Macrophage Involvement in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Comprehensive, Short Review

Antiresorptive agents such as bisphosphonates (BP) and denosumab are commonly prescribed for the management of primary bone malignancy, bone metastasis, osteoporosis, Paget disease, or other bone disorders. Medication-related osteonecrosis of the Jaws (MRONJ) is a rare but significant complication of antiresorptive medications. Duration, dose, and antiresorptive potency as well as concomitant diseases, additional medications, and local factors affect MRONJ incidence and severity. MRONJ pathophysiology is still poorly understood. Nevertheless, decreased bone resorption due to osteoclastic inhibition along with trauma, infection/inflammation, or blood supply inhibition are considered synergistic factors for disease development. In addition, previous data research examined the effects of antiresorptive medication on immune system components and introduced potential alterations on immune response as novel elements in MRONJ pathogenesis. Considering that macrophages are the first cells in the nonspecific immune response, it is not surprising that these multifaceted players attracted increased attention in MRONJ research recently. This current review attempted to elucidate the effects of antiresorptive medications on several aspects of macrophage activity in relation to the complex inflammatory microenvironment of MRONJ. Collectively, unravelling the mode of action and extent of macrophages’ potential contribution in MRONJ occurrence will provide novel insight in disease pathogenesis and potentially identify intrinsic therapeutic targets.

Enhancement of growth, antioxidative status, nonspecific immunity, and disease resistance in gibel carp (Carassius auratus) in response to dietary Flos populi extract

This study investigated the effects of dietary Flos populi extract (FPE) on the growth, antioxidation capability, innate immune response, and disease resistance in gibel carp. A total of 480 fish were fed with five different diets containing 0, 0.5, 1.0, 1.5, or 2.0 g kg−1 FPE (designated as control, D0.5, D1.0, D1.5, or D2.0 groups) for 45 days. The fish were challenged with A. hydrophila after the feeding trial. Compared with the control, the feed efficiency (FE), weight gain (WG), final body weight (FBW), and specific growth rate (SGR) were significantly improved in groups D1.0 and D1.5. Dietary FPE significantly increased serum superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) activities, as well as glutathione (GSH) content. The contents of protein carbonyl (PCC) and malondialdehyde (MDA) in serum decreased significantly. Additionally, FPE supplementation in diets resulted in significant improvement in serum lysozyme (LZM) and myeloperoxidase (MPO) activities, as well as immunoglobulin M (IgM) and complement 3 (C3) concentrations. The hepatic antioxidant enzymes (CAT and SOD) activities increased, whereas content of MDA decreased in fish treated with dietary FPE than those of control both pre- and post-challenged. After 12 h-challenge, an obvious downregulation of hepatic Kelch-like-ECH-associated protein 1 (Keap1), splenic tumor necrosis factor-α (TNF-α), interleukin (IL)-8, IL-1β, and toll-like receptor 2 (TLR2) mRNA levels was observed in fish treated with dietary FPE, whereas hepatic Nrf2 transcription level was upregulated compared to the control. Furthermore, compared to group D0.5, higher relative percent survival (RPS) was observed in gibel carp fed dietary 1.0–2.0 g/kg FPE. Our results reveal that FPE supplemented diet has a stimulatory effect on antioxidant capacity and nonspecific immune response, along with improved growth performance and enhanced resistance against A. hydrophila infection in juvenile gibel carp.

The Effect of Feed Supplementation with EM Bokashi® Multimicrobial Probiotic Preparation on Selected Parameters of Sow Colostrum and Milk as Indicators of the Specific and Nonspecific Immune Response

The aim of the study was to determine the effect of EM Bokashi® on selected parameters of the specific and nonspecific immune response of sows by in colostrum and milk samples. The percentage of cells with expression of CD19+, CD5+CD19+, CD21+, SWC3a (macrophage/monocyte), and CD11b+ molecules on the monocytes and granulocytes as well as the concentrations of lysozyme and acute phase proteins — serum amyloid-A (SAA) and haptoglobin (Hp) were evaluated. The study was carried out on a commercial pig farm, including 150 sows (Polish Large White × Polish Landrace) at the age of 2–4 years. Sixty female sows were divided into two groups: I — control and II — experimental. For the experimental group, a probiotic in the form of the preparation EM Bokashi® in the amount of 10 kg/tonne of feed was added to the basal feed from mating to weaning. The material for the study consisted of colostrum and milk. The samples were collected from all sows at 0, 24, 48, 72, 96, 120, 144, and 168 h after parturition. The study showed that exposure of the pregnant sow to the probiotic microbes contained in EM Bokashi® significantly affects the immunological quality of the colostrum and milk and caused an increase in the percentage of the subpopulations of B cells with CD19+, CD21+, and CD5+CD19+ expression in the colostrum and milk, which demonstrates an increase in the protective potential of colostrum and indicates stimulation of humoral immune mechanisms that protect the sow and the piglets against infections.

