evidence that physical activity commonly exerts anti-cancer effects, the mechanism(s)-of-action responsible for these beneficial outcomes is undefined and remains subject to ongoing speculation. In Part 2, we outline why altered immune regulation from physical activity - specifically to T cells - is likely an integral mechanism. We do this by first explaining how physical activity appears to modulate the cancer immunoediting process. In doing so, we highlight that augmented elimination of immunogenic cancer cells predominantly leads to the containment of cancers in a ‘precancerous’ or ‘covert’ equilibrium state, thus reducing the incidence of clinically diagnosed cancers among physically active individuals. In seeking to understand how physical activity might augment T cell function to avert cancer outgrowth, in Part 3 we appraise how physical activity affects the determinants of a successful T cell response against immunogenic cancer cells. Using the cancer immunogram as a basis for this evaluation, we assess the effects of physical activity on: (i) general T cell status in blood, (ii) T cell infiltration to tissues, (iii) presence of immune checkpoints associated with T cell exhaustion and anergy, (iv) presence of inflammatory inhibitors of T cells and (v) presence of metabolic inhibitors of T cells. The extent to which physical activity alters these determinants to reduce the risk of clinically diagnosed cancers – and whether physical activity changes these determinants in an interconnected or unrelated manner – is unresolved. Accordingly, we analyse how physical activity might alter each determinant, and we show how these changes may interconnect to explain how physical activity alters T cell regulation to prevent cancer outgrowth
Influence of iodide ingestion on nitrate metabolism and blood pressure following short-term dietary nitrate supplementation in healthy normotensive adults
Get PDFUptake of inorganic nitrate (NO3−) into the salivary circulation is a rate-limiting step for dietary NO3− metabolism in mammals. It has been suggested that salivary NO3− uptake occurs in competition with inorganic iodide (I−). Therefore, this study tested the hypothesis that I− supplementation would interfere with NO3− metabolism and blunt blood pressure reductions after dietary NO3− supplementation. Nine healthy adults (4 male, mean ± SD, age 20 ± 1 yr) reported to the laboratory for initial baseline assessment (control) and following six day supplementation periods with 140 mL·day−1 NO3−-rich beetroot juice (8.4 mmol NO3−·day−1) and 198 mg potassium gluconate·day−1 (nitrate), and 140 mL·day−1 NO3−-rich beetroot juice and 450 μg potassium iodide·day−1 (nitrate + iodide) in a randomized, cross-over experiment. Salivary [I−] was higher in the nitrate + iodide compared to the control and NIT trials (P 0.05). Systolic blood pressure was lower than control (112 ± 13 mmHg) in the nitrate (106 ± 13 mmHg) and nitrate + iodide (106 ± 11 mmHg) trials (P 0.05). In conclusion, co-ingesting NO3− and I− perturbed salivary NO3− uptake, but the increase in salivary and plasma [NO2−] and the lowering of blood pressure were similar compared to NO3− ingestion alone. Therefore, increased dietary I− intake, which is recommended in several countries worldwide as an initiative to offset hypothyroidism, does not appear to compromise the blood pressure reduction afforded by increased dietary NO3− intake
Investigating the utility of saliva immunoglobulins for the detection of myeloma and using myeloma proteins to clarify partition between oral and systemic immunity
Get PDFOBJECTIVES
Myeloma is characterised by the presence of monoclonal immunoglobulin (M-protein) and the free light chain (FLC) in blood. We investigated whether these M-proteins and FLC are detectable in myeloma patients' saliva to evaluate its utility for non-invasive screening and monitoring of haematological malignancies.
METHODS
A total of 57 patients with monoclonal gammopathy and 26 age-matched healthy participants provided paired serum and saliva samples for immunoglobulin characterisation and quantification.
