The triggering receptor expressed on myeloid cells 2-apolipoprotein E signaling pathway in diseases / 中华医学杂志(英文版)

Triggering receptor expressed on myeloid cells 2 (TREM2) is a membrane receptor on myeloid cells and plays an important role in the body's immune defense. Recently, TREM2 has received extensive attention from researchers, and its activity has been found in Alzheimer's disease, neuroinflammation, and traumatic brain injury. The appearance of TREM2 is usually accompanied by changes in apolipoprotein E (ApoE), and there has been a lot of research into their structure, as well as the interaction mode and signal pathways involved in them. As two molecules with broad and important roles in the human body, understanding their correlation may provide therapeutic targets for certain diseases. In this article, we reviewed several diseases in which TREM2 and ApoE are synergistically involved in the development. We further discussed the positive or negative effects of the TREM2-ApoE pathway on nervous system immunity and inflammation.

MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. MicroRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.

El caseinato de sodio y la caseína α inhiben la proliferación de la línea celular mieloide de ratón 32D clone 3 (32Dcl3) mediante el TNF-α / Sodium caseinate and alfa-casein inhibit proliferation of the mouse myeloid cell line 32D clone 3 (32Dcl3) via TNF-α

Resumen Introducción. Se ha demostrado que el caseinato de sodio y sus componentes (caseínas α, β y κ) inhiben la proliferación de la línea celular hematopoyética de ratón 32D clone 3 (32Dcl3) e inducen su diferenciación hacia macrófagos. Se sabe que la caseína α induce la producción de IL-1β y que esta última citocina inhibe la proliferación celular mediante la producción del factor de necrosis tumoral alfa (TNF-α), pero se desconoce si el caseinato de sodio y las caseínas inducen la producción de TNF y si este es el responsable de la inhibición de la proliferación. Objetivo. Evaluar si el caseinato de sodio y las caseínas α, β y κ inhiben la proliferación de la línea celular 32Dcl3 mediante la producción de TNF-α. Materiales y métodos. Se usaron diferentes concentraciones de caseinato de sodio y de las caseínas α, β y κ en las células 32Dcl3. Posteriormente, se evaluaron la viabilidad celular mediante una prueba con el MTT [3-(4,5-dimetiltiazol-2-ilo)-2,5-difeniltetrazol], la inducción de apoptosis con la citometría de flujo y la síntesis del TNF-α con el ELISA. Además, se hicieron pruebas de neutralización con anti-TNF-α en células 32Dcl3 tratadas con caseinato de sodio y caseína α, y se evaluó la proliferación celular. Resultados. Se encontró que el caseinato de sodio y las caseínas α, β y κ reducían la proliferación de la línea celular 32Dcl3 sin afectar la viabilidad, y que solo el caseinato y la caseína α inducían la apoptosis y la liberación al medio de TNF-α. La proliferación de células 32Dcl3 tratadas con caseinato y caseína α se restableció al usar anticuerpos anti-TNF-α. Conclusión. El TNF-α fue el principal responsable de la inhibición de la proliferación en las células 32Dcl3 tratadas con caseinato de sodio o caseína α.

Abstract Introduction: Sodium caseinate (CS) and its components (alpha-casein, beta-casein, and kappa-casein) have been shown to inhibit the proliferation of the mouse hematopoietic 32D clone 3 (32Dcl3) cell line and induce its differentiation into macrophages. It is well-known that alpha-casein induces IL-1β production and that this cytokine inhibits the proliferation via the production of tumor necrosis factor alpha (TNF-alpha), but it is not known if CS and the caseins inhibit the proliferation via TNF-alpha production. Objective: To evaluate if CS and alpha-casein, beta-casein and kappa-casein inhibit the proliferation on 32Dcl3 cell line via TNF-alpha. Materials and methods: We used different concentrations of CS, alpha-casein, beta-casein and kappa-casein in 32Dcl3 cells to evaluate cell proliferation. We assessed cell viability by MTT, induction to apoptosis by flow cytometry, and TNF-alpha synthesis by ELISA. Additionally, we performed anti-TNF-alpha neutralization assays on 32Dcl3 cells treated with CS and alpha-casein and we evaluated proliferation. Results: The results showed that CS, alpha-casein, beta-casein, and kappa-casein reduced proliferation of the 32Dcl3 cell line without affecting the viability and that only CS and alpha-casein induced apoptosis and the release of TNF-alpha. The 32Dcl3 cells treated with CS and alpha-casein reestablished their proliferation by using anti-TNF-alpha antibodies. Conclusion: TNF-alpha was the main responsible for the inhibition of proliferation in 32Dcl3 cells treated with CS or alpha-casein.

