Post-transcriptional circadian regulation in macrophages organizes temporally distinct immunometabolic states.

Our core timekeeping mechanism, the circadian clock, plays a vital role in immunity. Although the mechanics of circadian control over the immune response is generally explained by transcriptional activation or repression derived from this clock's transcription-translation negative-feedback loop, research suggests that some regulation occurs beyond transcriptional activity. We comprehensively profiled the transcriptome and proteome of murine bone marrow-derived macrophages and found that only 15% of the circadian proteome had corresponding oscillating mRNA, suggesting post-transcriptional regulation influences macrophage clock regulatory output to a greater extent than any other tissue previously profiled. This regulation may be explained by the robust temporal enrichment we identified for proteins involved in degradation and translation. Extensive post-transcriptional temporal-gating of metabolic pathways was also observed and further corresponded with daily variations in ATP production, mitochondrial morphology, and phagocytosis. The disruption of this circadian post-transcriptional metabolic regulation impaired immune functionality. Our results demonstrate that cell-intrinsic post-transcriptional regulation is a primary driver of circadian output in macrophages and that this regulation, particularly of metabolic pathways, plays an important role in determining their response to immune stimuli.

Circadian disruption in lung fibroblasts enhances NF-κB activity to exacerbate neutrophil recruitment.

Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung-specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro-inflammatory cytokine IL-1ß and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1-/- lung fibroblasts also displayed increased Cxcl5 expression under IL-1ß stimulation. Conditioned media obtained from IL-1ß-stimulated Bmal1-/- immortalized fibroblasts-induced greater neutrophil migration compared with Bmal1+/+ lung fibroblast controls. Phosphorylation of the NF-κB subunit, p65, was enhanced in IL-1ß-stimulated Bmal1-/- lung fibroblasts, and pharmacological inhibition of NF-κB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF-κB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response.

CUTANEOUS MYIASIS AND ITS RELATIONSHIP TO WELLNESS IN EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA) IN CAPE COD, MASSACHUSETTS.

Eastern box turtles (Terrapene carolina carolina) face a variety of anthropogenic, infectious, and environmental threats and have been affected by high morbidity and mortality disease events. Wellness parameters in free-ranging eastern box turtles with a high prevalence of myiasis on Cape Cod, MA, were documented to identify epidemiologic trends or associations with several health parameters. There were 109 samples collected from 59 individual box turtles over the course of 4 mon. Six turtles died over the course of this study. Fly larvae infestations varied in severity and were observed in the cutaneous and subcutaneous tissue (n = 18; 30.5%). Animals with myiasis had fewer plastron abnormalities than those without (P = 0.034), and all turtles found in bogs had evidence of fly larvae infections (P < 0.0001). Individuals with myiasis also had lower body condition index (P = 0.014), lower total white blood cells (P = 0.031), lower PCV (P < 0.0001), lower total solids (P < 0.0001), higher erythrocyte sedimentation rate (P < 0.0001), lower calcium (P = 0.018), and lower phosphorus (P = 0.017). Three turtles tested positive for terrapene herpesvirus 1, but presence was not associated with myiasis. Heavy metal analysis revealed no significant differences between turtles with and without myiasis. This study examined the health of a population of eastern box turtles, and continued health assessments will be beneficial in determining the impact of myiasis on future conservation plans.

Alterations in mitochondrial morphology as a key driver of immunity and host defence.

Mitochondria are dynamic organelles whose architecture changes depending on the cell's energy requirements and other signalling events. These structural changes are collectively known as mitochondrial dynamics. Mitochondrial dynamics are crucial for cellular functions such as differentiation, energy production and cell death. Importantly, it has become clear in recent years that mitochondrial dynamics are a critical control point for immune cell function. Mitochondrial remodelling allows quiescent immune cells to rapidly change their metabolism and become activated, producing mediators, such as cytokines, chemokines and even metabolites to execute an effective immune response. The importance of mitochondrial dynamics in immunity is evident, as numerous pathogens have evolved mechanisms to manipulate host cell mitochondrial remodelling in order to promote their own survival. In this review, we comprehensively address the roles of mitochondrial dynamics in immune cell function, along with modulation of host cell mitochondrial morphology during viral and bacterial infections to facilitate either pathogen survival or host immunity. We also speculate on what the future may hold in terms of therapies targeting mitochondrial morphology for bacterial and viral control.

