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Aim. To assess the proportion and profile of patients at high risk of febrile neutropenia (FN) receiving cytotoxic chemotherapy (CT), as well as the incidence of FN and dose-limiting neutropenia after one cycle of CT. Materials and methods. The paper presents the results of the FLAME study, the first Russian observational study in patients with solid tumors who received only cytotoxic CT or a combination with targeted, immuno-oncological drugs. By random sampling, the study retrospectively included 500 patients with a median age of 59 years (18–83 years) from 25 medical institutions in the Russian Federation. Results. CT regimens with a high (20%) risk of FN were received by 25.2% (126/500) of patients; 53% (265/500) of patients had intermediate risk, and half of them (132/265 [49.8%]) had at least one additional risk FN factor following international NCCN guidelines. Thus, a high risk of FN, according to the therapy and the assessment of individual prognostic adverse factors, was noted in 51.6% (258/500) of patients. 36.8% (95/258) of patients with high risk for FN received primary prophylaxis with granulocyte colony-stimulating factors. Conclusion. The study showed a significant proportion of patients with a high risk of FN, and most of them do not receive primary prophylaxis of FN.

GM-CSF and M-CSF, the hematopoietic colony-stimulating factors, induce various phenotypic changes in macrophage lineage populations and promote cell differentiation, respectively, into M1- and M2-like macrophages. The pro- and anti-inflammatory properties of macrophages generated by these colony-stimulating factors are well described, but the contribution of differentiation and polarization signals to the fibromodulatory activity of macrophages remains unexplored. To clarify the differences in the fibrogenesis regulation mechanisms inherent in differently activated macrophages, we studied the effects of macrophage-conditioned media on proliferation and differentiation of dermal fibroblasts. In this study, the human macrophages generated from peripheral blood monocytes were investigated. They were induced for differentiation by M-CSF or GM-CSF, being further polarized in the M1 direction with lipopolysaccharide and, in the M2 direction, with IL-4 or dexamethasone. Proliferative response of the fibroblasts was determined radiometrically by [3H]-thymidine incorporation. Differentiation into myofibroblasts was determined with flow cytometry technique, as expression of a specific marker α-smooth muscle actin (α-SMA). The level of macrophage TGF-β1 production was assessed using an appropriate ELISA kit. The data obtained indicate that the macrophages differentiated under the influence of “homeostatic” M-CSF are characterized by a moderate stimulating effect upon fibroblast proliferation, and the effects of M2 (IL-4) and M2 (Dex) macrophages exceed that of M1 (LPS), but do not differ significantly from each other. The M-CSF-induced M1 (LPS) and M2 (IL-4) macrophages, but not M2 (Dex), enhance the fibroblast differentiation and show similar level of stimulation. In contrast to M-CSF, the macrophages induced by “pro-inflammatory” GM-CSF exhibit a pronounced stimulatory effect on fibroblast proliferation, and the effects of M2 macrophages exceed those of M1 cells, being most pronounced for M2 (Dex). At the same time, only GM-CSF-induced M2 (IL-4) macrophages enhance fibroblast differentiation. Dexamethasone-polarized macrophages do not significantly affect fibroblast differentiation regardless of the CSF used (M-CSF or GM-CSF). The content of TGF-β1 in the supernatants of differently activated macrophages does not correlate with the level of stimulating effect of macrophage-conditioned media upon fibroblast differentiation. In general, the data obtained suggest the involvement of differentiation and polarization signals into modulation of pro- and anti-fibrogenic properties of macrophages.

