Mediators of monocyte chemotaxis and matrix remodeling are associated with mortality and pulmonary fibroproliferation in patients with severe COVID-19.

Acute respiratory distress syndrome (ARDS) has a fibroproliferative phase that may be followed by pulmonary fibrosis. Pulmonary fibrosis following COVID-19 pneumonia has been described at autopsy and following lung transplantation. We hypothesized that protein mediators of tissue remodeling and monocyte chemotaxis are elevated in the plasma and endotracheal aspirates of critically ill patients with COVID-19 who subsequently develop features of pulmonary fibroproliferation. We enrolled COVID-19 patients admitted to the ICU with hypoxemic respiratory failure. (n = 195). Plasma was collected within 24h of ICU admission and at 7d. In mechanically ventilated patients, endotracheal aspirates (ETA) were collected. Protein concentrations were measured by immunoassay. We tested for associations between protein concentrations and respiratory outcomes using logistic regression adjusting for age, sex, treatment with steroids, and APACHE III score. In a subset of patients who had CT scans during hospitalization (n = 75), we tested for associations between protein concentrations and radiographic features of fibroproliferation. Among the entire cohort, plasma IL-6, TNF-α, CCL2, and Amphiregulin levels were significantly associated with in-hospital mortality. In addition, higher plasma concentrations of CCL2, IL-6, TNF-α, Amphiregulin, and CXCL12 were associated with fewer ventilator-free days. We identified 20/75 patients (26%) with features of fibroproliferation. Within 24h of ICU admission, no measured plasma proteins were associated with a fibroproliferative response. However, when measured 96h-128h after admission, Amphiregulin was elevated in those that developed fibroproliferation. ETAs were not correlated with plasma measurements and did not show any association with mortality, ventilator-free days (VFDs), or fibroproliferative response. This cohort study identifies proteins of tissue remodeling and monocyte recruitment are associated with in-hospital mortality, fewer VFDs, and radiographic fibroproliferative response. Measuring changes in these proteins over time may allow for early identification of patients with severe COVID-19 at risk for fibroproliferation.

Dissecting thrombus-directed chemotaxis and random movement in neutrophil near-thrombus motion in flow chambers.

BACKGROUND: Thromboinflammation is caused by mutual activation of platelets and neutrophils. The site of thromboinflammation is determined by chemoattracting agents release by endothelium, immune cells, and platelets. Impaired neutrophil chemotaxis contributes to the pathogenesis of Shwachman-Diamond syndrome (SDS). In this hereditary disorder, neutrophils are known to have aberrant chemoattractant-induced F-actin properties. Here, we aim to determine whether neutrophil chemotaxis could be analyzed using our previously developed ex vivo assay of the neutrophils crawling among the growing thrombi. METHODS: Adult and pediatric healthy donors, alongside with pediatric patients with SDS, were recruited for the study. Thrombus formation and granulocyte movement in hirudinated whole blood were visualized by fluorescent microscopy in fibrillar collagen-coated parallel-plate flow chambers. Alternatively, fibrinogen, fibronectin, vWF, or single tumor cells immobilized on coverslips were used. A computational model of chemokine distribution in flow chamber with a virtual neutrophil moving in it was used to analyze the observed data. RESULTS: The movement of healthy donor neutrophils predominantly occurred in the direction and vicinity of thrombi grown on collagen or around tumor cells. For SDS patients or on coatings other than collagen, the movement was characterized by randomness and significantly reduced velocities. Increase in wall shear rates to 300-500 1/s led to an increase in the proportion of rolling neutrophils. A stochastic algorithm simulating leucocyte chemotaxis movement in the calculated chemoattractant field could reproduce the experimental trajectories of moving neutrophils for 72% of cells. CONCLUSIONS: In samples from healthy donors, but not SDS patients, neutrophils move in the direction of large, chemoattractant-releasing platelet thrombi growing on collagen.

Procyanidin B2 alleviates oxidized low-density lipoprotein-induced cell injury, inflammation, monocyte chemotaxis, and oxidative stress by inhibiting the nuclear factor kappa-B pathway in human umbilical vein endothelial cells.