Dysregulated haemostasis in thrombo-inflammatory disease.

Inflammatory disease is often associated with an increased incidence of venous thromboembolism in affected patients, although in most instances, the mechanistic basis for this increased thrombogenicity remains poorly understood. Acute infection, as exemplified by sepsis, malaria and most recently, COVID-19, drives 'immunothrombosis', where the immune defence response to capture and neutralise invading pathogens causes concurrent activation of deleterious prothrombotic cellular and biological responses. Moreover, dysregulated innate and adaptive immune responses in patients with chronic inflammatory conditions, such as inflammatory bowel disease, allergies, and neurodegenerative disorders, are now recognised to occur in parallel with activation of coagulation. In this review, we describe the detailed cellular and biochemical mechanisms that cause inflammation-driven haemostatic dysregulation, including aberrant contact pathway activation, increased tissue factor activity and release, innate immune cell activation and programmed cell death, and T cell-mediated changes in thrombus resolution. In addition, we consider how lifestyle changes increasingly associated with modern life, such as circadian rhythm disruption, chronic stress and old age, are increasingly implicated in unbalancing haemostasis. Finally, we describe the emergence of potential therapies with broad-ranging immunothrombotic functions, and how drug development in this area is challenged by our nascent understanding of the key molecular and cellular parameters that control the shared nodes of proinflammatory and procoagulant pathways. Despite the increasing recognition and understanding of the prothrombotic nature of inflammatory disease, significant challenges remain in effectively managing affected patients, and new therapeutic approaches to curtail the key pathogenic steps in immune response-driven thrombosis are urgently required.

A systematic review of temporal body weight and dietary intake patterns in adults: implications on future public health nutrition interventions to promote healthy weight.

PURPOSE: The global prevalence of overweight remains high; effective strategies that consider patterns of body weight changes to identify periods when adults are susceptible to weight gain are warranted. This systematic review aimed to investigate body weight patterns, and how they were associated with dietary intake and/or dietary behaviours (Prospero CRD42020161977). METHODS: Systematic literature search was conducted in the Medline, Embase, and CINAHL databases until November 2020. Observational studies in adults (18 years and over) that reported at least two measurements of weight and dietary intake in a year were included. Risk of bias was conducted using the Evidence Analysis Library by the Academy of Nutrition and Dietetics tool. This review included 16 unique studies after title, abstract, and full-text screening, and findings were narratively synthesised. RESULTS: Of the six studies conducted in the farming populations, five were conducted in countries with two seasons (dry vs. rainy seasons) and all studies observed higher body weight during the dry season (up to 3.1 kg difference between seasons). The remaining study was conducted in a sub-tropical country and did not observe temporal weight patterns. Higher dietary intake was also reported during the dry season in the tropical countries. In non-farming populations (n = 10), temporal patterns were also seen, where higher body weight and adiposity was observed during colder seasons (autumn and winter). However, the opposite was found in a study conducted in Iran, where higher weight was seen in summer. Concurrent with higher body weight, higher energy, fat, carbohydrate and soda consumption, and lower fiber and vegetable intake were observed. CONCLUSION: Temporal weight and dietary patterns exist, and they were country- and context-specific; these patterns were also related to factors such as activity levels, seasons and occupation. Future interventions should consider temporal patterns in the design and delivery of timely and tailored dietary interventions to promote optimal body weight. PROSPERO REGISTRATION: PROSPERO Registration: CRD42020161977.

Circadian clock protein BMAL1 regulates IL-1ß in macrophages via NRF2.