Febrile neutropenia is a serious chemotherapy-related adverse event that can lead to complications and death and it could be a significant burden on the organization of the health care system. The risk for febrile neutropenia is determined by chemotherapy-induced myelosuppression and the presence of patient-related risk factors. In the literature, various patient-related risk factors are taken into consideration. It was suggested that the patient age is the one of the most important ones. If the estimated risk for the febrile neutropenia is high, prophylactic use of myeloid growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor) is recommended. In patients with solid tumors and lymphomas it was shown that the prophylactic use of myeloid growth factors significantly reduces the incidence of febrile neutropenia, early mortality during chemotherapy and infection-induced mortality. In patients who develop febrile neutropenia, there is less evidence for the therapeutic use of myeloid growth factors compared to prophylactic use, although there is a clear benefit in reducing the time to neutrophil count recovery. There is a clear benefit for hospitalized patients, also, in reducing duration of hospitalization. In patients with febrile neutropenia who have not been previously treated with prophylactic myeloid factors, assessment of risk factors for the complications is advised. In patients with high-risk febrile neutropenia therapeutic use of growth should be considered.

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine/growth factor levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 h after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/control (CTRL) group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-α), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1α levels were lower than in vehicle (veh)/CTRL group. Notably, MIP-1α, TNF-α, keratinocyte derived chemokine (GRO/KC), GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, suggesting the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate MIA-induced inflammation. • MIA alters cytokine imbalance in maternal serum and fetal brain. • Fenofibrate partially rescues MIA-induced inflammation. • PPARα might be a therapeutic target to attenuate MIA-induced inflammation. [ABSTRACT FROM AUTHOR]

The porcine pathogen and zoonotic agent Streptococcus suis induces an exacerbated inflammation in the infected hosts that leads to sepsis, meningitis, and sudden death. Several virulence factors were described for S. suis of which the capsular polysaccharide (CPS) conceals it from the immune system, and the suilysin exhibits cytotoxic activity. Although neutrophils are recruited rapidly upon S. suis infection, their microbicidal functions appear to be poorly activated against the bacteria. However, during disease, the inflammatory environment could promote neutrophil activation as mediators such as the granulocyte colony-stimulating factor granulocyte (G-CSF) and the granulocyte-macrophages colony-stimulating factor (GM-CSF) prime neutrophils and enhance their responsiveness to bacterial detection. Thus, we hypothesized that CPS and suilysin prevent an efficient activation of neutrophils by S. suis, but that G-CSF and GM-CSF rescue neutrophil activation, leading to S. suis elimination. We evaluated the functions of porcine neutrophils in vitro in response to S. suis and investigated the role of the CPS and suilysin on cell activation using isogenic mutants of the bacteria. We also studied the influence of G-CSF and GM-CSF on neutrophil response to S. suis by priming the cells with recombinant proteins. Our study confirmed that CPS prevents S. suis-induced activation of most neutrophil functions but participates in the release of neutrophil-extracellular traps (NETs). Priming with G-CSF did not influence cell activation, but GM-CSF strongly promote IL-8 release, indicating its involvement in immunomodulation. However, priming did not enhance microbicidal functions. Studying the interaction between S. suis and neutrophils-first responders in host defense-remains fundamental to understand the immunopathogenesis of the infection and to develop therapeutical strategies related to neutrophils' defense against this bacterium., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bleuzé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Colony-stimulating factor 3 receptor (CSF3R) has been demonstrated to be associated with various hematological tumors, especially chronic neutrophilic leukemia; however, the detailed roles of CSF3R in other cancers remain to be explored., Methods: In the present study, we systematically analyzed the expression profiles of CSF3R in pan-cancer by comprehensive bioinformatics databases, such as Tumor Immune Estimation Resource, version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), etc. GEPIA2.0 was also used to analyze the relationship between CSF3R expression and patients' survival prognosis., Results: We found that the high expression of CSF3R was associated with a poor prognosis in the brain tumor patients, such as brain lower grade glioma and glioblastoma multiforme. In addition, we further investigated the genetic mutation and DNA methylation level of CSF3R in multiple cancers. Immune infiltration analysis showed that CSF3R expression was positively correlated with a variety of tumor-infiltrating immune cells in most cancers. Single cell sequencing indicated that CSF3R levels were correlated with several cancer-associated pathways, such as DNA damage, cell invasion, and stemness., Conclusions: Taken together, the role of CSF3R in multiple cancers might reveal its potential as a novel prognostic biomarker and therapeutic target for cancer patients., (© 2023 John Wiley & Sons Ltd.)