BACKGROUND: Oxidized low-density lipoprotein (ox-LDL) can initiate and affect almost all atherosclerotic events including endothelial dysfunction. In this text, the role and underlying molecular basis of procyanidin B2 (PCB2) with potential anti-oxidant and anti-inflammatory activities in ox-LDL-induced HUVEC injury were examined. METHODS: HUVECs were treated with ox-LDL in the presence or absence of PCB2. Cell viability and apoptotic rate were examined by CCK-8 assay and flow cytometry, respectively. The mRNA and protein levels of genes were tested by RT-qPCR and western blot assays, respectively. Potential downstream targets and pathways of apple procyanidin oligomers were examined by bioinformatics analysis for the GSE9647 dataset. The effect of PCB2 on THP-1 cell migration was examined by recruitment assay. The effect of PCB2 on oxidative stress was assessed by reactive oxygen species (ROS) level, malondialdehyde (MDA) content, and mitochondrial membrane potential (MMP). RESULTS: ox-LDL reduced cell viability, induced cell apoptosis, and facilitated the expression of oxidized low-density lipoprotein receptor 1 (LOX-1), C-C motif chemokine ligand 2 (MCP-1), vascular cell adhesion protein 1 (VCAM-1) in HUVECs. PCB2 alleviated ox-LDL-induced cell injury in HUVECs. Apple procyanidin oligomers triggered the differential expression of 592 genes in HUVECs (|log2fold-change| > 0.58 and adjusted p-value < 0.05). These dysregulated genes might be implicated in apoptosis, endothelial cell proliferation, inflammation, and monocyte chemotaxis. PCB2 inhibited C-X-C motif chemokine ligand 1/8 (CXCL1/8) expression and THP-1 cell recruitment in ox-LDL-stimulated HUVECs. PCB2 inhibited ox-LDL-induced oxidative stress and nuclear factor kappa-B (NF-κB) activation in HUVECs. CONCLUSION: PCB2 weakened ox-LDL-induced cell injury, inflammation, monocyte recruitment, and oxidative stress by inhibiting the NF-κB pathway in HUVECs.

Evaluation of Leukocyte Chemotaxis Induced by Human Fetal Membranes in an In Vitro Model.

Leukocyte infiltration into the maternal-fetal interface is a consequence of the robust inflammation in the gestational tissues during term labor and preterm labor with or without infection. During pregnancy, the fetal membranes act as a physical barrier that isolates the fetus into the amniotic cavity, keeping it in an optimal environment for its development. In addition, the fetal membranes possess immunological competencies such as the secretion of cytokines and chemokines in response to different stimuli. Clinical and experimental evidence indicates that these tissues are involved in the extensive chemotaxis of immune cells in normal or pathological conditions.Few studies have evaluated the chemotactic capacities of the fetal membranes considering that this tissue is composed of two adjacent tissues, the amnion and the chorion, which have different characteristics. Although these tissues function as a unit, their response is complex since there is an interaction between them, where each tissue contributes differently. The protocol described here allows us to evaluate the in vitro chemotactic capacities of fetal membranes in response to various applied stimuli, considering the contribution of each of their components (amnion and choriodecidua) using a Boyden chamber assay and phenotyping the chemo-attracted leukocytes by flow cytometry.

Epithelium-derived kallistatin promotes CD4+ T-cell chemotaxis to TH2-type inflammation in chronic rhinosinusitis.

BACKGROUND: The function of kallistatin in airway inflammation, particularly chronic rhinosinusitis with nasal polyps (CRSwNP), has not been elucidated. OBJECTIVE: We sought to investigate the role of kallistatin in airway inflammation. METHODS: Kallistatin and proinflammatory cytokine expression levels were detected in nasal polyps. For the in vivo studies, we constructed the kallistatin-overexpressing transgenic mice to elucidate the role of kallistatin in airway inflammation. Furthermore, the levels of plasma IgE and proinflammatory cytokines in the airways were evaluated in the kallistatin-/- rat in vivo model under a type 2 inflammatory background. Finally, the Notch signaling pathway was explored to understand the role of kallistatin in CRSwNP. RESULTS: We showed that the expression of kallistatin was significantly higher in nasal polyps than in the normal nasal mucosa and correlated with IL-4 expression. We also discovered that the nasal mucosa of kallistatin-overexpressing transgenic mice expressed higher levels of IL-4 expression, associating to TH2-type inflammation. Interestingly, we observed lower IL-4 levels in the nasal mucosa and lower total plasma IgE of the kallistatin-/- group treated with house dust mite allergen compared with the wild-type house dust mite group. Finally, we observed a significant increase in the expression of Jagged2 in the nasal epithelium cells transduced with adenovirus-kallistatin. This heightened expression correlated with increased secretion of IL-4, attributed to the augmented population of CD4+CD45+Notch1+ T cells. These findings collectively may contribute to the induction of TH2-type inflammation. CONCLUSIONS: Kallistatin was demonstrated to be involved in the CRSwNP pathogenesis by enhancing the TH2 inflammation, which was found to be associated with more expression of IL-4, potentially facilitated through Jagged2-Notch1 signaling in CD4+ T cells.

