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1.
The Effect of Inflammation on Bone.
Epsley, S, Tadros, S, Farid, A, Kargilis, D, Mehta, S, Rajapakse, CS
Frontiers in physiology. 2020;:511799
Abstract
Bone remodeling is the continual process to renew the adult skeleton through the sequential action of osteoblasts and osteoclasts. Nuclear factor RANK, an osteoclast receptor, and its ligand RANKL, expressed on the surface of osteoblasts, result in coordinated control of bone remodeling. Inflammation, a feature of illness and injury, plays a distinct role in skewing this process toward resorption. It does so via the interaction of inflammatory mediators and their related peptides with osteoblasts and osteoclasts, as well as other immune cells, to alter the expression of RANK and RANKL. Such chemical mediators include TNFα, glucocorticoids, histamine, bradykinin, PGE2, systemic RANKL from immune cells, and interleukins 1 and 6. Conditions, such as periodontal disease and alveolar bone erosion, aseptic prosthetic loosening, rheumatoid arthritis, and some sports related injuries are characterized by the result of this process. A thorough understanding of bone response to injury and disease, and ability to detect such biomarkers, as well as imaging to identify early structural and mechanical property changes in bone architecture, is important in improving management and outcomes of bone related pathology. While gut health and vitamin and mineral availability appear vitally important, nutraceuticals also have an impact on bone health. To date most pharmaceutical intervention targets inflammatory cytokines, although strategies to favorably alter inflammation induced bone pathology are currently limited. Further research is required in this field to advance early detection and treatments.
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2.
β-Glucan Metabolic and Immunomodulatory Properties and Potential for Clinical Application.
Murphy, EJ, Rezoagli, E, Major, I, Rowan, NJ, Laffey, JG
Journal of fungi (Basel, Switzerland). 2020;(4)
Abstract
β-glucans are complex polysaccharides that are found in several plants and foods, including mushrooms. β-glucans display an array of potentially therapeutic properties. β-glucans have metabolic and gastro-intestinal effects, modulating the gut microbiome, altering lipid and glucose metabolism, reducing cholesterol, leading to their investigation as potential therapies for metabolic syndrome, obesity and diet regulation, gastrointestinal conditions such as irritable bowel, and to reduce cardiovascular and diabetes risk. β-glucans also have immune-modulating effects, leading to their investigation as adjuvant agents for cancers (solid and haematological malignancies), for immune-mediated conditions (e.g., allergic rhinitis, respiratory infections), and to enhance wound healing. The therapeutic potential of β-glucans is evidenced by the fact that two glucan isolates were licensed as drugs in Japan as immune-adjuvant therapy for cancer in 1980. Significant challenges exist to further clinical testing and translation of β-glucans. The diverse range of conditions for which β-glucans are in clinical testing underlines the incomplete understanding of the diverse mechanisms of action of β-glucans, a key knowledge gap. Furthermore, important differences appear to exist in the effects of apparently similar β-glucan preparations, which may be due to differences in sources and extraction procedures, another poorly understood issue. This review will describe the biology, potential mechanisms of action and key therapeutic targets being investigated in clinical trials of β-glucans and identify and discuss the key challenges to successful translation of this intriguing potential therapeutic.
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3.
Magnitude of underweight, wasting and stunting among HIV positive children in East Africa: A systematic review and meta-analysis.