Synbiotic Effects of Saccharomycescerevisiae, Mannan Oligosaccharides, and β-glucan on Innate Immunity, Antioxidant Status, and Disease Resistance of Nile Tilapia, Oreochromis niloticus

Synbiotic (SYN) additives were assessed as an antibiotic alternative on the effects on the nonspecific immune response and disease resistance of O. niloticus to P. aeruginosa. Healthy fish (n = 120, average initial weight 18 ± 2 g) were allotted randomly into four experimental groups (3 replicates for each); 1) a control group with no additives (CON), 2) basal diet complemented with 0.1 g kg–1 diets of norfloxacin, NFLX, 3) basal diet fortified with 1 mL kg–1 diet of SYN, and 4) basal diet complemented with a mixture of NFLX and SYN, which was carried out for eight weeks. Results showed a significant increase (p < 0.01) in the serum immune parameters (total protein, globulin and albumin, nitric oxide (NO), and lysozyme activity) in the SYN group and the NFLX+SYN group compared with the CON and NFLX groups. The serum glucose, cholesterol, and triglycerides were higher in NFLX and NFLX+SYN groups than the CON and SYN groups. The catalase (CAT), superoxide dismutase, glutathione peroxidase (GPX) activities were significantly augmented in the NFLX+SYN group, followed by the SYN group compared with CON and NFLX groups. The cumulative mortality rate (CMR) of O. niloticus following the P. aeruginosa challenge was decreased in the SYN group compared to other groups. The results emphasize that synbiotic could be used as a norfloxacin alternative to enhance the related immunological parameters, including antioxidant activity and disease resistance against P. aeruginosa infection of O. niloticus.

IMMU-18. FAVORABLE OUTCOME IN REPLICATION REPAIR DEFICIENT HYPERMUTANT BRAIN TUMORS TO IMMUNE CHECKPOINT INHIBITION: AN INTERNATIONAL RRD CONSORTIUM REGISTRY STUDY

Pediatric brain tumors with replication repair deficiency (RRD) are hypermutant and may respond to immune checkpoint inhibition (ICI). We performed a consortium registry study of ICI in recurrent RRD cancers. Clinical and companion biomarkers were collected longitudinally on all patients. Biomarkers included tumor mutational burden (TMB), neoantigens and genetic signatures obtained from whole genome and exome sequencing. Immune inference was obtained by RNAseq and T cell rearrangement was collected in the tumor and in blood throughout treatment. Of the 46 tumors on the study, 32 were brain tumors with glioblastoma in 96%. Rapid, objective responses (&gt;50%) were observed in 50% of glioblastomas. Three year overall survival for the whole cohort was 48+/-8% which compares favorably with historical controls. Brain tumors fared worse with OS of 39+/-10% and late recurrences observed even after 2 years of therapy (p=0.02). Tumor size and acute “flare” constitute poor outcome throughout all cancers. While all tumors are hypermutant, TMB and predicted neoantigens correlated with response to ICI (p=0.02). Specific signatures extracted from SNVs and total mutations predicted response to ICI and favorable outcome (p=0.005). RNA inference and TCR reveal that the FLARE phenotype is mostly acute nonspecific immune response and not true progression. Finally, glioblastomas (n=8) which failed single agent ICI had favorable responses to combinational immunotherapies with prolonged survival of 65%+/-8% at one year after failure vs 0 for other patients (p=0.01). RRD glioblastomas exhibit favorable outcome and responses to ICI. Combinational therapies based on tumor and immune signatures of these cancers are necessary.

Peningkatan Respon Kebal Non-spesifik dan Pertumbuhan Ikan Nila (Oreochromis niloticus) Melalui Pemberian Jahe, Zingiber officinale

The purpose of this research was to evaluate the effect ginger supplemented in food on nonspecific immune response of nile tilapia. Juveniles with an average of weight of 27.31 g were obtained from Fish Culture and Development Board (BP3I) Tateli and then transported to Faculty of Fisheries and Marine Science. Fish were then cultured in 15 aquaria with a density of 15 fish per aquarium. Each aquarium was equipped with an aerator and used water recirculation system to keep the water quality still in good condition. After adaption for one weeks, fish was fed pellet supplemented with ginger powder as treatments at five different doses including A=0, B=2,5, C=5, D=7,5, and E=10 g/kg, each with three replications. Fish was fed as long as four weeks at 3%/bw/d, twice daily at 08.00 am and 17.00 pm. Data consisting of total leucocyte count and phagocytosis activity of phagocyte cells were collected at two weeks interval. Research results showed that supplementation of ginger powder into fish pellet had significant effect on the increase of nonspecific immune response. The highest total leucocyte count and phagocytosis activity of phagocyte cells was observed on fish fed pellet supplemented with 7.5 g/kg of food and significantly different as compared to those of control fish. As conclusion, supplementation of ginger powder into fish pellet could increase nonspecific immune response on nile tilapia. Keywords: Ginger, nonspecific immune response, total leucocytes count, phagocytosis activity, nile tilapia

Monocytes and cancer: promising role as a diagnostic marker and application in therapy

Interrelationship between a malignant tumor and the immunity are provided by the involvement of both adaptive and innate immune systems. Monocytes are major participants in nonspecific immune response and mediate their key function through refilling the pool of tumor-associated macrophages, dendritic cells and myeloid suppressor cells. All these populations regulate the relationship of tumor-infiltrating immunocompetent cells with tumor cells and with other components of the microenvironment, as well as tumor cell proliferation, angiogenesis, and dissemination. Monocytes, being direct participants of the chronic persistent inflammation, are involved in the inflammation impact on both tumor origin and progression. The study of the molecular mechanisms of monocyte recruitment and differentiation in malignant neoplasms seems to be a promising direction, both for a diagnostic purpose and as a search for targeting molecules for the control of macrophages and dendritic cells in the tumor microenvironment. In this review, the characteristics of peripheral blood monocytes are given, taking into account the heterogeneity of their population. Tie2+ cells and macrophage-polarized CD163+ and CD204+ -monocytes, as well as cancer-associated macrophage-like cells (CAMLs), are described as contributors to cancer disease progression and outcome. The involvement of monocyte subpopulations in the pathogenesis of oncological diseases of different localizations at the stages of the formation of monocyte precursors in the bone marrow, circulation in peripheral blood and differentiation in tumor tissue is shown.