The Deubiquitylase Otub1 Regulates the Chemotactic Response of Splenic B Cells by Modulating the Stability of the γ-Subunit Gng2.

The ubiquitin proteasome system performs the covalent attachment of lysine 48-linked polyubiquitin chains to substrate proteins, thereby targeting them for degradation, while deubiquitylating enzymes (DUBs) reverse this process. This posttranslational modification regulates key features both of innate and adaptative immunity, including antigen presentation, protein homeostasis and signal transduction. Here we show that loss of one of the most highly expressed DUBs, Otub1, results in changes in murine splenic B cell subsets, leading to a significant increase in marginal zone and transitional B cells and a concomitant decrease in follicular B cells. We demonstrate that Otub1 interacts with the γ-subunit of the heterotrimeric G protein, Gng2, and modulates its ubiquitylation status, thereby controlling Gng2 stability. Proximal mapping of Gng2 revealed an enrichment in partners associated with chemokine signaling, actin cytoskeleton and cell migration. In line with these findings, we show that Otub1-deficient B cells exhibit greater Ca2+ mobilization, F-actin polymerization and chemotactic responsiveness to Cxcl12, Cxcl13 and S1P in vitro, which manifests in vivo as altered localization of B cells within the spleen. Together, our data establishes Otub1 as a novel regulator of G-protein coupled receptor signaling in B cells, regulating their differentiation and positioning in the spleen.

Aportación clínica de la SPECT/TC en la gammagrafía con leucocitos marcados con 99mTc-HMPAO en infección de prótesis de cadera y rodilla / The clinical contribution of SPECT/CT with 99mTc-HMPAO-labeled leukocyte scintigraphy in hip and knee prosthetic infections

OBJETIVO: La gammagrafía con leucocitos marcados con 99mTc-HMPAO ha resultado un método de estudio específico y altamente sensible en el diagnóstico y seguimiento de pacientes con sospecha de infección protésica. El objetivo de este estudio retrospectivo fue evaluar la utilidad de la SPECT/TC en infección protésica. MATERIAL Y MÉTODOS: Se realizó una gammagrafía con leucocitos marcados con 99mTc-HMPAO a 37 pacientes con prótesis articular (11 hombres y 26 mujeres; rango de edades de 38 a 84 años; edad media+/-DE, 65,7+/-5,6 años). Se obtuvieron imágenes planares 2, 4 y 24horas después de la inyección. A las 4horas se realizó SPECT/TC usando una gammacámara híbrida de doble detector con TC de baja energía. En todos los pacientes se compararon los resultados de la gammagrafía con los resultados de la intervención quirúrgica, el cultivo y el seguimiento clínico. RESULTADOS: De 37 pacientes estudiados con leucocitos marcados con 99mTc-HMPAO, con gammagrafía y SPECT/TC, 17 (45,9%) tenían infección protésica y 20 (54,1%) tenían afecciones protésicas no infecciosas. La gammagrafía con leucocitos marcados con 99mTc-HMPAO fue verdadero positivo para infección en 16 de 37 pacientes y verdadero negativo en 20 de 37 pacientes. La SPECT/TC proporciona una localización anatómica precisa de todos los posibles focos. Considerando el diagnóstico final, la SPECT/TC aportó una contribución clínica significativa en 22 de 37 pacientes (59,4%). La sensibilidad, especificidad, valor predictivo negativo y valor predictivo positivo fueron del 100%, 59,1%, 100%, 62,5% en las imágenes planares y de 100%, 90,1%, 100%, 88,2% en la imagen planar más SPECT/TC respectivamente. DISCUSIÓN: Nuestros resultados indican que la realización de la SPECT/TC puede mejorar el estudio con leucocitos marcados con 99mTc-HMPAO en pacientes con sospecha de osteomielitis, y proporcionar una localización anatómica y una definición precisa del alcance de la infección

