RESUMO
BACKGROUND: Benralizumab is an eosinophil-depleting anti-interleukin-5 receptor α monoclonal antibody. The efficacy and safety of benralizumab in patients with eosinophilic esophagitis are unclear. METHODS: In a phase 3, multicenter, double-blind, randomized, placebo-controlled trial, we assigned patients 12 to 65 years of age with symptomatic and histologically active eosinophilic esophagitis in a 1:1 ratio to receive subcutaneous benralizumab (30 mg) or placebo every 4 weeks. The two primary efficacy end points were histologic response (≤6 eosinophils per high-power field) and the change from baseline in the score on the Dysphagia Symptom Questionnaire (DSQ; range, 0 to 84, with higher scores indicating more frequent or severe dysphagia) at week 24. RESULTS: A total of 211 patients underwent randomization: 104 were assigned to receive benralizumab, and 107 were assigned to receive placebo. At week 24, more patients had a histologic response with benralizumab than with placebo (87.4% vs. 6.5%; difference, 80.8 percentage points; 95% confidence interval [CI], 72.9 to 88.8; P<0.001). However, the change from baseline in the DSQ score did not differ significantly between the two groups (difference in least-squares means, 3.0 points; 95% CI, -1.4 to 7.4; P = 0.18). There was no substantial between-group difference in the change from baseline in the Eosinophilic Esophagitis Endoscopic Reference Score, which reflects endoscopic abnormalities. Adverse events were reported in 64.1% of the patients in the benralizumab group and in 61.7% of those in the placebo group. No patients discontinued the trial because of adverse events. CONCLUSIONS: In this trial involving patients 12 to 65 years of age with eosinophilic esophagitis, a histologic response (≤6 eosinophils per high-power field) occurred in significantly more patients in the benralizumab group than in the placebo group. However, treatment with benralizumab did not result in fewer or less severe dysphagia symptoms than placebo. (Funded by AstraZeneca; MESSINA ClinicalTrials.gov number, NCT04543409.).
Assuntos
Anticorpos Monoclonais Humanizados , Esofagite Eosinofílica , Eosinófilos , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/tratamento farmacológico , Método Duplo-Cego , Esofagite Eosinofílica/tratamento farmacológico , Esofagite Eosinofílica/imunologia , Subunidade alfa de Receptor de Interleucina-5/antagonistas & inibidores , Contagem de LeucócitosRESUMO
BACKGROUND: Dupilumab, a fully human monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation, has shown efficacy and safety in a phase 3 trial involving patients with chronic obstructive pulmonary disease (COPD) and type 2 inflammation and an elevated risk of exacerbation. Whether the findings would be confirmed in a second phase 3 trial was unclear. METHODS: In a phase 3, double-blind, randomized trial, we assigned patients with COPD who had a blood eosinophil count of 300 cells per microliter or higher to receive subcutaneous dupilumab (300 mg) or placebo every 2 weeks. The primary end point was the annualized rate of moderate or severe exacerbations. Key secondary end points, analyzed in a hierarchical manner to adjust for multiplicity, included the changes from baseline in the prebronchodilator forced expiratory volume in 1 second (FEV1) at weeks 12 and 52 and in the St. George's Respiratory Questionnaire (SGRQ; scores range from 0 to 100, with lower scores indicating better quality of life) total score at week 52. RESULTS: A total of 935 patients underwent randomization: 470 were assigned to the dupilumab group and 465 to the placebo group. As prespecified, the primary analysis was performed after a positive interim analysis and included all available data for the 935 participants, 721 of whom were included in the analysis at week 52. The annualized rate of moderate or severe exacerbations was 0.86 (95% confidence interval [CI], 0.70 to 1.06) with dupilumab and 1.30 (95% CI, 1.05 to 1.60) with placebo; the rate ratio as compared with placebo was 0.66 (95% CI, 0.54 to 0.82; P<0.001). The prebronchodilator FEV1 increased from baseline to week 12 with dupilumab (least-squares mean change, 139 ml [95% CI, 105 to 173]) as compared with placebo (least-squares mean change, 57 ml [95% CI, 23 to 91]), with a significant least-squares mean difference at week 12 of 82 ml (P<0.001) and at week 52 of 62 ml (P = 0.02). No significant between-group difference was observed in the change in SGRQ scores from baseline to 52 weeks. The incidence of adverse events was similar in the two groups and consistent with the established profile of dupilumab. CONCLUSIONS: In patients with COPD and type 2 inflammation as indicated by elevated blood eosinophil counts, dupilumab was associated with fewer exacerbations and better lung function than placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; NOTUS ClinicalTrials.gov number, NCT04456673.).