A variety of innate immune responses and functions are dependent on time of day, and many inflammatory conditions are associated with dysfunctional molecular clocks within immune cells. However, the functional importance of these innate immune clocks has yet to be fully characterized. NRF2 plays a critical role in the innate immune system, limiting inflammation via reactive oxygen species (ROS) suppression and direct repression of the proinflammatory cytokines, IL-1ß and IL-6. Here we reveal that the core molecular clock protein, BMAL1, controls the mRNA expression of Nrf2 via direct E-box binding to its promoter to regulate its activity. Deletion of Bmal1 decreased the response of NRF2 to LPS challenge, resulting in a blunted antioxidant response and reduced synthesis of glutathione. ROS accumulation was increased in Bmal1-/- macrophages, facilitating accumulation of the hypoxic response protein, HIF-1α. Increased ROS and HIF-1α levels, as well as decreased activity of NRF2 in cells lacking BMAL1, resulted in increased production of the proinflammatory cytokine, IL-1ß. The excessive prooxidant and proinflammatory phenotype of Bmal1-/- macrophages was rescued by genetic and pharmacological activation of NRF2, or through addition of antioxidants. Our findings uncover a clear role for the molecular clock in regulating NRF2 in innate immune cells to control the inflammatory response. These findings provide insights into the pathology of inflammatory conditions, in which the molecular clock, oxidative stress, and IL-1ß are known to play a role.

Impaired Production and Diurnal Regulation of Vascular RvDn-3 DPA Increase Systemic Inflammation and Cardiovascular Disease.

RATIONALE: Diurnal mechanisms are central to regulating host responses. Recent studies uncovered a novel family of mediators termed as specialized proresolving mediators that terminate inflammation without interfering with the immune response. OBJECTIVE: Herein, we investigated the diurnal regulation of specialized proresolving mediators in humans and their role in controlling peripheral blood leukocyte and platelet activation. METHODS AND RESULTS: Using lipid mediator profiling and healthy volunteers, we found that plasma concentrations of n-3 docosapentaenoic acid-derived D-series resolvins (RvDn-3 DPA) were regulated in a diurnal manner. The production and regulation of these mediators was markedly altered in patients at risk of myocardial infarct. These changes were associated with decreased 5-lipoxygenase expression and activity, as well as increased systemic adenosine concentrations. We also found a significant negative correlation between plasma RvDn-3 DPA and markers of platelet, monocyte, and neutrophil activation, including CD63 and CD11b. Incubation of RvDn-3 DPA with peripheral blood from healthy volunteers and patients with cardiovascular disease significantly and dose-dependently decreased platelet and leukocyte activation. Furthermore, administration of RvD5n-3 DPA to ApoE-/- (apolipoprotein E deficient) mice significantly reduced platelet-leukocyte aggregates, vascular thromboxane B2 concentrations, and aortic lesions. CONCLUSIONS: These results demonstrate that peripheral blood RvDn-3 DPA are diurnally regulated in humans, and dysregulation in the production of these mediators may lead to cardiovascular disease.

Daily variation in macrophage phagocytosis is clock-independent and dispensable for cytokine production.

Innate immune responses vary in a circadian manner, and more recent investigations aim to understand the underlying molecular mechanisms. Cytokine production varies significantly over the course of a day depending on the time of stimulation by pathogens or Toll-like receptor ligands, and multiple signaling pathways linked to the cell-autonomous circadian clock modulate innate immunity. Recognition of foreign material, especially by innate immune cells, engages a myriad of receptors, which trigger inflammatory responses, as well as endocytosis and degradation and/or processing for antigen presentation. Because of the close connection between particle engulfment and inflammation, it has been proposed that phagocytic uptake may drive cytokine production in phagocytes. Here we show that bacterial particle ingestion by mouse peritoneal macrophages displays temporal variation, but is independent of the cell-intrinsic circadian clock in an ex vivo setting. Although cytokine production is dependent on phagocytosis, uptake capacity across 12 hr does not translate into 24-hr rhythms in cytokine production. In vivo, time-of-day variations in phagocytic capacity are not found, whereas a time of day and clock-dependent cytokine response is maintained. These data show that efficiency of bacterial phagocytosis and the 24-hr rhythmicity of cytokine production by macrophages are independent of one another and should be studied separately.