Antitumor effect of TW-37, a BH3 mimetic in human oral cancer / 한국실험동물학회지

TW-37 is a small molecule B cell lymphoma-2 (Bcl-2) homology 3 mimetic with potential anticancer activities. However, the in vivo anti-cancer effect of TW-37 in human oral cancer has not been properly studied yet. Here, we attempted to confirm antitumor activity of TW37 in human oral cancer. TW-37 significantly inhibited cell proliferation and increased the number of dead cells in MC-3 and HSC-3 human oral cancer cell lines. TW-37 enhanced apoptosis of both cell lines evidenced by annexin V/propidium iodide double staining, sub-G1 population analysis and the detection of cleaved poly (ADP-ribose) polymerase and caspase-3. In addition, TW-37 markedly downregulated the expression of Bcl-2 protein, while not affecting Bcl-xL or myeloid cell leukemia-1. In vivo, TW-37 inhibited tumor growth in a nude mice xenograft model without any significant liver and kidney toxicities. Collectively, these data reveal that TW-37 may be a promising small molecule to inhibit human oral cancer.

Expressão de proteínas relacionadas às células mieloides de pacientes com doença peri-implantar / Expression of myeloid cell-related proteins from patients having peri-implant diseases

O objetivo geral do presente estudo foi avaliar a expressão das proteínas relacionadas às células mieloides em pacientes com mucosite peri-implantar e peri-implantite; bem como a correlação desses biomarcadores com os parâmetros clínicos da doença peri-implantar. Os objetivos específicos foram avaliar os níveis de CSF-1, IL-34, IL-1ß, na saliva e no fluido peri-implantar de pacientes com doença peri-implantar e as correlações clínicas (estudo 1) e avaliar os níveis de sTREM-1, PGLYRP1, MMP-8, TIMP-1 e a razão MMP-8/TIMP-1 na saliva de pacientes com mucosite peri-implantar, peri-implantite, gengivite e periodontite e as correlações clínicas; bem como analisar a influência da existência concomitante da periodontite na expressão desses biomarcadores em pacientes com doença peri-implantar (estudo 2). No estudo 1, quarenta e três pacientes foram divididos em dois grupos: (1) Mucosite peri-implantar e (2) Peri-implantite; para o estudo 2, além dos pacientes do estudo 1, foram acrescidos pacientes com gengivite e com periodontite. Os parâmetros clínicos avaliados foram: profundidade de bolsa (PB), nível de inserção clínico (NIC), índice de placa e sangramento à sondagem. A saliva não estimulada foi coletada nos pacientes do estudo 1 e 2 e o fluido peri-implantar foi coletado no estudo 1. Os níveis dos biomarcadores foram mensurados através do ELISA. No estudo 1, os resultados das características clínicas de boca toda demonstraram que a PB dos pacientes com peri-implantite foi significativamente maior quando comparada aos pacientes com mucosite (p = 0,036). No estudo 2, a PB (p <0,001) e o NIC (p <0,001) dos pacientes com periodontite foi significativamente maior quando comparada aos demais pacientes. Tanto no estudo 1 quanto no estudo 2, a análise dos parâmetros peri-implantares mostrou que os pacientes com peri-implantite apresentaram maior PB nos implantes (p = 0,003) em comparação aos pacientes com mucosite. A análise dos níveis salivares de CSF-1, IL-34, IL-1ß, sTREM-1, PGLYRP1 e MMP-8 não apresentaram diferença significativa entre os grupos e também não foi encontrada correlação significativa desses biomarcadores com os parâmetros clínicos. No estudo 1, níveis de CSF-1 no fluido peri-implantar foram significativamente maiores nos pacientes com peri-implantite (p = 0,028), mostrando potencial para discriminar entre peri-implantite e mucosite (AUC = 0,695, IC 95% 0,53-0,85; p = 0,029). No estudo 2, os níveis salivares de MMP-8 foram significativamente maiores nos pacientes com doença peri-implantar e presença da periodontite concomitante (p = 0,03). Assim, pôde-se concluir que os níveis salivares das proteínas relacionadas às células mieloides não apresentaram diferença estatística entre os pacientes com mucosite e peri-implantite, sem correlação com os parâmetros clínicos. Os níveis de CSF-1 estavam elevados no fluido peri-implantar de pacientes com peri-implantite, sugerindo assim, um potencial osteoclastogênico alterado. Não observamos diferenças significativas nos níveis de sTREM-1, PGLYRP1 e MMP-8 entre pacientes com doenças periodontais e peri-implantares. Além disso, a presença da periodontite concomitante em pacientes com doença peri-implantar pode afetar os níveis salivares de MMP-8.(AU)