Assuntos
Anticorpos Monoclonais Humanizados , Eosinófilos , Doença Pulmonar Obstrutiva Crônica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Eosinófilos/imunologia , Volume Expiratório Forçado/efeitos dos fármacos , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/imunologia , Injeções Subcutâneas , Contagem de Leucócitos , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Qualidade de Vida , Progressão da Doença , Fumar/efeitos adversosRESUMO
ABSTRACT: Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of hematopoietic progenitor cells and is associated with an increased risk of thrombotic events (TEs). Established risk factors for TEs in patients with PV include advanced age, TE history, and elevated hematocrit. Although an association of TE with elevated white blood cell (WBC) counts has been suggested by retrospective studies, this relationship needs further validation. The prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL) study collected prospective clinical data from 2510 patients with PV with a median follow-up of 44.7 months (range, 2-59 months) from enrollment. Using time-dependent covariate Cox proportional hazards models, blood counts were individually modeled with sex, age, disease duration, TE history at enrollment (baseline covariates), and treatment (time-dependent covariate). Analysis of 2271 participants identified 142 TEs in 106 patients. Significant associations with initial TE occurrence during the study period were observed for hematocrit level >45% (hazard ratio [HR], 1.84; 95% confidence interval [95% CI], 1.234-2.749; P = .0028) and WBCs >11 × 109/L (HR, 2.35; 95% CI, 1.598-3.465; P < .0001). Elevated WBC count was significantly associated with initial TE occurrence in both low-risk and high-risk PV. When hematocrit was controlled at ≤45%, WBC count >12 × 109/L was significantly associated with TE occurrence (HR, 1.95; 95% CI, 1.066-3.554; P = .0300). The results support incorporation of WBC count into PV risk stratification and studies of treatment strategies, and indicate the importance of controlling both hematocrit and WBC count in disease management. This trial was registered at www.clinicaltrials.gov as #NCT02252159.
Assuntos
Policitemia Vera , Trombose , Humanos , Policitemia Vera/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Trombose/etiologia , Fatores de Risco , Contagem de LeucócitosRESUMO
The gut microbiota influences development1-3 and homeostasis4-7 of the mammalian immune system, and is associated with human inflammatory8 and immune diseases9,10 as well as responses to immunotherapy11-14. Nevertheless, our understanding of how gut bacteria modulate the immune system remains limited, particularly in humans, where the difficulty of direct experimentation makes inference challenging. Here we study hundreds of hospitalized-and closely monitored-patients with cancer receiving haematopoietic cell transplantation as they recover from chemotherapy and stem-cell engraftment. This aggressive treatment causes large shifts in both circulatory immune cell and microbiota populations, enabling the relationships between the two to be studied simultaneously. Analysis of observed daily changes in circulating neutrophil, lymphocyte and monocyte counts and more than 10,000 longitudinal microbiota samples revealed consistent associations between gut bacteria and immune cell dynamics. High-resolution clinical metadata and Bayesian inference allowed us to compare the effects of bacterial genera in relation to those of immunomodulatory medications, revealing a considerable influence of the gut microbiota-together and over time-on systemic immune cell dynamics. Our analysis establishes and quantifies the link between the gut microbiota and the human immune system, with implications for microbiota-driven modulation of immunity.
Assuntos
Microbioma Gastrointestinal/imunologia , Leucócitos/citologia , Leucócitos/imunologia , Fatores Etários , Teorema de Bayes , Transplante de Microbiota Fecal , Feminino , Humanos , Contagem de Leucócitos , Linfócitos/citologia , Linfócitos/imunologia , Monócitos/citologia , Monócitos/imunologia , Neutrófilos/citologia , Neutrófilos/imunologia , Reprodutibilidade dos TestesRESUMO
As an essential component of immunity, macrophages have key roles in mammalian host defense, tissue homeostasis, and repair, as well as in disease pathogenesis and pathophysiology. A source of fascination and extensive research, in this Opinion we challenge the utility of the M1-M2 paradigm, and discuss the importance of accurate characterization of human macrophages. We comment on the application of single cell analytics to define macrophage subpopulations and how this could advance therapeutic options. We argue that human macrophage cell therapy can be used to alleviate many diseases, and offer a viewpoint on the knowledge gaps that must be filled to render such a therapeutic approach a reality and, ideally, a common future practice in precision medicine.