Bone Microdamage in Acute Knee Injury.

PURPOSE OF REVIEW: This review summarizes what is known about how bone tissue responds to microdamage, and how this applies to the subchondral region. This has significant relevance to acute joint injury, and is related to the occurrence of bone marrow lesions (BMLs) which are seen by MRI in 80% of acute knee joint injuries. Here, we review what is known about these phenomena (microcracks and BMLs) in the literature and discuss potential mechanisms by which they may be linked. RECENT FINDINGS: The recent findings in this field have shown that microcracks in bone initiate targeted remodeling via RANKL expression in osteocytes. Other work has shown that subchondral microcracks co-localize with BMLs as viewed by MRI. Finally, BMLs are associated with pain and structural joint degeneration. This paper demonstrates that subchondral microcracks likely occur during acute joint injury, and are closely linked to BML that are seem by clinical MRI and thus are potentially involved in the subsequent joint degeneration that occurs after injury.

Chrono-tailored drug delivery systems: recent advances and future directions.

Circadian rhythms influence a range of biological processes within the body, with the central clock or suprachiasmatic nucleus (SCN) in the brain synchronising peripheral clocks around the body. These clocks are regulated by external cues, the most influential being the light/dark cycle, in order to synchronise with the external day. Chrono-tailored or circadian drug delivery systems (DDS) aim to optimise drug delivery by releasing drugs at specific times of day to align with circadian rhythms within the body. Although this approach is still relatively new, it has the potential to enhance drug efficacy, minimise side effects, and improve patient compliance. Chrono-tailored DDS have been explored and implemented in various conditions, including asthma, hypertension, and cancer. This review aims to introduce the biology of circadian rhythms and provide an overview of the current research on chrono-tailored DDS, with a particular focus on immunological applications and vaccination. Finally, we draw on some of the key challenges which need to be overcome for chrono-tailored DDS before they can be translated to more widespread use in clinical practice.

The influence of pediatric cancer treatment on taste perception and food hedonics: a systematic review.

CONTEXT: Children with cancer are at risk of poor nutritional status during treatment and into survivorship. Objectively measured taste perception and self-reported food hedonics are 2 factors that may influence food intake. OBJECTIVE: This 2-armed systematic review examined whether chemotherapy and radiotherapy affect (1) taste perception and (2) hedonic experiences of children and survivors of childhood cancer. DATA SOURCE: A 2-armed systematic literature search was conducted in the Medline, CINAHL, Embase, and PsychInfo database until June 2022. The effects of cancer treatment on objective taste perception or food hedonics (ie, food liking or aversion and appetite) were examined. DATA EXTRACTION: Peer-reviewed articles published in English of studies that included children (aged <18 years) or survivors of childhood cancer (any age) were reviewed. Risk of bias was determined using the Evidence Analysis Library by the Academy of Nutrition and Dietetics. DATA ANALYSIS: A total of 1417 articles in the taste search arm and 3862 articles in the hedonics search arm were identified. Of these, 9 and 4 articles were eligible for review, respectively. Cancer treatment had highly variable effects on taste perception during treatment and into survivorship. Learned food aversions were experienced by children receiving chemotherapy treatment and liking of meats and salty foods by children with cancer was affected. The impact of treatment on appetite varied. CONCLUSIONS: Cancer treatment did not uniformly affect taste perception. Food liking may be negatively affected, and learned food aversions may develop during cancer treatment. To establish the clinical relevance of childhood cancer treatment on taste perception and food hedonics, more research is required. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no.CRD42020207127.

Access to nutrition services and information after active cancer treatment: a mixed methods study.