The general aim of present study was to evaluate the expression of myeloid cell-related proteins from patients having peri-implant mucositis and peri-implantitis; as well as their correlation to clinical parameters of peri-implant disease. The specific aims were to evaluate levels of CSF-1, IL-34, IL-1ß, in saliva and peri-implant crevicular fluid from patients having peri-implant disease and their correlation to clinical parameters (study 1) and to evaluate levels of sTREM- 1, PGIMRP1, MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in saliva from patients having peri-implant mucositis, peri-implantitis, gingivitis and periodontitis, and their correlation to clinical parameters; as well as to analyze the influence of the concomitant existence of periodontitis in the expression of these biomarkers in patients having peri-implant disease (study 2). In study 1, forty-three patients were divided into two groups: (1) peri-implant mucositis and (2) Peri-implantitis; for study 2, in addition to the patients in study 1, patients with gingivitis and periodontitis were added. The following clinical parameters were evaluated: probing depth (PD), clinical attachment level (CAL), visible plaque index and bleeding on probing. Unstimulated whole saliva was collected in the patients in study 1 and 2, and peri-implant crevicular fluid was collected in study 1. Biomarker levels were measured by ELISA. In study 1, regarding full-mouth periodontal parameters, PD from patients having peri-implantitis was significantly higher when compared to patients with mucositis (p = 0.036). In study 2, PD (p <0.001) and CAL (p <0.001) from patients with periodontitis were significantly higher when compared to the other patients. In both study 1 and study 2, regarding the peri-implant clinical characteristics showed that peri-implantitis patients presented higher PD in implants (p = 0.003) compared to the mucositis patients. When comparing the salivary levels of CSF-1, IL-34, IL-1ß, sTREM-1, PGLYRP1 and MMP-8, there was no significant difference between groups and no significant correlation of these biomarkers with clinical parameters was found. In study 1, CSF-1 levels were higher in peri-implant crevicular fluid from peri-implantitis compared with mucositis patients (p=0.028), showing potential to discriminate between peri-implantitis and mucositis (AUC = 0.695, 95% CI 0.53 -0.85, p = 0.029). In study 2, concomitant periodontitis resulted in higher significant levels of MMP-8 in patients with peri-implant disease (p = 0.03). Thus, based on these results, we can conclude that the salivary levels of myeloid cell-related proteins showed no difference between patients with peri-implant mucositis and peri-implantitis. There was also no significant correlation between biomarkers salivary levels and clinical parameters. Increased levels of CSF-1 in peri-implant crevicular fluid were found in peri-implantitis patients, thus suggesting an altered osteoclastogenic potential. We did not observe significant differences in levels of sTREM-1, PGLYRP1 and MMP-8 among patients with periodontal and peri-implant diseases. In addition, concomitant periodontitis in patients with peri-implant disease may affect salivary levels of MMP-8(AU)

Ginseng-Derived Panaxadiol Saponins Promote Hematopoiesis Recovery in Cyclophosphamide-Induced Myelosuppressive Mice: Potential Novel Treatment of Chemotherapy-Induced Cytopenias / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the potential efficacy of panaxadiol saponins component (PDS-C), a biologically active fraction isolated from total ginsenosides, to reverse chemotherapy-induced myelosuppression and pancytopenia caused by cyclophamide (CTX).</p><p><b>METHODS</b>Mice with myelosuppression induced by CTX were treated with PDS-C at a low- (20 mg/kg), moderate- (40 mg/kg), or high-dose (80 mg/kg) for 7 consecutive days. The level of peripheral white blood cell (WBC), neutrophil (NEU) and platelet (PLT) were measured, the histopathology and colony formation were observed, the protein kinase and transcription factors in hematopoietic cells were determined by immunohistochemical staining and Western blot.</p><p><b>RESULTS</b>In response to PDS-C therapy, the peripheral WBC, NEU and PLT counts of CTX-induced myelosuppressed mice were significantly increased in a dose-dependent manner. Similarly, bone marrow histopathology examination showed reversal of CTX-induced myelosuppression with increase in overall bone marrow cellularity and the number of hematopoietic cells (P<0.01). PDS-C also promoted proliferation of granulocytic and megakaryocyte progenitor cells in CTX-treated mice, as evidenced by significantly increase in colony formation units-granulocytes/monocytes and -megakaryocytes (P<0.01). The enhancement of hematopoiesis by PDS-C appears to be mediated by an intracellular signaling pathway, this was evidenced by the up-regulation of phosphorylated mitogen-activated protein kinase (p-MEK) and extracellular signal-regulated kinases (p-ERK), and receptor tyrosine kinase (C-kit) and globin transcription factor 1 (GATA-1) in hematopoietic cells of CTX-treated mice (P<0.05).</p><p><b>CONCLUSIONS</b>PDS-C possesses hematopoietic growth factor-like activities that promote proliferation and also possibly differentiation of hematopoietic progenitor cells in myelosuppressed mice, probably mediated by a mechanism involving MEK and ERK protein kinases, and C-kit and GATA-1 transcription factors. PDS-C may potentially be a novel treatment of myelosuppression and pancytopenia caused by chemotherapy.</p>