Assuntos
Fatores Imunológicos , Imunoterapia , Animais , Humanos , Macrófagos , Medicina de Precisão , Contagem de Leucócitos , MamíferosRESUMO
Community-acquired pneumonia (CAP) is a leading cause of hospitalization and mortality in the elderly. The peripheral blood neutrophil CD64 (nCD64) index is increasingly recognized for its association with poor pneumonia prognosis. A comprehensive investigation involving 128 elderly patients diagnosed with CAP, including 96 with non-severe CAP and 32 with severe CAP, from January 2020 to January 2021 was performed. The nCD64 index, CD4+, CD8+, C-reactive protein (CRP), white blood cell (WBC) count, procalcitonin (PCT), neutrophil (NEUT), and B lymphocyte count were determined using flow cytometry. Our findings reveal that patients with severe CAP exhibited significantly higher levels of nCD64 index, NEUT, WBC, CRP, and PCT. Intriguingly, lower CRP, nCD64 index, CURB-65 score, and PCT were associated with a higher survival rate. Notably, the nCD64 index demonstrated remarkable predictive efficiency for 28-d survival in CAP patients [area under the curve (AUC) = 0.907], surpassing other markers and even showing enhanced predictive power when combined with the CURB-65 score (AUC = 0.905). Furthermore, a negative association was observed between the nCD64 index and both CD4+, CD4+/CD8+ ratios, and B lymphocytes, highlighting its potential role in immune dysregulation. These findings underscore the critical importance of the nCD64 index in the early diagnosis, risk stratification, and prognostic evaluation of infections and immune responses in elderly CAP patients.
Assuntos
Infecções Comunitárias Adquiridas , Pneumonia , Humanos , Idoso , Prognóstico , Neutrófilos , Proteína C-Reativa/análise , Pneumonia/diagnóstico , Contagem de Leucócitos , Infecções Comunitárias Adquiridas/diagnósticoRESUMO
LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes), encoded by the TNFSF14 gene, is a cytokine belonging to the TNF superfamily. On binding to its receptors, herpes virus entry mediator and lymphotoxin ß receptor, it activates inflammatory responses. We conducted this study to determine whether plasma LIGHT levels are elevated in Crohn's disease (CD) in a pediatric population with the aim of nominating this cytokine as a therapeutic target. We used a single-molecule immunoassay to determine the circulating levels of free LIGHT in plasma from pediatric patients with CD in our biobank (n = 183), a panel of healthy pediatric (n = 9) or adult (n = 22) reference samples, and pediatric biobank controls (n = 19). We performed correlational analyses between LIGHT levels and the clinical characteristics of the CD cohort, including age, Montreal classification, family history, medical/surgical therapy, and routine blood test parameters. LIGHT levels were greatly elevated in CD, with an average of 305 versus 32.4 pg/ml for controls from the biobank (p < 0.0001). The outside reference samples showed levels of 57 pg/ml in pediatric controls and 55 pg/ml in adults (p < 0.0001). We found a statistically significant correlation between white blood cell count and free LIGHT (p < 0.046). We conclude that free, soluble LIGHT is increased 5- to 10-fold in pediatric CD across an array of disease subtypes and characteristics.
Assuntos
Doença de Crohn , Adulto , Criança , Humanos , Citocinas , Contagem de Leucócitos , Linfotoxina-alfaRESUMO
C-type lectin domain family 4, member a4 (Clec4a4) is a C-type lectin inhibitory receptor specific for glycans thought to be exclusively expressed on murine CD8α− conventional dendritic cells. Using newly generated Clec4a4-mCherry knock-in mice, we identify a subset of Clec4a4-expressing eosinophils uniquely localized in the small intestine lamina propria. Clec4a4+ eosinophils evinced an immunomodulatory signature, whereas Clec4a4− eosinophils manifested a proinflammatory profile. Clec4a4+ eosinophils expressed high levels of aryl hydrocarbon receptor (Ahr), which drove the expression of Clec4a4 as well as other immunomodulatory features, such as PD-L1. The abundance of Clec4a4+ eosinophils was dependent on dietary AHR ligands, increased with aging, and declined in inflammatory conditions. Mice lacking AHR in eosinophils expanded innate lymphoid cells of type 2 and cleared Nippostrongylus brasiliensis infection more effectively than did wild-type mice. These results highlight the heterogeneity of eosinophils in response to tissue cues and identify a unique AHR-dependent subset of eosinophils in the small intestine with an immunomodulatory profile.