Abate, BB, Aragie, TG, Tesfaw, G
PloS one. 2020;(9):e0238403
Abstract
BACKGROUND Malnutrition on the background of HIV (Human Immunodeficiency Virus) infection is a complex medical condition that carries significant morbidity and mortality for affected children, with greater mortality from SAM (Severe Acute Malnutrition) among HIV-positive children than their HIV-negative peers. HIV-induced immune impairment heightened risk of opportunistic infection and can worsen nutritional status of children. HIV infection often leads to nutritional deficiencies through decreased food intake, mal-absorption and increased utilization and excretion of nutrients, which in turn can hasten death. OBJECTIVE The aim of this systematic review and meta-analysis was to assess the magnitude of underweight, wasting and stunting among HIV positive children in East Africa. METHODS The authors systematically reviewed and meta-analyzed studies that assessed the prevalence of underweight, wasting and stunting among HIV positive children in East Africa from PubMed, Cochrane Library, Google Scholar, and Gray Literatures using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guideline. The last search date was December 30/2019. The data was extracted in excel sheet considering country, study design, year of publication, prevalence reported. Then the authors transformed the data to STATA 14 for analysis. Heterogeneity across the studies was assessed by the Q and the I2 test. A weighted inverse variance random-effects model was used to estimate the magnitude of underweight, wasting and stunting. The subgroup analysis was done by country, year of publication, and study design. To examine publication bias, a funnel plot and Egger's regression test were used. RESULTS For the analysis a total of 22 studies with 22074 patients were used. The pooled prevalence of under-weight, wasting, and stunting among HIV positive children in East Africa was found to be 41.63% (95%CI; 35.69-47.57; I2 = 98.7%; p<0.001), 24.65% (95%CI; 18.34-30.95; I2 = 99.2%; p<0.001), and 49.68% (95%CI; 42.59-56.77; I2 = 99.0%; p<0.001) respectively. The prevalence of under-weight among HIV positive children was found to be 49.67% in Ethiopia followed by 42.00 in Rwanda. It was high among cohort studies (44.87%). Based on the year of publication, the prevalence of under-weight among HIV positive children was found to be 40.88% from studies conducted from January 2008-December 2014, while it was 43.68% from studies conducted from 2015-2019. The prevalence of wasting among HIV positive children was found to be 29.7% in Tanzania followed by 24.94% in Ethiopia. Based on the study design, the prevalence of wasting among HIV positive children was found to be high in cohort studies (31.15%). The prevalence of stunting among HIV positive children was found to be 51.63% in Ethiopia, followed by 48.21% in Uganda. CONCLUSIONS The results presented above provide evidence of a higher prevalence of under nutrition among HIV positive children in East Africa. Despite the country level variations of child under nutrition in East Africa, still it is high in all aspects compared to the studies from other parts of Africa. It is recommended that further systematic review and meta-analysis need to be conducted on magnitude of malnutrition among HIV positive children in Sub-Saharan Africa as a whole.
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4.
Ramadan intermittent fasting and immunity: An important topic in the era of COVID-19.
Faris, MAE, Salem, ML, Jahrami, HA, Madkour, MI, BaHammam, AS
Annals of thoracic medicine. 2020;(3):125-133
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Abstract
WITH the growing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome (SARS)-related coronavirus (SARS-CoV-2) infection, a parallel growing interest arose concerning potential preventive and adjunct therapies, dietary and lifestyle modifications, and remedies that may boost the immunity against SARS-CoV-2 infection. Furthermore, as Ramadan intermittent religious fasting that is practiced by about one and a half billion Muslims throughout the globe is coincide this year with COVID-19 pandemic, a growing debate rose concerning the expected impact of fasting during Ramadan month and the associated dietary and lifestyle behaviors on the body's immunity against the pandemic infection. Published literature was searched to find out how intermittent fasting (IF) and its model of Ramadan affect the various aspects related to the body's immunity against microbial infections. IF was found to impact immunity by changing different related elements, including oxidative stress and inflammation, metabolism, body weight, and body composition. Dietary and lifestyle modifications during Ramadan month and their impact on immunity, such as water intake and hydration status, sleep duration and timing, caloric intake and mealtime, and social and spirtual activities, were addressed. Further research is warranted to figure out how IF during ramadan affects immunity against SARS-CoV-2 infection.
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5.
Current Understanding of the Mechanisms Underlying Immune Evasion From PD-1/PD-L1 Immune Checkpoint Blockade in Head and Neck Cancer.