Antibiotic treatment may lead to side effects that require mechanistic explanation. We investigated the effect of azithromycin (AZM) treatment on bone marrow-derived macrophage (Mφ) generation, their functional output, and the subsequent effect on bacterial clearance in a mouse model of S. flexneri infection. To our fascination, AZM increased PU.1, C/EBPβ, CSF-1R/pCSF-1R expressions leading to M2-skewed in vitro BMDM generation. Altered Mφ-functions like- phagocytosis, oxidative stress generation, inflammasome-activation, cytokine release, and phenotype (pro-inflammatory-M1, anti-inflammatory-M2) even in the presence of infection were observed with AZM treatment. AZM increased CD206, egr2, arg1 (M2-marker) expression and activity while reducing CD68, inducible nitric oxide (iNOS) expression, and activity (M1-marker) in Mφs during infection. Pro-inflammatory cytokines (TNF-α, IL-12, IL-1β) were reduced and anti-inflammatory IL-10 release was augmented by AZM-treated-iMφs (aiMφs) along with decreased asc, nlrp3, aim2, nlrp1a, caspase1 expressions, and caspase3 activity signifying that aMφs/aiMφs were primed towards an anti-inflammatory phenotype. Interestingly, CSF-1R blockade increased NO, IL-12, TNF-α, IL-1β, decreased TGF-β release, and CD206 expression in aiMφs. T-cell co-stimulatory molecule cd40, cd86, and cd80 expressions were decreased in ai/aM1-Mφs and co-cultured CD8 + , CD4 + T-cells had decreased proliferation, t-bet, IFN-γ, IL-17, IL-2 but increased foxp3, TGF-β, IL-4 which were rescued with CSF-1R blockade. Thus AZM affected Mφ-functions and subsequent T-cell responses independent of its antibacterial actions. This was validated in the balb/c model of S. flexneri infection. We conclude that AZM skewed BMDM generation to anti-inflammatory M2-like via increased CSF-1R expression. This warrants further investigation of AZM-induced altered-Mφ-generation during intracellular infections., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Phthalates are common plasticizers present in medical-grade plastics and other everyday products. Di-ethylhexyl phthalate (DEHP) has been noted as a causative risk factor for the initiation and augmentation of cardiovascular functional disorders. G-CSF is a glycoprotein found in numerous tissues throughout the body and is currently applied in clinical practice and has been tested in congestive heart failure. We aimed to examine in depth the effect of DEHP on the histological and biochemical structure of the cardiac muscle in adult male albino rats and the mechanisms underlying the possible ameliorative effect of G-CSF. Forty-eight adult male albino rats were divided into control group, DEHP group, DEHP+ G-CSF group and DEHP-recovery group. We measured serum levels of aspartate aminotransferase (AST), creatine kinase MB isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Left ventricular sections were processed for light and electron microscope examination, and immunohistochemical staining of Desmin, activated Caspase-3 and CD34. DEHP significantly increased enzyme levels, markedly distorted the normal architecture of cardiac muscle fibers, downregulated Desmin protein levels and enhanced fibrosis, and apoptosis. G-CSF treatment significantly decreased the enzyme levels compared to DEHP group. It enhanced CD34 positive stem cells recruitment to injured cardiac muscle, therefore improved the ultrastructural features of most cardiac muscle fibers via anti-fibrotic and anti-apoptotic effects in addition to increased Desmin protein expression levels. The recovery group showed partial improvement due to persistent DEHP effect. In conclusion, administration of G-CSF effectively corrected the histopathological, immunohistochemical and biochemical alterations in the cardiac muscle after DEHP administration by stem cells recruitment, Desmin protein regulation, antifibrotic and antiapoptotic mechanisms., (© 2023. The Author(s).)