Association of Chemokines and Chemokine Receptor Expression with Monocytic-Myeloid-Derived Suppressor Cells during Tumor Progression

Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells that show increased expression in cancer patients; however, the molecular mechanisms underlying their generation and function are unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer (BC), the presence and relevance of monocytic (Mo)-MDSCs are unknown. Here, we report for the first time increased chemokine and chemokine receptor production by Mo-MDSCs in BC patients. A clear population of Mo-MDSCs with the typical cell surface phenotype (human leukocyte antigen-antigen D related [HLA-DR]low/− CD11b+ CD33+ CD14+) increased significantly during disease progression. In addition, the chemokine receptor expression level on Mo-MDSCs in patients with invasive BC was the highest. Furthermore, different chemokine receptor expression patterns were noted in Mo-MDSCs between healthy controls (HC) and BC patients. Additionally, CD4 T cells proliferations were significantly decreased in the invasive BC groups compared with the HC group. However, the ductal carcinoma in situ (DCIS) group had no significantly compared with the HC group. Our data suggest that monitoring chemokine and chemokine receptor production by Mo-MDSCs may represent a novel and simple biomarker for assessing disease progression in BC patients.

Expression of triggering receptors expressed by myeloid cells-1 in macrophages stimulated by Porphyromonas gingivalis-lipopolysaccharide / 华西口腔医学杂志

OBJECTIVE@#Soluble triggering receptors expressed by myeloid cells-1 (sTREM-1) and inflammatory cytokine tumor necrosis factor-α (TNF-α) in macrophage cells were stimulated by Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) to investigate the expression of triggering receptors expressed by myeloid cells-1 (TREM-1) and further explore the correlation between TREM-1 and the pathogenesis of periodontitis.@*METHODS@#THP-1 cells (a human monocytic cell line derived from an acute monocytic leukemia patient) were induced to differentiate THP-1 macrophages by phorbol-12-myristate-13-acetate and were injected with 0 (blank control), 0.5, or 1.0 μg·mL⁻¹ Pg-LPS. The THP-1 cells were then grouped in accordance with incubation time, and each group was incubated for 4, 6, 12, or 24 h. The expression of the TREM-1 mRNA in macrophages was detected by real-time quantitative polymerase chain reaction, while the expression of TREM-1 protein was detected by Western blot; the site where TREM-1 protein expression was observed in macrophages was detected by immunofluorescence staining, and the expression of soluble sTREM-1 and TNF-α in cell culture medium was detected by enzyme-linked immunosorbent assay.@*RESULTS@#Compared with the blank control group, the expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in Pg-LPS-stimulated macrophages was significantly upregulated (P<0.05). The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the supernatant of cell culture was higher in the 1.0 μg·mL⁻¹ Pg-LPS group than in the 0.5 μg·mL⁻¹ group; this expression was statistically significant since the 6, 4, and 4 h time point (P<0.05). Cell immunofluorescence staining showed that TREM-1 protein was positive when the THP-1 macrophages was stimulated by Pg-LPS (1.0 μg·mL⁻¹) for 24 h, and the staining sites of TREM-1 were mainly located in the cell membrane of the macrophages (P<0.05). The expression level of TNF-α increased in groups stimulated by Pg-LPS, and the expression level of TNF-α was significantly higher in 1.0 μg·mL⁻¹ Pg-LPS stimulated groups than in 0.5 μg·mL⁻¹ Pg-LPS-stimulated groups since the 6 h time point (P<0.05). The expressions of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in 0.5 μg·mL⁻¹ Pg-LPS-stimulated macrophages were positively correlated with one another (r=1, P<0.05), but no statistically significant correlation was found in the expression of TNF-α. The positive correlation between sTREM-1 and TNF-α expressions was detected when macrophages were stimulated by 1.0 μg·mL⁻¹ Pg-LPS (r=1, P<0.05).@*CONCLUSIONS@#The expression of TREM-1 mRNA, TREM-1 protein, and sTREM-1 in the culture supernatant in Pg-LPS-stimulated macrophages was significantly upregulated on the basis of the concentration of Pg-LPS; moreover, their upregulation was positively correlated with one another. The expression of TNF-α in the supernatant of cell culture was also upregulated and was positively correlated with the expression of sTREM-1 at the group of high Pg-LPS concentration (1.0 μg·mL⁻¹). Results reveal that TREM-1, which has been realized as a proinflammatory receptor protein, can promote the development of periodontitis by regulating the expression of TNF-α in macrophages.