Kok, VC
Frontiers in oncology. 2020;:268
Abstract
Starting in 2014, large phase III clinical trials began to disclose the study results of using programmed death (PD)-1 immune checkpoint inhibitors (ICIs) (pembrolizumab, nivolumab) and PD-ligand (L)1 (atezolizumab, durvalumab, avelumab) ICIs immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). In the recurrent and metastatic (R/M), cisplatin-refractory setting, nivolumab achieved a 2.2-fold increase of the median 1-year overall survival as compared with investigators' choice of salvage chemotherapy (36.0 vs. 16.6%). A paradigm shift to the winning regimen, pembrolizumab combined with platinum and infusional fluorouracil, has outperformed the past gold standard of cetuximab-based platinum and fluorouracil combination in terms of overall survival (median, 13.6 vs. 10.1 mo) when administered as the first-line treatment for R/M HNSCC. Nevertheless, many patients still did not respond to the PD-1/PD-L1 checkpoint inhibitor treatment, indicating innate, adapted, or quickly acquired resistance to the immunotherapy. The mechanisms of resistance to ICIs targeting the PD-1/PD-L1 signaling pathway in the context of HNSCC are the focus of this review. The past 5 years have seen improved understanding of the mechanisms underlying checkpoint inhibition resistance in tumor cells, such as: tumor cell adaption with malfunction of the antigen-presenting machinery via class I human leukocyte antigen (HLA), reintroduction of cyclin D-cyclin-dependent kinase (CDK) 4 complex to cell cycles, enrichment of CD44+ cancer stem-like cells, or development of inactivating mutation in IKZF1 gene; impairment of T-cell functions and proliferation through mutations in the interferon-γ-regulating genes, suppression of the stimulator of interferon genes (STING) pathway, or resulted from constitutional nutritional iron deficiency state; metabolic reprogramming by cancer cells with changes in metabolites such as GTP cyclohydrolase 1, tetrahydrobiopterin, kynurenine, indoleamine 2,3-dioxygenase, and arginase 1; defective dendritic cells, CD-69 sufficient state; and the upregulation or activation of the alternative immune checkpoints, including lymphocyte activation gene-3 (LAG3), T-cell immunoglobulin and ITIM domain (TIGIT)/CD155 pathway, T-cell immunoglobulin mucin-3 (TIM-3), and V domain-containing Ig suppressor of T-cell activation (VISTA). Several potential biomarkers or biosignatures, which could predict the response or resistance to the PD-1/PD-L1 checkpoint immunotherapy, are also discussed.
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6.
What about glucocorticoids in primary Sjögren's syndrome?
Priori, R, Mastromanno, L, Izzo, R
Clinical and experimental rheumatology. 2020;(4):237-244
Abstract
Glucocorticoids (GCs) are involved in several physiological processes such as metabolism, water and electrolyte balance, growth, cardiovascular and cognitive functions, reproduction. Furthermore, they exert different effects on innate and adaptive immune cells. Due to their anti-inflammatory and immunosuppressive functions, these drugs are largely used for the treatment of inflammatory and autoimmune diseases. In comparison to other autoimmune rheumatic diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), to date no reliable evidence is available for the use of systemic GCs in Sjögren's syndrome (SS), which is still based on case reports, case studies, retrospective or prospective studies and a small number of randomised controlled trials (RCTs). Despite this gap in our knowledge, GCs are commonly used in SS for glandular, joint, cutaneous, lung, haematological, renal, neurological involvement. More recently, some sets of recommendations for the management of SS have provided a few pieces of advice regarding the use of GCs in this condition. Future studies should not neglect the role of GCs, as this traditional therapeutic weapon can still have a role in the management of SS. Accordingly, this review will address and discuss the use of systemic GCs in isolated or primary SS.
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7.
Immune-Kynurenine Pathways and the Gut Microbiota-Brain Axis in Anxiety Disorders.
Evrensel, A, Ünsalver, BÖ, Ceylan, ME
Advances in experimental medicine and biology. 2020;:155-167
Abstract
Anxiety disorders are a complex set of illnesses in which genetic factors, particularly stress, play a role in the etiopathogenesis. In recent years, inflammation and intestinal microbiota have also been included in this complex network of relationships. The functions associated with tryptophan catabolism and serotonin biosynthesis have long been associated with anxiety disorders. Tryptophan catabolism progresses toward the path of the kynurenine in the presence of stress and inflammation. The catabolism of kynurenine is a pathway in which many enzymes play a role and a large number of catabolites with neuroactive properties occur. The body's serotonin biosynthesis is primarily performed by enterochromaffin cells located in the intestines. A change in the intestinal microbiota composition (dysbiosis) directly affects the serotonin biosynthesis. Stress, unhealthy nutrition, and the use of antibiotics cause dysbiosis. In the light of this new perspective, the role of dysbiosis-induced inflammation and kynurenine pathway catabolites activated sequentially come into prominence in the etiopathogenesis of anxiety disorders.
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Do the Bugs in Your Gut Eat Your Memories? Relationship between Gut Microbiota and Alzheimer's Disease.
Borsom, EM, Lee, K, Cope, EK
Brain sciences. 2020;(11)
Abstract
The human microbiota is composed of trillions of microbial cells inhabiting the oral cavity, skin, gastrointestinal (GI) tract, airways, and reproductive organs. The gut microbiota is composed of dynamic communities of microorganisms that communicate bidirectionally with the brain via cytokines, neurotransmitters, hormones, and secondary metabolites, known as the gut microbiota-brain axis. The gut microbiota-brain axis is suspected to be involved in the development of neurological diseases, including Alzheimer's disease (AD), Parkinson's disease, and Autism Spectrum Disorder. AD is an irreversible, neurodegenerative disease of the central nervous system (CNS), characterized by amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Microglia and astrocytes, the resident immune cells of the CNS, play an integral role in AD development, as neuroinflammation is a driving factor of disease severity. The gut microbiota-brain axis is a novel target for Alzheimer's disease therapeutics to modulate critical neuroimmune and metabolic pathways. Potential therapeutics include probiotics, prebiotics, fecal microbiota transplantation, and dietary intervention. This review summarizes our current understanding of the role of the gut microbiota-brain axis and neuroinflammation in the onset and development of Alzheimer's disease, limitations of current research, and potential for gut microbiota-brain axis targeted therapies.