OBJECTIVES: White blood cell scanning with 99mTc-hexamethylpropylene amine oxime (HMPAO) has proven a sensitive and specific imaging method in the diagnosis of suspected prosthesis infection. The aim of this retrospective study was to evaluate the usefulness of SPECT/CT performed simultaneously using a hybrid imaging device of prosthesis infections. MATERIALS AND METHODS: 99mTc-HMPAO scintigraphy was performed on 37 patients (11 men and 26 women; age range 38-84 years; mean age+/-SD, 65.7+/-5.6 years). Planar scans were acquired 2.4 and 24hour after injection. SPECT/CT was obtained 4 h after injection, using a dual-head hybrid gama camera coupled with a low-power x-ray tube. In all patients, scintigraphic results were matched with the results of surgery, cultures and clinical follow-up. RESULTS: Seventeen (45,9%) out of 37 patients had prosthesis infection and 20 (54,1%) out of 37 patients had non-infectious prosthesis pathologies with 99mTc-HMPAO scintigraphy and SPECT/CT. The 99mTc-HMPAO scintigraphy was true-positive for infection in 16 of 37 patients and true-negative in 20 of 37 patients. SPECT/CT provided an accurate anatomic localization of all positive foci. With regard to the final diagnosis, SPECT/CT added a significant clinical contribution in 22 of 37 patients (59,4%). Sensitivity, specificity, negative predictive value and positive predictive values were 100%,59.1%,100%,62.5% in planar images with 99mTc-HMPAO scintigraphy and 100%,90.1%,100%,88.2% in the planar+SPECT/CT imaging, respectively. DISCUSSION: Our results indicate that SPECT/CT performed using a hybrid device can improve imaging with 99mTc-HMPAO scintigraphy in patients with suspected osteomyelitis by providing accurate anatomic localization and precise definition of the extent of infection

Essential oil composition and antichemotactic activity of stenachaenium benth species native to south Brazil / Composición y actividad antiquimiotaxica del aceite esencial de especies stenachaenium benth. nativas de sur de Brasil

Chemical composition of essential oils from four Stenachaenium species from South Brazil were established by gas chromatography coupled with mass spectrometry (GC/MS). The major compounds identified in the oil of S. megapotamicum were a coumarin derivative, 2H-1-benzopyran-2-one,7-(3-methylbutoxy) (24.0 percent), beta-bisabolene (12.8 percent) and thymol methyl ether (7.1 percent). The oil of S. adenanthum contained mainly pogostol (14.0 percent). S. riedelli oil showed significant presence of aliphatic compounds, with predominance of hexadecanoic acid in all samples (leaves, inflorescence and leaves collected during of inflorescence period). Hexadecanoic acid (23.8 percent) was also the main component in S. macrocephalum. Concerning antichemotactic activity, all the oil samples tested showed a significant leukocyte migration inhibition compared to chemotactic stimulant (lipopolysaccharide from Escherichia coli - LPS), at concentrations of 1 to 5 μg/mL, except for S. adenanthum. These results suggest that the essential oils of some Stenachaenium species could inhibit acute inflammatory process, because the migration of neutrophils occurs mainly in the early inflammatory process.

Se estableció la composición química de los aceites esenciales de cuatro especies de Stenachaenium del Sur de Brasil mediante cromatografía de gases acoplada a espectrometría de masas (CG/EM). Los compuestos mayoritarios identificados en el aceite de S. megapotamicum fueron: un derivado de cumarina, 2H-1-benzopiran-2-ona,7- (3-metilbutoxi) (24,0 por ciento), beta-bisaboleno (12,8 por ciento) y éter metil timol (7,1 por ciento). El aceite de S. adenanthum presentó principalmente pogostol (14,0 por ciento). El aceite de S. riedelli mostró una significativa presencia de compuestos alifáticos, con predominio de ácido hexadecanoico en todas las muestras (hojas, inflorescencias y hojas recolectadas durante del período de la inflorescencia). También el ácido hexadecanoico (23,8 por ciento) fue el principal componente en S. macrocephalum. En cuanto a la actividad antichemotaxica, todas las muestras de aceites ensayadas a concentraciones de 1 a 5 μg/ml, excepto para S. adenanthum, mostraron una inhibición significativa en la migración de leucocitos en comparación con agente quimiotáctico (lipopolisacárido de Escherichia coli – LPS). Estos resultados sugieren que los aceites esenciales provenientes de diferentes especies de Stenachaenium podrían inhibir procesos inflamatorios agudos, debido a que la migración de los neutrófilos se produce principalmente en el proceso inflamatorio temprano.