Pseudo-Chediak-Higashi granules in myeloid cells in therapy-related AML with RUNX1-RUNX1T1

No abstract available.

Role of inflammasomes in inflammatory autoimmune rheumatic diseases

Inflammasomes are intracellular multiprotein complexes that coordinate anti-pathogenic host defense during inflammatory responses in myeloid cells, especially macrophages. Inflammasome activation leads to activation of caspase-1, resulting in the induction of pyroptosis and the secretion of pro-inflammatory cytokines including interleukin (IL)-1β and IL-18. Although the inflammatory response is an innate host defense mechanism, chronic inflammation is the main cause of rheumatic diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), and Sjögren's syndrome (SS). Since rheumatic diseases are inflammatory/autoimmune disorders, it is reasonable to hypothesize that inflammasomes activated during the inflammatory response play a pivotal role in development and progression of these diseases. Indeed, previous studies have provided important observations that inflammasomes are actively involved in the pathogenesis of inflammatory/autoimmune rheumatic diseases. In this review, we summarize the current knowledge on several types of inflammasomes during macrophage-mediated inflammatory responses and discuss recent research regarding the role of inflammasomes in the pathogenesis of inflammatory/autoimmune rheumatic diseases. This avenue of research could provide new insights for the development of promising therapeutics to treat inflammatory/autoimmune rheumatic diseases.

Control of Innate and Adaptive Lymphocytes by the RAR-Retinoic Acid Axis

Lymphocytes, such as T cells, B cells, and innate lymphoid cells (ILCs), play central roles in regulating immune responses. Retinoic acids (RAs) are vitamin A metabolites, produced and metabolized by certain tissue cells and myeloid cells in a tissue-specific manner. It has been established that RAs induce gut-homing receptors on T cells, B cells, and ILCs. A mounting body of evidence indicates that RAs exert far-reaching effects on functional differentiation and fate of these lymphocytes. For example, RAs promote effector T cell maintenance, generation of induced gut-homing regulatory and effector T cell subsets, antibody production by B cells, and functional maturation of ILCs. Key functions of RAs in regulating major groups of innate and adaptive lymphocytes are highlighted in this article.

Out-sourcing for Trans-presentation: Assessing T Cell Intrinsic and Extrinsic IL-15 Expression with Il15 Gene Reporter Mice

IL-15 is a cytokine of the common γ-chain family that is critical for natural killer (NK), invariant natural killer T (iNKT), and CD8 memory T cell development and homeostasis. The role of IL-15 in regulating effector T cell subsets, however, remains incompletely understood. IL-15 is mostly expressed by stromal cells, myeloid cells, and dendritic cells (DCs). Whether T cells themselves can express IL-15, and if so, whether such T cell-derived IL-15 could play an autocrine role in T cells are interesting questions that were previously addressed but answered with mixed results. Recently, three independent studies described the generation of IL-15 reporter mice which facilitated the identification of IL-15-producing cells and helped to clarify the role of IL-15 both in vitro and in vivo. Here, we review the findings of these studies and place them in context of recent reports that examined T cell-intrinsic IL-15 expression during CD4 effector T cell differentiation.