PURPOSE: Evidence-based guidelines for cancer strongly support nutrition and dietetic services for people with cancer and carers in order to improve patient-centred and health service outcomes. Access to nutrition services and information after completing active cancer treatment is relatively unknown in Australia. This study aimed to determine the availability, accessibility, barriers, and preferences to nutrition services and information after cancer treatment in Australia. METHODS: Utilising mixed methods, people with cancer and carers completed a cross-sectional survey, and a sub-group of participants completed a semi-structured interview. The survey evaluated the availability of nutrition services, nutrition information searched, barriers, and preferences for nutrition information. Semi-structured interviews explored participant experience with nutrition services and information. RESULTS: The 149 participants (including 10 carers) were predominately male and with a diagnosis of prostate cancer (63%). Overall, 23% of participants received nutrition information from a dietitian after cancer treatment. Participants (78%) indicated that accessing a nutrition specialist is the main barrier to receiving nutrition care after treatment. Most searched nutrition information on the internet (55%) and found the information easy to understand (89%), but conflicting (52%). Thematic analysis of interviews in fourteen cancer patients revealed three key themes pertaining to (1) preferred referral and timing of nutrition services, (2) lack of confidence in publicly available nutrition information, and (3) streamlining nutrition services for greater access. CONCLUSION: Access to a dietitian and evidence-based information after cancer treatment is limited for people with cancer and carers in Australia, despite the high interest and need for ongoing nutrition care. IMPLICATIONS FOR CANCER SURVIVORS: Models of care evaluating the provision of appropriate nutrition care and information provision after cancer treatment are needed to address this unmet survivorship need.

Exploring dietitians' practice and perspectives on the role of dietary patterns during cancer treatment: A qualitative study.

BACKGROUND: Dietitians are nutrition professionals equipped with specialised skills required to prevent and treat malnutrition in cancer. Optimisation of dietary intake is recommended as the primary nutrition strategy for the treatment of cancer-related malnutrition. However, it is unclear whether dietary patterns, described as the combination, quantity, and frequency of food consumption, are considered. This study examined dietitians' current food-based management of malnutrition; explored dietitians' awareness of dietary patterns and assessed barriers and enablers to the use of dietary patterns in clinical practice. METHODS: This qualitative study consisted of semi-structured interviews with oncology dietitians. Dietitians were recruited through national nutrition societies, social media, and professional networks. Audio-recorded interviews were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Fourteen oncology dietitians from across four Australian states and territories participated. Three themes were identified: (i) principles to guide nutritional care, (ii) dietary patterns as a gap in knowledge and practice, and (iii) opportunities for better care with systems as both a barrier and enabler. Dietetic practice was food-focussed, encouraging energy and protein-rich foods consistent with nutrient-focussed evidence-based guidelines. Dietitians encouraged one of two nutrition-related approaches, either encouraging intake of 'any tolerated food' or 'foods supportive on longer-term health'. Dietitians were generally unaware of dietary patterns and questioned their relevance in certain clinical situations. A multidisciplinary team approach, adequate food service and dissemination of dietary patterns research and education were identified as opportunities for better patient care. CONCLUSIONS: Recommendations for the treatment of malnutrition vary between oncology dietitians and uncertainty exists regarding dietary patterns and their relevance in clinical practice. Further exploration into the role of dietary patterns to treat cancer-related malnutrition and education for dietitians are required prior to implementation of a dietary patterns approach into clinical practice.

Dietary patterns linked to lower odds of malnutrition are associated with all-cause and cancer mortality in adults with cancer.