Cigarette smoking in different manners induces acute lung injury in rats / 浙江大学学报·医学版

To investigate the effects of cigarette smoking in different manners on acute lung injury in rats.The commercially available cigarettes with tar of 1,5, 11 mg were smoked in Canada depth smoking (health canada method, HCM) manner, and those with tar of 11 mg were also smoked in international standard (ISO) smoking manner. Rats were fixed and exposed to mainstream in a manner of nose-mouth exposure. After 28 days, the bronchoalveolar lavage fluids from left lung were collected for counting and classification of inflammatory cells and determination of pro-inflammatory cytokines IL-1β and TNF-α. The right lungs were subjected to histological examination and determination of myeloperoxidase (MPO) and superoxide dismutase (SOD) activities and glutathione, reactive oxygen species (ROS) and malondialdehyde (MDA) levels.In both HCM and ISO manners, the degree of lung injury was closely related to the tar content of cigarettes, and significant decrease in the body weight of rats was observed after smoking for one week. In a HCM manner, smoking with cigarette of 11 mg tar resulted in robust infiltration of macrophages, lymphocytes and neutrophils into lungs, significant increase in IL-1β and TNF-α levels and MPO activities, and significant decrease in GSH levels and SOD activities and increase in ROS and MDA levels (all<0.05). Smoking with cigarette of 5 mg tar led to moderate increase in IL-1β and TNF-α levels, and MPO activities (all<0.05), and moderate decrease in GSH levels and SOD activities and increase of ROS and MDA levels (all<0.05). However, smoking with cigarette of 1 mg tar affected neither inflammatory cell infiltration nor IL-1β and TNF-α levels.Cigarette smoking in nose-mouth exposure manner can induce acute lung injury in rats; and the degree of lung injury is closely related to the content of tar and other hazards in cigarettes.

Functional activity of neutrophilic polymorphonuclear leukocytes in the first five days postpartum / Atividade funcional de leucócitos polimorfonucleares neutrofílicos nos primeiros cinco dias após o parto

PURPOSE: To assess the chemotactic activity and phagocytic response of neutrophilic polymorphonuclear leukocytes among women in the first five days postpartum.METHODS: A prospective, cross-sectional clinical-laboratory study was conducted. Data of 31 postpartum women during the first five days after vaginal delivery were compared with those of 24 healthy non-pregnant non-postpartum women matched for age. The inclusion criteria were postpartum, clinically and obstetrically healthy women; vaginal delivery, singleton pregnancy carried to term; non-hypertensive, hyperglycemic, allergic, malnourished or with autoimmune or neoplastic diseases; not having received vaccines or blood products in the last three months. The Control Group was chosen according to the same inclusion criteria but involving non-pregnant non-postpartum women. The chemotactic activity of neutrophilic polymorphonuclear leukocytes was assessed by determining the distance from directed migration to bacterial lipopolysaccharide, in three Boyden chamber assays. The phagocytic response was identified by assessing the Zymosan particles' ingestion in three assays carried out in Leighton tubes. The Student's t-test was used in the statistical analysis, adopting a 5% level of significance.RESULTS: The chemotactic activity of neutrophilic polymorphonuclear leukocytes from postpartum women in the presence of homologous (73.2±6.9) and autologous (78.6±13.9) sera showed a significant increase compared to the values observed in the Control Group (64.1±4.1 and 66.6±5.4). Both chemotactic response and phagocytosis ingestion phase of neutrophilic polymorphonuclear leukocytes were significantly increased (p<0.05) in postpartum women compared to healthy non-pregnant and non-postpartum women.CONCLUSION: There was an increase in the chemotactic activity and phagocytic response of neutrophilic polymorphonuclear leukocytes during the first five days after vaginal delivery in women.