Prostate cancer remains a serious condition threatening the health of men. Due to the complicated nature of the tumour microenvironment (TME), conventional treatments face challenges including poor prognosis and tumour resistance, therefore new therapeutic strategies are urgently needed. Small interfering RNA (siRNA), a double-stranded non-coding RNA, regulates specific gene expression through RNA interference. Tumour-associated macrophages (TAMs) are a potential therapeutic target in cancer immunotherapy. Colony stimulating factor-1/colony stimulating factor-1 receptor (CSF-1/CSF-1R) signaling pathway plays a crucial role in the polarization of the immunosuppressive TAMs, M2 macrophages. Downregulation of CSF-1R is known to reprogram the immunosuppressive TAMs, M2 macrophages, to the immunostimulatory phenotype, M1 macrophages. Sialic acid is a ligand for Siglec-1 (CD169) which is overexpressed on M2 macrophages with little expression in other phenotypes. Therefore, a sialic acid-targeted cyclodextrin-based nanoparticle was developed to specifically deliver CSF-1R siRNA to M2 macrophages. The nanoparticles were studied in vitro using both human and mouse prostate cancer cell lines. Results show that the targeted nanoparticles achieved cell specific delivery to M2 macrophages via the sialic acid-CD169 axis. The expression of CSF-1R was significantly downregulated in M2 macrophages (29.64% for targeted vs 19.31% for non-targeted nanoparticles in THP-1-derived M2 macrophages and 38.94% for targeted vs 18.51% for non-targeted nanoparticles in RAW 264.7-derived M2 macrophages, n = 4, p < 0.01). The resulting reprograming of M2 macrophages to M1 enhanced the level of apoptosis in the prostate cancer cells in a Transwell model (49.17% for targeted vs 37.68% for non-targeted nanoparticles in PC-3 cells and 69.15% for targeted vs 44.73% for non-targeted nanoparticles in TRAMP C1 cells, n = 3, p < 0.01). Thus, this targeted cyclodextrin-based siRNA drug delivery system provides a potential strategy for prostate cancer immunotherapy., Competing Interests: Declarations of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that commonly manifests as cutaneous rashes, renal disease, gastrointestinal dysfunction, and cytopenia. Hematological anomalies are frequently associated with drug-induced toxicity in SLE patients. Colony-stimulating factors have been used to treat drug-induced cytopenia in past case reports; however, evidence suggests that colony-stimulating factors can exacerbate autoimmune disorders, including SLE. This case report presents two patients with SLE exacerbations after colony-stimulating factor administration. The first case is a young male with SLE who developed pancytopenia with a white blood cell count (WBC) of 1 × 10 9 cells/L. The patient was administered filgrastim during his initial admission and presented to the hospital 2 days after discharge in cardiac arrest with a WBC of 66.7 × 10 9 cells/L. The second case is a 49-year-old female with SLE who was administered sargramostim in response to a WBC count of 9 × 10 9 cells/L. The patient experienced a drastic increase in WBC followed by a cardiac arrest. These cases highlight the need for more research regarding the safe use of colony-stimulating factors in SLE patients.

Objective: In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments., Methods: Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein-protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools., Results: Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 ( Ptgs2 ), chemokine (C-X-C motif) ligand 2 ( Cxcl2 ), colony-stimulating factor 2 (granulocyte-macrophage) ( Csf2 ), matrix metallopeptidase 13 ( Mmp13 ), amphiregulin ( Areg ), plasminogen activator, urokinase receptor ( Plaur ), fos-like antigen 1 ( Fosl1 ), epiregulin ( Ereg ), activating transcription factor 3 ( Atf3 ), and transferrin receptor ( Tfrc ). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway., Conclusions: These pathways and DEGs may serve as targets for gene therapy.