Relation between anaemia and bone marrow features and serum erythropoietin in dogs with chronic kidney disease / Relação entre anemia e achados de medula óssea e eritropoetina sérica em cães com doença renal crônica

Chronic anaemia is one of the most severe complications of chronic kidney disease, contributing to morbidity and mortality caused by the disease; therefore, bone marrow cytological evaluation is needed to monitor the progression of anaemia. This study aimed to correlate the anaemia in dogs at different stages of chronic kidney disease with their serum biochemistry, myelogram results and serum erythropoietin findings. Sixty-three dogs were grouped according to International Renal Interest Society (IRIS) classification in stages 1, 2, 3 and 4. Haematologic, serum and urinary biochemistry and serum erythropoietin were performed for comparison with the findings of bone marrow cytology obtained by aspiration of the manubrium. Cytological findings for erythroid hypoplasia were described in 93.65% of dogs, and the anaemia was observed in 84.1% of them. The haematological findings were correlated with azotaemia (p<0.05). It was concluded that the erythroid hypoplasia has correlation with persistent anaemia in dogs at all stages of chronic kidney disease, with iron deficiency in dogs in the early stages and with peripheral destruction of erythrocytes caused by azotaemia.(AU)

A anemia crônica é umas das complicações mais graves da doença renal crônica, contribuindo para a morbidade e mortalidade causada pela doença; Portanto, a avaliação citológica da medula óssea é necessária para monitorar a progressão da anemia. Assim, esse estudo objetivou correlacionar a anemia em cães em diferentes estágios da doença renal crônica aos achados de bioquímica sérica, mielograma e concentração sérica de eritropoietina. Sessenta e três cães foram agrupados de acordo com a classificação da International Renal Interest Society (IRIS) em estágios 1, 2, 3 e 4. Foram realizadas análises hematológicas, bioquímicas séricas e urinárias, e dosagem sérica de eritropoetina para comparação com os achados medulares obtidos por citologia aspirativa do manúbrio. Os achados citológicos de hipoplasia eritróide foram descritos em 93,65% dos cães, e a anemia foi observada em 84,1% dos cães. Os resultados hematológicos foram correlacionados com azotemia (p<0,05). Concluiu-se que a hipoplasia eritróide teve associação com a anemia persistente em cães em todas as fases de doença renal crônica, com deficiência de ferro em cães em fases iniciais e com a destruição periférica dos eritrócitos causada pela azotemia.(AU)

Neoplasias mieloproliferativas. De la clínica a la biología molecular / Myeloproliferative neoplasms. From clinic to molecular biology

Las neoplasias mieloproliferativas (NMPs), son hemopatías clonales crónicas de la línea mieloide cuya anomalía se presenta a nivel de la célula madre hematopoyética en la médula ósea, llevando a una proliferación excesiva, expansión y acumulo de células mieloides sin bloqueo de la maduración o la función y se denominan de acuerdo con la línea predominante en la proliferación neoplásica ya sea eritroide, granulocítica o plaquetaria. El grado de expansión es variable a nivel de médula ósea (MO), sangre periférica y tejidos 1-3. Históricamente, la leucemia mieloide crónica (LMC) fue descrita de 1839 a 1845 por Alfred Donné, John Hughes y Robert Virchow. La mielofibrosis primitiva (MFP) por Gustav Heuck en 1879; Luis Henry Vaquez en unión con William Osler describieron por primera vez un caso de Policitemia Vera (PV) en 1892 y la tromobocitemia esencial (TE) fue descrita por Emil Epstein y Alfred Goedel en 1934. El término síndrome mieloproliferativo (SMP) fue propuesto por primera vez por el hematólogo Americano William Dameshek en 1951, quien describió las semejanzas de estas entidades en la evolución clínica 4,5. Una vez conocido el cromosoma Filadelfia en 1960, denominado así por los científicos Peter Noweel y David Hungerford por la localización geográfica de sus institutos de trabajo, se consideró aparte la leucemia mieloide crónica (LMC). La caracterización de la anomalía molecular del cromosoma Filadelfia en la LMC, la traslocación BCR-ABL fue hecha por Janet Rowley en 1973, y progresivamente se logró establecer que la fusión de ABL cuya actividad en estado natural implica regulación de la proliferación, adherencia y apoptosis se descontrola al fusionarse con el BCR 6. Se confirmó así la separación de la LMC de las neoplasias BCR-ABL negativas clásicas.