OBJECTIVES: Dietary patterns, characterised by protein, polyunsaturated fatty acids, and vitamin D, reduce the odds of malnutrition in cancer survivors. However, it is unclear whether these dietary patterns also improve prognosis. This study prospectively examined associations between dietary patterns linked to lower odds of malnutrition and the risk of all-cause and cancer mortality in adult cancer survivors from the UK Biobank cohort. DESIGN: Prospective observational study. SETTING AND PARTICIPANTS: Cancer survivors from the UK Biobank (mean ± SD, 7.1 ± 6.3 years since diagnosis) were included (n = 2415; 59.7 ± 7.1 years; 60.7% female). MEASUREMENTS: Dietary intake was estimated using the Oxford WebQ 24-h dietary assessment. Dietary patterns ('high oily fish and nuts', and 'low oily fish') were derived using reduced rank regression (response variables: protein (g/kg/day), polyunsaturated fatty acids (g/day) and vitamin D (µg/day)). Cox proportional hazard models estimated hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and cancer mortality. Nonlinear relationships were examined using restricted cubic splines. Models were adjusted for demographic and health characteristics. Sub-group analyses investigated relationships in sub-samples of adults with i) high nutritional risk (lung, gastrointestinal, haematological, or head and neck tumours) and ii) recent cancer diagnosis (cancer diagnosis within two years prior to assessment). RESULTS: Deaths due to all-causes (n = 305) and cancer (n = 249) were identified during a median 10.4 (IQR: 10.2-10.8) years follow-up. There were no statistically significant linear associations between the dietary patterns and all-cause or cancer mortality. However, a U-shaped association between the 'high oily fish and nuts' pattern, characterised by higher intake of oily fish and nuts and seeds, and all-cause mortality (p-non-linearity = 0.004) was identified, as well as with all-cause (p-non-linearity = 0.006) and cancer mortality (p-non-linearity = 0.035) in adults with a high nutritional risk cancer diagnosis (lung, gastrointestinal, haematological, or head and neck tumours), indicating that both above and below mean intake was associated with increased risk. The 'low oily fish' pattern, characterised by lower oily fish but higher potato intake, also had a non-linear association with all-cause mortality (p-non-linearity = 0.046) where lower but not higher than mean intake increased mortality risk. No dietary patterns were significantly associated with mortality in adults with a recent cancer diagnosis. CONCLUSION: 'High oily fish and nuts' or 'low oily fish' dietary patterns that were protective against malnutrition were associated with risk of all-cause and cancer mortality in adults with cancer. Future research should assess the efficacy of these dietary patterns in the acute treatment period when malnutrition is most prevalent.

Risk factors for low muscle mass, malnutrition, and (probable-) sarcopenia in adults with or without a history of cancer in the UK Biobank.

BACKGROUND AND AIMS: Early identification of people at risk of cancer-related malnutrition, low muscle mass (LMM) and sarcopenia is crucial to mitigate the impact of adverse outcomes. This study investigated risk factors associated with LMM, malnutrition and (probable-) sarcopenia and whether these varied in people with or without a history of cancer. METHODS: Participants in the UK Biobank, with or without a history of cancer, who completed the Oxford WebQ at the baseline assessment were included. LMM was estimated from fat-free mass derived from bioelectrical impedance analysis, and low muscle strength from handgrip strength, and used to identify probable or confirmed sarcopenia following the European Working Group on Sarcopenia in Older People 2 definition. The Global Leadership Initiative on Malnutrition criteria were applied to determine malnutrition. Generalised linear models were used to estimate prevalence ratios (PR) for associations between risk factors (clinical, functional, nutritional) and study outcomes. RESULTS: Overall, 50,592 adults with (n = 2,287, mean ± SD 59.7 ± 7.1 years) or without (n = 48,305, mean ± SD 55.8 ± 8.2 years) cancer were included. For all participants (PRs [cancer, without cancer]), slow walking pace (PR 1.85; 1.99), multimorbidity (PR 1.72; 1.51), inflammation (PR 2.91; 2.07), and low serum 25(OH)D (PR 1.85, 1.44) were associated with higher prevalence of LMM, while higher energy intake (PR 0.55; 0.49) was associated with lower prevalence. Slow walking pace (PR 1.54 [cancer], 1.51 [without cancer]) and higher protein intake (PR 0.18 [cancer]; 0.11 [without cancer]) were associated with increased or decreased prevalence of malnutrition, respectively regardless of cancer status. Multimorbidity was the only common factor associated with higher prevalence (PR 1.79 [cancer], 1.68 [without cancer]) of (probable-)sarcopenia in all participants. CONCLUSION: Risk factors for LMM and malnutrition were similar in adults with and without cancer, although these varied between LMM and malnutrition. These findings have implications for the future of risk stratification, screening and assessment for these conditions and the development or modification of existing screening tools.