Background: Few studies evaluated the post-endoscopic adverse events in patients with neutropenia. We investigated the development of infectious events after endoscopic procedures in neutropenic patients with hematologic diseases., Methods: Patients with neutropenia and hematologic diseases who underwent endoscopic procedures were enrolled. Neutropenia was defined as an absolute neutrophil count < 1500 cells/mm 3 and its severity was subdivided as mild, moderate (< 1000 cells/mm 3 ), and severe (< 500 cells/mm 3 ). Infectious events were defined as fever or bacteremia within 7 days after endoscopy. We assessed the development and risk factors of infectious events after endoscopic procedures., Results: We identified 528 procedures in 479 patients (51.0 ± 1.0 years). Antibiotics were used in 455 (95.0%) cases within 3 days of endoscopy. Infectious events were observed in 154 patients (32.2%): 22.9% in mild, 29.5% in moderate, and 43.1% in severe neutropenia. Fever developed in 147 cases (30.7%). Among patients with blood culture studies (n = 267), bacteremia was found in 22 cases (8.2%). In univariate analysis, patients with myelodysplastic syndrome, poor performance status, severe neutropenia, non-use of immunosuppressive drugs, and without history of hematopoietic stem cell transplantation and colony-stimulating factor use were positively correlated with infectious events. Poor performance status was the strongest factor for the development of infectious events in multivariate analysis (OR 10.3; 95% CI 4.4-23.3; P < 0.01)., Conclusions: Procedural invasiveness and severity of neutropenia did not appear to affect infectious events after endoscopic procedure with the use of antibiotics. Neutropenic patients who have poor performance status require careful evaluation for appropriate indications of endoscopic evaluation., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background & Aims: Despite remarkable advances in treatment, most patients with hepatocellular carcinoma (HCC) respond poorly to anti-programmed cell death 1 (anti-PD1) therapy. A deeper insight into the tolerance mechanism of HCC against this therapy is urgently needed., Methods: We performed next-generation sequencing, multiplex immunofluorescence, and dual-color immunohistochemistry and constructed an orthotopic HCC xenograft tumor model to identify the key gene associated with anti-PD1 tolerance. A spontaneously tumorigenic transgenic mouse model, an in vitro coculture system, mass cytometry, and multiplex immunofluorescence were used to explore the biological function of zinc finger protein 64 (ZFP64) on tumor progression and immune escape. Molecular and biochemical strategies like RNA-sequencing, chromatin immunoprecipitation-sequencing and mass spectrometry were used to gain insight into the underlying mechanisms of ZFP64., Results: We showed that ZFP64 is frequently upregulated in tumor tissues from patients with anti-PD1-resistant HCC. Elevated ZFP64 drives anti-PD1 resistance by shifting macrophage polarization toward an alternative activation phenotype (M2) and fostering an inhibitory tumor microenvironment. Mechanistically, we primarily demonstrated that protein kinase C alpha (PKCα) directly phosphorylates ZFP64 at S226, leading to its nuclear translocation and the transcriptional activation of macrophage colony-stimulating factor (CSF1). HCC-derived CSF1 transforms macrophages to the M2 phenotype to drive immune escape and anti-PD1 tolerance. Notably, Gö6976, a protein kinase inhibitor, and lenvatinib, a multi-kinase inhibitor, reset the tumor microenvironment and restore sensitivity to anti-PD1 by blocking the PKCα/ZFP64/CSF1 axis., Conclusions: We propose that the PKCα/ZFP64/CSF1 axis is critical for triggering immune evasion and anti-PD1 tolerance. Inhibiting this axis with Gö6976 or lenvatinib overcomes anti-PD1 resistance in HCC., Lay Summary: Despite remarkable treatment progress, most patients with hepatocellular carcinoma respond poorly to anti-PD1 therapy (a type of immunotherapy). A deeper insight into the tolerance mechanisms to this therapy is urgently needed. Herein, we unravel a previously unexplored mechanism linking tumor progression, macrophage polarization, and anti-PD1 resistance, and offer an attractive novel target for anti-PD1 combination therapy, which may benefit patients with hepatocellular carcinoma., Competing Interests: Conflicts of interest The authors have declared no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Colony-stimulating factors (CSFs) are glycoproteins that stimulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. But numerous studies have shown that these factors can stimulate the proliferation of non-hematopoietic cells, including cancer cells. Hence, in this study, Macrophage-CSF (M-CSF), macrophage-granulocyte CSF (GM-CSF), and granulocyte-SCF (G-CSF) were evaluated in the serum of patients with breast tumors and their relationship with pathological and paraclinical parameters of the disease. In this study, 62 patients