OBJETIVO: Avaliar a atividade quimiotática e a resposta fagocitária dos leucócitos polimorfonucleares neutrofílicos entre puérperas nos cinco primeiros dias após o parto.MÉTODOS: Um estudo clínico-laboratorial prospectivo e transversal foi realizado. Dados de 31 puérperas nos cinco primeiros dias após o parto vaginal foram comparados aos de 24 mulheres saudáveis não gestantes e não puérperas, por meio da idade. Os critérios de inclusão foram puérperas clínica e obstetricamente saudáveis; parto vaginal; gestação de feto único a termo; não hipertensas, hiperglicêmicas, alérgicas ou desnutridas ou portadoras de doenças autoimunes ou neoplasias; sem terem recebido vacinas ou hemoderivados nos últimos três meses. O Grupo Controle foi selecionado utilizando-se os mesmos critérios, mas com mulheres não gestantes e não puérperas. A atividade quimiotática por leucócitos polimorfonucleares neutrofílicos foi avaliada determinando-se a distância da migração dirigida ao lipopolissacarídeo bacteriano em três ensaios utilizando-se câmaras de Boyden. A resposta fagocitária foi identificada por meio da ingestão de partículas de zymosan em três ensaios, que foram realizados em tubos de Leighton. Na análise estatística, empregou-se o teste tde Student, adotando-se o nível de significância de 5%.RESULTADOS: A atividade quimiotática dos leucócitos polimorfonucleares neutrofílicos de mulheres no pós-parto, na presença de soro homólogo (73,2±6,9) e autólogo (78,6±13,9), mostrou diferença significante quando comparada aos valores observados no Grupo Controle (64,1±4,1 e 66,6±5,4). A resposta quimiotática e a etapa de ingestão da fagocitose por leucócitos polimorfonucleares neutrofílicos apresentaram acréscimos expressivos (p<0,05) em puérperas ao compararem-se aos valores de mulheres saudáveis não gestantes e não puérperas.CONCLUSÃO: Houve um aumento da atividade quimiotática e da resposta fagocitária por leucócitos polimorfonucleares neutrofílicos nos primeiros cinco dias após parto vaginal nas mulheres.

Interleukin-17 is a favorable prognostic marker for colorectal cancer

Purpose. The role of interleukin-17 (IL-17) in the tumor microenvironment is controversial. We analyzed the in situ tumor expression of IL-17 in colorectal cancer (CRC), adenoma and non-tumor tissue to explore the possible correlation of IL-17 expression to clinicopathological characteristics, tumor-infiltrating neutrophils (TINs) and survival in CRC. Methods. We reviewed the records of 78 consecutive patients diagnosed with CRC. Archival tissues were used. Thirty-six patients with colorectal adenoma were also included. From the 78 CRC patients, we randomly chose 40 cases and collected non-tumor tissue at 10 cm from the edge of the resected tumor. Immunohistochemistry was performed using anti-IL-17 and anti-CD15 (targeting neutrophils) antibody, respectively. Real-time PCR was used to detect IL-17 mRNA in different tissues. Associations between IL-17 expression, clinicopathological parameters and prognosis were evaluated. Results. The level of IL-17 mRNA was higher in CRC than in adenoma and non-tumor tissue (P < 0.05). Positive IL-17 protein expression was observed more frequently in CRC as compared to colorectal adenoma and non-tumor tissue, respectively (P < 0.01). IL-17 expression correlated to well differentiation and early stage CRC. The number of CD15+ neutrophils significantly increased in CRC and positively correlated to the expression of IL-17 (P < 0.05). Both Kaplan–Meier analysis and multivariate Cox regression analysis indicated that patients with positive IL-17 expression showed better overall survival. Conclusions. The association between IL-17 expression and the clinicopathological parameters, as well as the clinical outcome suggests a significant role of IL-17 in CRC. IL-17 is a marker of favorable prognosis (AU)

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Manifestación inicial de leucemia linfoblástica aguda en la mama. Descripción de un caso y revisión de la bibliografía / Initial manifestation of acute lymphoblastic leukemia in the breast. Description of a case and a literature review

Presentamos un caso de leucemia linfoblástica aguda (LLA) de células precursoras B en una mujer de 19 años que inició en forma de nódulo único en la mama derecha. La paciente recibió tratamiento con quimioterapia y, posteriormente, transplante HLA (del inglés Human Leukocyte Antigens) idéntico de donante no emparentado. Dos años después de iniciarse la enfermedad, tuvo una recaída y presentó múltiples nódulos bilaterales en las mamas. Hasta la fecha, sólo se han publicado 33 casos de LLA en mama, y sólo 11 de ellos, incluido el nuestro, con afectación mamaria como manifestación inicial de la leucemia. Es importante tener en cuenta la LLA en casos de mujeres jóvenes con lesiones bilaterales y múltiples en mama, ya que los estudios radiológicos son inespecíficos. Estas pacientes, además de un estudio histológico, podrían beneficiarse de un estudio de sangre periférica de inicio con el fin de acelerar el proceso diagnóstico (AU)