Assuntos
Eosinófilos , Receptores de Hidrocarboneto Arílico , Receptores de Superfície Celular , Eosinofilia/terapia , Hipersensibilidade Alimentar/terapia , Imunomodulação , Intestino Delgado , Contagem de Leucócitos , Ligantes , Receptores de Hidrocarboneto Arílico/genéticaRESUMO
BACKGROUND: Blood eosinophils and fractional exhaled nitric oxide (Feno) are prognostic biomarkers for exacerbations and predict lung function responses to dupilumab in adolescents and adults with asthma. OBJECTIVE: We evaluated the relationship between baseline blood eosinophils and Feno and response to dupilumab in children with asthma. METHODS: Children aged 6 to 11 years with uncontrolled moderate-to-severe asthma (n = 408) were randomized to receive dupilumab 100/200 mg by body weight or volume-matched placebo every 2 weeks for 52 weeks. Annualized exacerbation rate (AER) reduction and least squares mean change in prebronchodilator percent predicted forced expiratory volume in 1 second (ppFEV1) at week 12 were assessed according to cutoff baseline levels for Feno (<20 ppb vs ≥20 ppb) and blood eosinophil count (<150, ≥150 to <300, ≥300 to <500, and ≥500 cells/µL). Quadrant analyses in populations defined by biomarker thresholds and spline models across continuous end points assessed the relationship with Feno and eosinophil count. Interaction testing evaluated the independent roles of Feno and blood eosinophils as predictive markers. RESULTS: Exacerbation risk and magnitude of AER reduction increased in subgroups with higher baseline biomarker levels. Quadrant analyses revealed that disease of patients with either elevated Feno or eosinophil counts demonstrated a clinical response to dupilumab. Interaction testing indicated blood eosinophil counts or Feno independently added value as predictive biomarkers. CONCLUSIONS: In children with uncontrolled moderate-to-severe asthma, blood eosinophil counts and Feno are clinically relevant biomarkers to identify those at risk for asthma exacerbations, as well as those with disease with clinical response to dupilumab. TRIAL REGISTRATION: Liberty Asthma VOYAGE ClinicalTrials.gov NCT02948959.
Assuntos
Anticorpos Monoclonais Humanizados , Asma , Biomarcadores , Eosinófilos , Óxido Nítrico , Humanos , Asma/tratamento farmacológico , Asma/diagnóstico , Asma/metabolismo , Criança , Eosinófilos/imunologia , Masculino , Feminino , Óxido Nítrico/metabolismo , Prognóstico , Anticorpos Monoclonais Humanizados/uso terapêutico , Teste da Fração de Óxido Nítrico Exalado , Contagem de Leucócitos , Antiasmáticos/uso terapêutico , ExpiraçãoRESUMO
Macrophages are an integral part of all organs in the body, where they contribute to immune surveillance, protection, and tissue-specific homeostatic functions. This is facilitated by so-called niches composed of macrophages and their surrounding stroma. These niches structurally anchor macrophages and provide them with survival factors and tissue-specific signals that imprint their functional identity. In turn, macrophages ensure appropriate functioning of the niches they reside in. Macrophages thus form reciprocal, mutually beneficial circuits with their cellular niches. In this review, we explore how this concept applies to the spleen, a large secondary lymphoid organ whose primary functions are to filter the blood and regulate immunity. We first outline the splenic micro-anatomy, the different populations of splenic fibroblasts and macrophages and their respective contribution to protection of and key physiological processes occurring in the spleen. We then discuss firmly established and potential cellular circuits formed by splenic macrophages and fibroblasts, with an emphasis on the molecular cues underlying their crosstalk and their relevance to splenic functionality. Lastly, we conclude by considering how these macrophage-fibroblast circuits might be impaired by aging, and how understanding these changes might help identify novel therapeutic avenues with the potential of restoring splenic functions in the elderly.