with breast cancer who had not received any treatment and 54 healthy women who matched the age group with the patient group were included as a control group. After obtaining informed consent, 5ml of peripheral blood was taken from both groups, and their serum was isolated. Serum levels of the studied cytokines were measured by the cytokine-bead array method. Data were analyzed using SPSS18 software and a significance level of 0.05. The mean serum levels of M-CSF, G-CSF, and GM-CSF growth factors in patients with breast cancer were 63.48, 16.13, and 6.11pg/ml, respectively. Although the statistical analysis did not show a significant difference between serum levels of these growth factors in the patient and control groups (p <0.05), further studies showed that with increasing disease stages from I to III, serum levels of GM-CSF significantly. Decreases (p = 0.016). Overall, the results of this study indicated the antitumor role of GM-CSF in breast cancer. However, confirmation of these results requires more complete studies with larger sample sizes.

Periprosthetic joint infection (PJI), a devastating complication of total joint replacement, is of incompletely understood pathogenesis and may sometimes be challenging to clinically distinguish from other causes of arthroplasty failure. We characterized human gene expression in 93 specimens derived from surfaces of resected arthroplasties, comparing transcriptomes of subjects with infection- versus non-infection-associated arthroplasty failure. Differential gene expression analysis confirmed 28 previously reported potential biomarkers of PJI, including bactericidal/permeability increasing protein (BPI), cathelicidin antimicrobial peptide (CAMP), C-C-motif chemokine ligand 3 (CCL3), 4(CCL4) and C-X-C-motif chemokine ligand 2 (CXCL2), colony stimulating factor 2 receptor beta (CSF2RB), colony stimulating factor 3 (CSF3), alpha-defensin (DEFA4), Fc fragment of IgG receptor 1B (CD64B), intercellular adhesion molecule 1 (ICAM1), interferon gamma (IFNG), interleukin 13 receptor subunit alpha 2 (IL13RA2), interleukin 17D (IL17D), interleukin 1 (IL1A, IL1B, IL1RN), interleukin 2 receptors (IL2RA, IL2RG), interleukin 5 receptor (IL5RA), interleukin 6 (IL6), interleukin 8 (IL8), lipopolysaccharide binding protein (LBP), lipocalin (LCN2), lactate dehydrogenase C (LDHC), lactotransferrin (LTF), matrix metallopeptidase 3 (MMP3), peptidase inhibitor 3 (PI3), and vascular endothelial growth factor A (VEGFA), and identified three novel molecules of potential diagnostic use for detection of PJI, namely C-C-motif chemokine ligand CCL20, coagulation factor VII (F7), and B cell receptor FCRL4. Comparative analysis of infections caused by staphylococci versus bacteria other than staphylococci and Staphylococcus aureus versus Staphylococcus epidermidis showed elevated expression of interleukin 13 (IL13), IL17D, and MMP3 in staphylococcal infections, and of IL1B, IL8, and platelet factor PF4V1 in S. aureus compared to S. epidermidis infections. Pathway analysis of over-represented genes suggested activation of host immune response and cellular maintenance and repair functions in response to invasion of infectious agents. The data presented provides new potential targets for diagnosis of PJI and for differentiation of PJI caused by different infectious agents., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Although cancer-associated thrombosis (CAT) is relatively uncommon in breast cancer compared to other solid cancers, as breast cancer is the most commonly diagnosed cancer in women worldwide, the financial and personal cost of breast cancer associated thrombosis (BrCAT) is significant. This increasing risk of BrCAT over time parallels modern developments in breast cancer management. This review comprehensively reports the evidence for BrCAT in the context of modern breast cancer treatments. The risk of BrCAT is most pronounced within the first 3 months to year of diagnosis. The risk of BrCAT increases with operating time, paralleling the increasing frequency of immediate breast reconstruction. Systemic therapies such as chemotherapy and tamoxifen have well recognised thrombogenic effects, that are exacerbated by surgery and supplementary treatments such as colony-stimulating factors, steroids, and bisphosphonates however risk assessment tools are not designed specifically for this lower-VTE risk cancer. Cyclin-dependent kinases 4 and 6 (CDK4/6) Inhibitors, used in metastatic breast cancer, with trials ongoing in early disease, appear to have a class thrombogenic effect, although there is no increase CAT risk with other breast cancer targeted therapies. Given the numerous prothrombotic treatments facing patients within the first year of diagnosis, from surgery, chemotherapy, targeted therapies and endocrine therapy, a more personalised approach considering the additive effects of each individual patient's pathway, as well as their pre-existing risk factors, needs to be considered., (Copyright © 2021. Published by Elsevier Ltd.)