We present a case of acute lymphoblastic leukaemia (ALL) in a 19-year female who presented with solitary mass in the right breast as an initial presentation of the disease. The patient received chemotherapy treatment with the PETHEMA LAL-high risk 2003 protocol, and later an HLA-identical bone marrow transplantation was performed. Two years after onset of the disease she had a recurrence, having multiple nodes in both breasts. She then had an HLA-identical bone marrow transplantation from was performed. Two years later, she showed recurrence of ALL in both breasts. To the best of our knowledge, only 33 cases have been reported in the literature, and in only 11 of them, including our, the infiltration of the breast was the initial presentation of the disease. A high level of suspicion is important in those cases of young women with bilateral and multiple masses, because unfortunately there is no reliable imaging pattern suggestive of leukemic infiltration of the breast. In addition to a histological study, a complete blood count should be performed at start up to speed up the diagnosis (AU)

Identification of novel peptides that stimulate human neutrophils

Neutrophils play a key role in innate immunity, and the identification of new stimuli that stimulate neutrophil activity is a very important issue. In this study, we identified three novel peptides by screening a synthetic hexapeptide combinatorial library. The identified peptides GMMWAI, MMHWAM, and MMHWFM caused an increase in intracellular Ca2+ in a concentration-dependent manner via phospholipase C activity in human neutrophils. The three peptides acted specifically on neutrophils and monocytes and not on other non-leukocytic cells. As a physiological characteristic of the peptides, we observed that the three peptides induced chemotactic migration of neutrophils as well as stimulated superoxide anion production. Studying receptor specificity, we observed that two of the peptides (GMMWAI and MMHWFM) acted on formyl peptide receptor (FPR)1 while the other peptide (MMHWAM) acted on FPR2. Since the three novel peptides were specific agonists for FPR1 or FPR2, they might be useful tools to study FPR1- or FPR2-mediated immune response and signaling.

Papel do hormônio insulina na modulação dos fenômenos inflamatórios / Role of insulin hormone in modulation of inflammatory phenomena

Evidence demonstrates the involvement of hormones in the development of inflammatory response. Inflammation evokes marked structural alterations of microvasculature, besides migration of leukocytes from microcirculation to the site of lesion. These alterations are caused primarily by release or activation of endogenous mediators, in which hormones play an integral role in this regulatory system. Binding sites for many hormones may be characterized by vascular structures and hematogenous cells involved with the inflammatory response. Quantitative alterations of inflammatory events involving the decrease in microvascular response to inflammatory mediators, deficiency in the leukocyte-endothelium interaction, reduction of cell concentration in the inflammatory exudate, and failure of the phagocyte function of mononuclear cells were observed in insulin-deficient states. Therefore, inflammation is not merely a local response, but rather a process controlled by hormones in which insulin plays an essential role in modulation of these phenomena, and assures tissue repair and emodeling within the limits of normality.

Evidências demonstram o envolvimento dos hormônios no desenvolvimento da resposta inflamatória. A inflamação evoca alterações estruturais marcantes da microvasculatura, além da migração dos leucócitos da microcirculação para o foco da lesão. Essas alterações são ocasionadas principalmente pela liberação ou ativação de mediadores endógenos, na qual os hormônios participam integralmente desse sistema regulador. Sítios de ligação para muitos hormônios podem ser caracterizados em estruturas vasculares e células hematógenas envolvidas com a resposta inflamatória. Alterações quantitativas dos eventos inflamatórios envolvendo a diminuição da resposta microvascular aos mediadores inflamatórios, deficiência entre a interação leucócito-endotélio, redução da concentração celular no exudato inflamatório e falha na função fagocitária dos mononucleares foram observadas em estados insulino-deficientes. Portanto, a inflamação não é meramente uma resposta local, mas um processo controlado por hormônios, no qual a insulina desempenha um papel essencial modulando esses fenômenos, e assegurando uma reparação e um remodelamento tecidual dentro dos limites da normalidade.