Role of Triggering Receptor Expressed on Myeloid Cell-1 Expression in Mammalian Target of Rapamycin Modulation of CD8T-cell Differentiation during the Immune Response to Invasive Pulmonary Aspergillosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Triggering receptor expressed on myeloid cell-1 (TREM-1) may play a vital role in mammalian target of rapamycin (mTOR) modulation of CD8+ T-cell differentiation through the transcription factors T-box expressed in T-cells and eomesodermin during the immune response to invasive pulmonary aspergillosis (IPA). This study aimed to investigate whether the mTOR signaling pathway modulates the proliferation and differentiation of CD8+ T-cells during the immune response to IPA and the role TREM-1 plays in this process.</p><p><b>METHODS</b>Cyclophosphamide (CTX) was injected intraperitoneally, and Aspergillus fumigatus spore suspension was inoculated intranasally to establish the immunosuppressed IPA mouse model. After inoculation, rapamycin (2 mg.kg-1.d-1) or interleukin (IL)-12 (5 μg/kg every other day) was given for 7 days. The number of CD8+ effector memory T-cells (Tem), expression of interferon (IFN)-γ, mTOR, and ribosomal protein S6 kinase (S6K), and the levels of IL-6, IL-10, galactomannan (GM), and soluble TREM-1 (sTREM-1) were measured.</p><p><b>RESULTS</b>Viable A. fumigatus was cultured from the lung tissue of the inoculated mice. Histological examination indicated greater inflammation, hemorrhage, and lung tissue injury in both IPA and CTX + IPA mice groups. The expression of mTOR and S6K was significantly increased in the CTX + IPA + IL-12 group compared with the control, IPA (P = 0.01; P= 0.001), and CTX + IPA (P = 0.034; P= 0.032) groups, but significantly decreased in the CTX + IPA + RAPA group (P < 0.001). Compared with the CTX + IPA group, the proportion of Tem, expression of IFN-γ, and the level of sTREM-1 were significantly higher after IL-12 treatment (P = 0.024, P= 0.032, and P= 0.017, respectively), and the opposite results were observed when the mTOR pathway was blocked by rapamycin (P < 0.001). Compared with the CTX + IPA and CTX + IPA + RAPA groups, IL-12 treatment increased IL-6 and downregulated IL-10 as well as GM, which strengthened the immune response to the IPA infection.</p><p><b>CONCLUSIONS</b>mTOR modulates CD8+ T-cell differentiation during the immune response to IPA. TREM-1 may play a vital role in signal transduction between mTOR and the downstream immune response.</p>

A Case of Malignancy-associated Histiocytoid Sweet Syndrome in a Patient with AML / 대한피부과학회지

Sweet syndrome is a disorder characterized by painful, erythematous, cutaneous plaques and nodules of rapid onset accompanied by fever, leukocytosis, and neutrophilia. We encountered a case of a recurrent histiocytoid Sweet syndrome in a patient with acute myeloid leukemia (AML). A 64-year-old Korean man was diagnosed with complete remission of AML and had symptomatic nodules and plaques on the dorsal sides of both hands. Approximately 3 years prior, he also had symptomatic plaques at the same site and had been diagnosed with MDS (Myelodysplastic syndrome). We performed a biopsy and diagnosed this case as a malignancy-associated histiocytoid Sweet syndrome. Most Sweet syndrome cases are acute; in contrast, this case was chronic with a relapse. In addition, histopathologic examination showed a dense histiocytic infiltration. These histiocytoid cells are usually misinterpreted as histiocytes; however, they are actually immature myeloid cells. Herein, we report a case of a recurrent malignancy-associated histiocytoid Sweet syndrome in a patient with a hematologic disorder.

IL-32-induced Inflammatory Cytokines Are Selectively Suppressed by α1-antitrypsin in Mouse Bone Marrow Cells

The induction of interleukin (IL)-32 in bone marrow (BM) inflammation is crucial in graft versus host disease (GvHD) that is a common side effect of allogeneic BM transplantation. Clinical trials on α-1 antitrypsin (AAT) in patients with GvHD are based on the preliminary human and mouse studies on AAT reducing the severity of GvHD. Proteinase 3 (PR3) is an IL-32-binding protein that was isolated from human urine. IL-32 primarily induces inflammatory cytokines in myeloid cells, probably due to PR3 expression on the membrane of the myeloid lineage cells. The inhibitory activity of AAT on serine proteinases may explain the anti-inflammatory effect of AAT on GvHD. However, the anti-inflammatory activity of AAT on BM cells remains unclear. Mouse BM cells were treated with IL-32γ and different inflammatory stimuli to investigate the anti-inflammatory activity of AAT. Recombinant AAT-Fc fusion protein inhibited IL-32γ-induced IL-6 expression in BM cells, but failed to suppress that induced by other stimuli. In addition, the binding of IL-32γ to PR3 was abrogated by AAT-Fc. The data suggest that the specific anti-inflammatory effect of AAT in mouse BM cells is due to the blocking of IL-32 binding to membrane PR3.