Assuntos
Macrófagos , Baço , Idoso , Fibroblastos , Homeostase , Humanos , Contagem de LeucócitosRESUMO
Hepatitis B virus (HBV) damages liver cells through abnormal immune responses. Mitochondrial metabolism is necessary for effector functions of white blood cells (WBCs). The aim was to investigate the altered counts and mitochondrial mass (MM) of WBCs by two novel indicators of mitochondrial mass, MM and percentage of low mitochondrial membrane potential, MMPlow%, due to chronic HBV infection. The counts of lymphocytes, neutrophils and monocytes in the HBV infection group were in decline, especially for lymphocyte (p = 0.034) and monocyte counts (p = 0.003). The degraded MM (p = 0.003) and MMPlow% (p = 0.002) of lymphocytes and MM (p = 0.005) of monocytes suggested mitochondrial dysfunction of WBCs. HBV DNA within WBCs showed an extensive effect on mitochondria metabolic potential of lymphocytes, neutrophils and monocytes indicated by MM; hepatitis B e antigen was associated with instant mitochondrial energy supply indicated by MMPlow% of neutrophils; hepatitis B surface antigen, antiviral therapy by nucleos(t)ide analogues and prolonged infection were also vital factors contributing to WBC alterations. Moreover, degraded neutrophils and monocytes could be used to monitor immune responses reflecting chronic liver fibrosis and inflammatory damage. In conclusion, MM combined with cell counts of WBCs could profoundly reflect WBC alterations for monitoring chronic HBV infection. Moreover, HBV DNA within WBCs may be a vital factor in injuring mitochondria metabolic potential.
Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Mitocôndrias , Humanos , Hepatite B Crônica/virologia , Hepatite B Crônica/patologia , Masculino , Feminino , Vírus da Hepatite B/patogenicidade , Adulto , Mitocôndrias/metabolismo , Pessoa de Meia-Idade , Contagem de Leucócitos , Leucócitos/metabolismo , DNA Viral/sangue , Potencial da Membrana Mitocondrial , Monócitos/metabolismo , Monócitos/imunologia , Monócitos/virologia , Monócitos/patologia , Neutrófilos/metabolismo , Neutrófilos/imunologiaRESUMO
Monocytes are innate immune cells that are continuously produced in bone marrow which enter and circulate the vasculature. In response to nutrient scarcity, monocytes migrate back to bone marrow, where, upon refeeding, they are rereleased back into the bloodstream to replenish the circulation. In humans, the variability in monocyte behavior in response to fasting and refeeding has not been characterized. To investigate monocyte dynamics in humans, we measured blood monocyte fluctuations in 354 clinically healthy individuals after a 12-h overnight fast and at 3 and 6 h after consuming a mixed macronutrient challenge meal. Using cluster analysis, we identified three distinct monocyte behaviors. Group 1 was characterized by relatively low fasting monocyte counts that markedly increased after consuming the test meal. Group 2 was characterized by relatively high fasting monocyte counts that decreased after meal consumption. Group 3, like Group 1, was characterized by lower fasting monocyte counts but increased to a lesser extent after consuming the meal. Although monocyte fluctuations observed in Groups 1 and 3 align with the current paradigm of monocyte dynamics in response to fasting and refeeding, the atypical dynamic observed in Group 2 does not. Although generally younger in age, Group 2 subjects had lower whole body carbohydrate oxidation rates, lower HDL-cholesterol levels, delayed postprandial declines in salivary cortisol, and reduced postprandial peripheral microvascular endothelial function. These unique characteristics were not explained by group differences in age, sex, or body mass index (BMI). Taken together, these results highlight distinct patterns of monocyte responsiveness to natural fluctuations in dietary fuel availability.NEW & NOTEWORTHY Our study composed of adult volunteers revealed that monocyte dynamics exhibit a high degree of individual variation in response to fasting and refeeding. Although circulating monocytes in most volunteers behaved in ways that align with previous reports, many exhibited atypical dynamics demonstrated by elevated fasting blood monocyte counts that sharply decreased after meal consumption. This group was also distinguished by lower HDL levels, reduced postprandial endothelial function, and a delayed postprandial decline in salivary cortisol.