RESULTS
Myeloma patients had IgG or IgA M-protein levels ranging up to five times and FLC levels up to a thousand times normal levels of polyclonal immunoglobulins. Despite these highly elevated levels, only two IgG and no IgA M-proteins or FLC could be detected in paired saliva samples. Most patients had reduced levels of serum polyclonal immunoglobulins, but all had normal levels of salivary IgA.
CONCLUSIONS
Immunoglobulin transfer from blood is not determined by levels in the systemic circulation and more likely dictated by periodontal inflammation and the integrity of the oral epithelium. Immunoglobulins secreted by bone marrow plasma cells do not substantially enter saliva, which represents a poor medium for myeloma diagnosis. These findings, along with normal salivary IgA levels despite systemic immunoparesis, support a strong partitioning of oral from systemic humoral immunity
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 Fcγ-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 ∼30-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 CD3−CD56+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+CD45−/dimCD19− 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 – 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 – the daratumumab target antigen – 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
Gamma frequency entrainment attenuates amyloid load and modifies microglia
Get PDFChanges in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)[subscript 1-40] and Aβ [subscript 1-42] isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ[subscript 1-40] and Aβ[subscript 1-42] levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer's-disease-associated pathology.National Institutes of Health (U.S.) (Grant 1R01EY023173)National Institutes of Health (U.S.) (Grant 1DP1NS087724)National Institutes of Health (U.S.) (Grant RF1AG047661)National Institutes of Health (U.S.) (Grant ROIGM104948
Influence of iodide ingestion on nitrate metabolism and blood pressure following short-term dietary nitrate supplementation in healthy normotensive adults
Get PDFThis paper was accepted for publication in the journal Nitric Oxide and the definitive published version is available at http://dx.doi.org/10.1016/j.niox.2016.12.008Uptake of inorganic nitrate (NO3−) into the salivary circulation is a rate-limiting step for dietary NO3− metabolism in mammals. It has been suggested that salivary NO3− uptake occurs in competition with inorganic iodide (I−). Therefore, this study tested the hypothesis that I− supplementation would interfere with NO3− metabolism and blunt blood pressure reductions after dietary NO3− supplementation. Nine healthy adults (4 male, mean ± SD, age 20 ± 1 yr) reported to the laboratory for initial baseline assessment (control) and following six day supplementation periods with 140 mL·day−1 NO3−-rich beetroot juice (8.4 mmol NO3−·day−1) and 198 mg potassium gluconate·day−1 (nitrate), and 140 mL·day−1 NO3−-rich beetroot juice and 450 μg potassium iodide·day−1 (nitrate + iodide) in a randomized, cross-over experiment. Salivary [I−] was higher in the nitrate + iodide compared to the control and NIT trials (P < 0.05). Salivary and plasma [NO3−] and [NO2−] were higher in the nitrate and nitrate + iodide trials compared to the control trial (P < 0.05). Plasma [NO3−] was higher (474 ± 127 vs. 438 ± 117 μM) and the salivary-plasma [NO3−] ratio was lower (14 ± 6 vs. 20 ± 6 μM), indicative of a lower salivary NO3− uptake, in the nitrate + iodide trial compared to the nitrate trial (P < 0.05). Plasma and salivary [NO2−] were not different between the nitrate and nitrate + iodide trials (P > 0.05). Systolic blood pressure was lower than control (112 ± 13 mmHg) in the nitrate (106 ± 13 mmHg) and nitrate + iodide (106 ± 11 mmHg) trials (P < 0.05), with no differences between the nitrate and nitrate + iodide trials (P > 0.05). In conclusion, co-ingesting NO3− and I− perturbed salivary NO3− uptake, but the increase in salivary and plasma [NO2−] and the lowering of blood pressure were similar compared to NO3− ingestion alone. Therefore, increased dietary I− intake, which is recommended in several countries worldwide as an initiative to offset hypothyroidism, does not appear to compromise the blood pressure reduction afforded by increased dietary NO3− intake
Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.
Get PDFRATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Evaluating the anti-tumour effects of physical activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance
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