Neutrophilic Leukemoid Reaction Associated with Malignancy Initially Suspected as Chronic Neutrophilic Leukemia

Although neutrophilia can manifest from various causes, it is important to be able to distinguish chronic neutrophilic leukemia (CNL) from neutrophilic leukemoid reactions (NLR). In this paper, we describe four cases of leukocytosis with neutrophilia, including one case of CNL with a T618I mutation in colony stimulating factor 3 receptor (CSF3R) and three cases of NLR associated with malignancy or sepsis, which were initially suspected as CNL. Of the three NLR cases, one was associated with ovarian cancer, one with monoclonal gammopathy of undetermined significance and one with multiple myeloma with sepsis. This study demonstrated that confirming the clonality of myeloid cells with CSF3R T618I could contribute to making an accurate differential diagnosis between CNL and NLR in patients with solid cancers or plasma cell neoplasms caused by paraneoplastic syndromes and/or infection.

Genetic Predisposition of Polymorphisms in HMGB1-Related Genes to Breast Cancer Prognosis in Korean Women / 한국유방암학회지

PURPOSE: The high mobility group box 1 (HMGB1) protein has roles in apoptosis and immune responses by acting as a ligand for receptor for advanced glycation end products (RAGE), Toll-like receptors (TLRs), and triggering receptor expressed on myeloid cells 1. In particular, HMGB1/RAGE is involved in tumor metastasis by inducing matrix metalloproteinase 2 (MMP2) and MMP9 expression. We investigated the associations between genetic variations in HMGB1-related genes and disease-free survival (DFS) and overall survival (OS) in Korean female breast cancer patients. METHODS: A total of 2,027 patients in the Seoul Breast Cancer Study were included in the analysis. One hundred sixteen single nucleotide polymorphisms (SNPs) were extracted from eight genes. A multivariate Cox proportional hazards model was used to estimate the hazard ratio and 95% confidence interval (CI) of each SNP. The effects of the SNPs on breast cancer prognosis were assessed at cumulative levels with polygenic risk scores. RESULTS: The SNPs significantly associated with DFS were rs243867 (hazard ratio, 1.26; 95% CI, 1.05–1.50) and rs243842 (hazard ratio, 1.24; 95% CI, 1.03–1.50); both SNPs were in MMP2. The SNPs significantly associated with OS were rs243842 in MMP2 (hazard ratio, 1.33; 95% CI 1.03–1.71), rs4145277 in HMGB1 (hazard ratio, 1.29; 95% CI, 1.00–1.66), rs7656411 in TLR2 (hazard ratio, 0.76; 95% CI, 0.60–0.98), and rs7045953 in TLR4 (hazard ratio, 0.50; 95% CI, 0.29–0.84). The polygenic risk score results for the DFS and OS patients showed third tertile hazard ratios of 1.72 (95% CI, 1.27–2.34) and 2.75 (95% CI, 1.79–4.23), respectively, over their first tertile references. CONCLUSION: The results of the present study indicate that genetic polymorphisms in HMGB1-related genes are related to breast cancer prognosis in Korean women.

Colony Stimulating Factor 3 Mutations and Myeloid Malignancies / 中国医学科学院学报

Granulocyte colony stimulating factor (G-CSF) plays a major role in the proliferation, differentiation, and activation of neutrophil cell line hematopoietic cells. G-CSF exert the function depending on its binding to colony-stimulating factor 3 receptor (CSF3R), a homo-dimer receptor located on the surface of effector cells. Some recent studies have demonstrated that CSF3R mutations play a significant role in many diseases. Some of the hematopoietic diseases, especially myeloid malignancies (e.g. chronic neutrophilic leukemia) are related to the presence of various CSF3R mutations, which leads to abnormal G-CSF signal pathways. Also, the downstream kinases can be the treatment targets for these diseases. This review summarizes CSF3R mutations, mechanisms of mutations, and their contributions to the myeloid malignancies, with an attempt to further reveal the pathogenesis of myeloid malignancies, inform the diagnosis and clinical treatment of the myeloid malignancies, and provide clues for the research and development of new molecular target drugs.