Glycolytic reprogramming fuels myeloid cell-driven hypercoagulability.

BACKGROUND: Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease; however, its role in inflammation-induced hypercoagulability is poorly understood. OBJECTIVES: We aimed to evaluate the role of inflammation-associated metabolic reprogramming in regulating blood coagulation. METHODS: We used novel myeloid cell-based global hemostasis assays and murine models of immunometabolic disease. RESULTS: Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity through reduced plasminogen activator inhibitor 1 activity. Macrophage polarization or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and activated protein C generation compared with macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. CONCLUSION: Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thromboinflammatory disease.

Dietary patterns, malnutrition, muscle loss and sarcopenia in cancer survivors: findings from the UK Biobank.

PURPOSE: To identify dietary patterns derived from protein, polyunsaturated fatty acids (PUFA) and vitamin D and examine associations with malnutrition, low muscle mass and sarcopenia in cancer survivors. METHODS: This cross-sectional study included cancer survivors (n = 2415) from the UK Biobank (age [mean ± SD] 59.7 ± 7.1 years; 60.7% female). The Oxford WebQ 24-h dietary assessment estimated food and nutrient intakes. Reduced rank regression derived dietary patterns (response variables: protein [g/kg/day], PUFA [g/day] and vitamin D [µg/day]). Adjusted logistic regression analysis examined associations between dietary patterns and malnutrition, low muscle mass and sarcopenia. RESULTS: Three dietary patterns were identified: (i) 'high oily fish and nuts', characterised by higher oily fish and nuts and seeds intake; (ii) 'low oily fish', characterised by lower oily fish intake and higher potato intake; and (iii) 'meat and dairy', characterised by higher intake of meat, poultry and dairy. Eighteen percent of participants were malnourished, 5% had low muscle mass and 6.5% had sarcopenia. Odds of being malnourished were significantly lower with adherence to a 'high oily fish and nuts' pattern (OR: 0.57; 95% CI: 0.50, 0.65) and 'low oily fish' pattern (OR: 0.81; 95% CI: 0.73, 0.90). The 'meat and dairy' pattern was not associated with malnutrition. No dietary patterns were associated with low muscle mass or sarcopenia. CONCLUSIONS: Energy-rich dietary patterns were associated with lower odds of malnutrition in cancer survivors but did not influence muscle mass or sarcopenia risk. IMPLICATIONS FOR CANCER SURVIVORS: Better understanding of dietary patterns may improve cancer-related outcomes for cancer survivors.

Current Insights in Nutrition Assessment and Intervention for Malnutrition or Muscle Loss in People with Lung Cancer: A Narrative Review.

Up to 70% of people with lung cancer may be affected by cancer-related malnutrition or muscle loss, depending on treatment modality and disease stage. This narrative review explores recent studies on malnutrition and muscle loss as well as nutritional and multimodal interventions to treat these conditions in the context of the changing treatment landscape in lung cancer. Various types of interventions, including individualized counseling, protein and other specific nutrient supplementation, as well as multimodal interventions to treat malnutrition and muscle loss, have been investigated. Overall, individualized dietary counseling, increasing protein intake, and supplementation with omega-3 (n-3) fatty acids appear to be beneficial for some, albeit varying, patient outcomes. Multimodal interventions, generally including a nutrition and exercise component, show promising results; however, the impact on patient outcomes is mixed. A key finding of this review is a lack of large, randomized trials to guide nutrition intervention specifically in people with lung cancer. Despite the high prevalence of malnutrition and muscle loss in people with lung cancer and the known adverse outcomes, current evidence for nutrition intervention is limited. A targeted effort is required to improve the quality of evidence for nutrition intervention in this population to provide support for clinicians to deliver effective nutrition care.