Tenosynovial giant cell tumor-diffuse type (diffuse TSGCT) is a benign but locally aggressive proliferative disorder of the synovium. Treatment is usually surgical, although in cases of extensive disease complete synovectomy is not possible and local recurrence rates are high. Pexidartinib (trade name Turalio®), a colony-stimulating factor-1 (CSF-1) inhibitor, was shown in a recent phase III trial to effectively treat diffuse TSGCT and is FDA approved for the treatment of adult patients with symptomatic diffuse TSGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Pexidartinib is available only through a restricted program under a risk evaluation and mitigation strategy (REMS) because of the risk of hepatotoxicity. Magnetic resonance imaging (MRI) is the preferred imaging modality for the diagnosis and surveillance of TSGCT. Here we present three patients with diffuse TSGCT of the knee who underwent multiple MRIs over several years while on pexidartinib. We describe the disease burden and signal characteristics on MRI and correlate with the response reported in the patients' medical records. Given that the use of pexidartinib and other CSF inhibitors is likely to increase, musculoskeletal radiologists should be aware of this novel non-operative treatment and the MRI appearance of diffuse TSGCT during therapy., (© 2021. ISS.)

Background and Objective: Colony-stimulating factor-1 receptor (CSF-1R) regulates myeloid cell function and mediates osteoclastogenesis. CSF-1R blockade has been suggested as a potential therapeutic target to halt inflammation and bone resorption; however, the expression and function of CSF-1R in human gingiva is yet unknown., Methods: Gingival tissue was collected from 22 non-periodontitis controls and 31 periodontitis (PD) patients. CSF-1R expression in gingival tissue was assessed with q-PCR, western blot, and immunohistochemistry (IHC). Cell surface expression of CSF-1R was analyzed by flow cytometry. The effects of CSF-1R inhibition on the production of inflammatory mediators by inflamed gingival tissue explants and peripheral blood mononuclear cells (PBMCs) were assessed with a bead-based multiplex array and ELISA., Results: CSF-1R protein expression was increased in gingival tissue from PD patients compared with controls as assessed with western blot (1.5-fold increase) and IHC (4.5-fold increase). Similar proportions of HLA-DR + CD64 + cells and comparable CSF-1R expression in this cell population were found in gingival tissue from PD patients and controls. In peripheral blood monocytes, CSF-1R was predominantly expressed by non-classical and intermediate monocytes. Targeting CSF-1R in gingival tissue explants attenuated the production of MMP-1, MMP-2, MMP-12, and MMP-13. The blocking in PBMCs attenuated the production of IL-8 and MMP-9., Conclusion: These results indicate that CSF-1R is elevated in PD, and its inhibition attenuates inflammatory mediators in the inflamed gingival tissue and circulating myeloid cells. Together these findings suggest that CSF-1R might be involved in regulating inflammatory processes in PD, and a potential therapeutic target to reduce the harmful inflammation., (© 2021 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.)