Intratumoral Administration of Secondary Lymphoid Chemokine and Unmethylated Cytosine-phosphorothioate-guanine Oligodeoxynucleotide Synergistically Inhibits Tumor Growth in Vivo

Secondary lymphoid tissue chemokine (SLC), which is expressed in T cell zones of secondary lymphoid organs, including the spleen and lymph nodes, strongly recruits both T lymphocytes and mature dendritic cells. As appropriate interaction of tumor-specific T cells and mature dendritic cells, equipped with tumor antigens, is a prerequisite for effective T cell immunity against established tumors, we mobilized lymphocytes and dendritic cells to tumor sites by intratumoral injection of secondary lymphoid tissue chemokine-Fc (SLC-Fc) fusion protein using the B16F10 murine melanoma model. Activation of dendritic cells, another prerequisite for the effective activation of naive tumor-specific T cells, was achieved by the addition of immunostimulatory cytosine-phosphorothioate-guanine oligodeoxynucleotide (CpG-ODN) into the tumor site. Intratumoral administration of SLC-Fc or CpG-ODN revealed antitumor effects against B16F10 murine melanoma grown in the subcutaneous space. Co-treatment of SLC-Fc and CpG-ODN displayed synergistic effects in reducing the tumor size. The synergistic antitumor effect in co-treatment group was correlated with the synergistic/additive increase in the infiltration of CD4+ T cells and CD11c+ dendritic cells in the tumor mass compared to the single treatment groups. These results suggest that the combined use of chemokines and adjuvant molecules may be a possible strategy in clinical tumor immunotherapy.

Lysophosphatidylglycerol inhibits formyl peptide receptor like-1-stimulated chemotactic migration and IL-1beta production from human phagocytes

In this study, we observed that lysophosphatidylglycerol (LPG) completely inhibited a formyl peptide receptor like-1 (FPRL1) agonist (MMK-1)-stimulated chemotactic migration in human phagocytes, such as neutrophils and monocytes. LPG also dramatically inhibited IL-1beta production by another FPRL1 agonist serum amyloid A (SAA) in human phagocytes. However, LPG itself induced intracellular calcium increase and superoxide anion production in human phagocytes. Keeping in mind that phagocytes migration and IL-1beta production by FPRL1 are important for the induction of inflammatory response, our data suggest that LPG can be regarded as a useful material for the modulation of inflammatory response induced by FPRL1 activation.

LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.

LL-37 inhibits serum amyloid A-induced IL-8 production in human neutrophils

Serum amyloid A (SAA) has been regarded as an important mediator of inflammatory responses. The effect of several formyl peptide receptor-like 1 (FPRL1) ligands on the production of IL-8 by SAA was investigated in human neutrophils. Among the ligands tested, LL-37 was found to specifically inhibit SAA-induced IL-8 production in transcriptional and post-transcriptional levels. Since SAA stimulated IL-8 production via ERK and p38 MAPK in human neutrophils, we tested the effect of LL-37 on SAA induction for these two MAPKs. LL-37 caused a dramatic inhibition of ERK and p38 MAPK activity, which is induced by SAA. LL-37 was also found to inhibit SAA-stimulated neutrophil chemotactic migration. Further, the LL-37-induced inhibitory effect was mediated by FPRL1. Our findings indicate that LL-37 is expected to be useful in the inhibition of SAA signaling and for the development of drugs against SAA-related inflammatory diseases.

Construction of murine CCL21 eukaryotic expression plasmid and chemotactic function of its products / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To construct the murine CCL21 eukaryotic expression plasmid, and to investigate the chemotactic function of its products.</p><p><b>METHODS</b>Murine CCL21 cDNA was amplified by RT-PCR from murine total RNA, and was inserted into eukaryotic expression plasmid pcDNA3.1 after confirmation of sequencing. The recombinant CCL21 plasmid was transferred into mouse forestomach carcinoma (MFC) cells and the chemotactic function of expressed products was detected by chemotaxis assay.</p><p><b>RESULT</b>Gene sequencing, gel electrophoresis of PCR products and restrictive digestion proved the successful construction of CCL21, and its expression was confirmed by Western Blot. The transfected tumor cells had a significant chemotactic function to DC.</p><p><b>CONCLUSION</b>The recombinant murine CCL21 eukaryotic expression plasmid has been successfully constructed, and its expression products in tumor cells have a marked chemotactic function to DC.</p>

Función endotelial en la arteria que causa el infarto: ¿es importante la modalidad del tratamiento de reperfusión? / No disponible

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