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9.
First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE2-receptor E-type 4 (EP4), in patients with advanced cancers.
Hong, DS, Parikh, A, Shapiro, GI, Varga, A, Naing, A, Meric-Bernstam, F, Ataman, Ö, Reyderman, L, Binder, TA, Ren, M, et al
Journal for immunotherapy of cancer. 2020;(1)
Abstract
BACKGROUND E7046 is a highly selective, small-molecule antagonist of the E-type prostanoid receptor 4 (EP4) for prostaglandin E2, an immunosuppressive mediator of the tumor immune microenvironment. This first-in-human phase 1 study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, maximum tolerated dose (MTD) and recommended phase 2 dose of E7046. METHODS This first-in-human study enrolled 30 patients with advanced tumors of cancer types associated with high levels of myeloid infiltrates. E7046 was administered orally once-daily in sequential escalating dose cohorts (125, 250, 500, and 750 mg) with ≥6 patients per cohort. Tumor assessments were performed every 6 weeks. Paired tumor biopsies and blood samples, before and on treatment, were collected for pharmacokinetic and pharmacodynamic characterization of the treatment. RESULTS No dose-limiting toxicities were observed, and the MTD was not reached. E7046 had an elimination half-life (t1/2) of 12 hours, and drug exposure increased dose-dependently from 125 to 500 mg. Target modulation by E7046 was supported by changes in genes downstream of EP4 with concurrent enhanced antitumoral immune responses. A best response of stable disease (per irRECIST) was reported in 23% of patients treated with E7046 (n=30) (125 mg: n=2; 250 mg: n=2; 750 mg: n=3). Over half (4/7) of the patients with stable disease had treatment duration of 18 weeks or more, and three patients (3/15; 20%) achieved metabolic responses. CONCLUSIONS In this first-in-human study, E7046 administered orally once daily demonstrated manageable tolerability, immunomodulatory effects, and a best response of stable disease (≥18 weeks) in several heavily pretreated patients with advanced malignancies. The 250 and 500 mg doses are proposed for further development in the combination setting. TRIAL REGISTRATION NUMBER NCT02540291.
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10.
Tumor Cell-Intrinsic Immunometabolism and Precision Nutrition in Cancer Immunotherapy.
Cuyàs, E, Verdura, S, Martin-Castillo, B, Alarcón, T, Lupu, R, Bosch-Barrera, J, Menendez, JA
Cancers. 2020;(7)
Abstract
One of the greatest challenges in the cancer immunotherapy field is the need to biologically rationalize and broaden the clinical utility of immune checkpoint inhibitors (ICIs). The balance between metabolism and immune response has critical implications for overcoming the major weaknesses of ICIs, including their lack of universality and durability. The last decade has seen tremendous advances in understanding how the immune system's ability to kill tumor cells requires the conspicuous metabolic specialization of T-cells. We have learned that cancer cell-associated metabolic activities trigger shifts in the abundance of some metabolites with immunosuppressory roles in the tumor microenvironment. Yet very little is known about the tumor cell-intrinsic metabolic traits that control the immune checkpoint contexture in cancer cells. Likewise, we lack a comprehensive understanding of how systemic metabolic perturbations in response to dietary interventions can reprogram the immune checkpoint landscape of tumor cells. We here review state-of-the-art molecular- and functional-level interrogation approaches to uncover how cell-autonomous metabolic traits and diet-mediated changes in nutrient availability and utilization might delineate new cancer cell-intrinsic metabolic dependencies of tumor immunogenicity. We propose that clinical monitoring and in-depth molecular evaluation of the cancer cell-intrinsic metabolic traits involved in primary, adaptive, and acquired resistance to cancer immunotherapy can provide the basis for improvements in therapeutic responses to ICIs. Overall, these approaches might guide the use of metabolic therapeutics and dietary approaches as novel strategies to broaden the spectrum of cancer patients and indications that can be effectively treated with ICI-based cancer immunotherapy.