Assuntos
Jejum , Hidrocortisona , Monócitos , Período Pós-Prandial , Humanos , Período Pós-Prandial/fisiologia , Jejum/fisiologia , Masculino , Feminino , Adulto , Monócitos/metabolismo , Hidrocortisona/sangue , Hidrocortisona/metabolismo , Pessoa de Meia-Idade , Adulto Jovem , Voluntários Saudáveis , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Idoso , Contagem de Leucócitos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/metabolismoRESUMO
Observational studies have suggested a protective role for eosinophils in colorectal cancer (CRC) development and implicated neutrophils, but the causal relationships remain unclear. Here, we aimed to estimate the causal effect of circulating white blood cell (WBC) counts (N = ~550 000) for basophils, eosinophils, monocytes, lymphocytes and neutrophils on CRC risk (N = 52 775 cases and 45 940 controls) using Mendelian randomisation (MR). For comparison, we also examined this relationship using individual-level data from UK Biobank (4043 incident CRC cases and 332 773 controls) in a longitudinal cohort analysis. The inverse-variance weighted (IVW) MR analysis suggested a protective effect of increased basophil count and eosinophil count on CRC risk [OR per 1-SD increase: 0.88, 95% CI: 0.78-0.99, P = .04; OR: 0.93, 95% CI: 0.88-0.98, P = .01]. The protective effect of eosinophils remained [OR per 1-SD increase: 0.88, 95% CI: 0.80-0.97, P = .01] following adjustments for all other WBC subtypes, to account for genetic correlation between the traits, using multivariable MR. A protective effect of increased lymphocyte count on CRC risk was also found [OR: 0.84, 95% CI: 0.76-0.93, P = 6.70e-4] following adjustment. Consistent with MR results, a protective effect for eosinophils in the cohort analysis in the fully adjusted model [RR per 1-SD increase: 0.96, 95% CI: 0.93-0.99, P = .02] and following adjustment for the other WBC subtypes [RR: 0.96, 95% CI: 0.93-0.99, P = .001] was observed. Our study implicates peripheral blood immune cells, in particular eosinophils and lymphocytes, in CRC development, highlighting a need for mechanistic studies to interrogate these relationships.
Assuntos
Neoplasias Colorretais , Eosinófilos , Humanos , Contagem de Leucócitos , Neutrófilos , Fenótipo , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Análise da Randomização Mendeliana/métodos , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Eosinophils exhibit anti-tumor cytotoxic responses in the tumor microenvironment and may contribute to tumor immunosurveillance. To assess the relationship between circulating eosinophils and cancer risk, we analyzed data from 443,542 adults aged 38-73 in the UK Biobank, who were initially cancer-free, had over a year of follow-up, and baseline white blood cell count measurements. Using multivariable Cox regression, we estimated hazard ratios (aHR) and 95% confidence intervals (95%CI) for each quartile increase in absolute eosinophil count (AEC) across 58 cancer types, adjusting for relevant confounders. During a median follow-up of 5.8 years, 22,747 incident cancer cases were diagnosed. We observed an inverse association, which met Bonferroni significance, between AEC and overall cancer risk (aHR, 95%CI 0.97, 0.95-0.98). Notably, 16 cancer types showed borderline associations (p <.05) with AEC, with 12 types displaying an inverse relationship. These included four hematologic cancers (acute and other myeloid leukemia, other lymphocytic leukemia, and chronic lymphocytic leukemia/small lymphocytic lymphoma; aHR range; 0.58-0.87) and eight nonhematologic cancers (melanoma and nose/middle ear, soft tissue/heart, gum/other mouth, tongue, lung, colon, and breast cancers; aHR range: 0.65-0.95). Higher AEC showed a borderline significant association with increased risk for intrahepatic bile duct cancer, Hodgkin lymphoma, diffuse large B-cell lymphoma, and chronic myeloid leukemia (aHR range: 1.13-1.42). Our study, the largest to date, provides insights into the relationship between blood eosinophils and a comprehensive list of incident cancers. The inverse association between AEC and overall cancer risk suggests a protective role for eosinophils in tumor surveillance.
Assuntos
Bancos de Espécimes Biológicos , Eosinófilos , Neoplasias , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Reino Unido/epidemiologia , Idoso , Neoplasias/epidemiologia , Adulto , Fatores de Risco , Contagem de Leucócitos , Incidência , Seguimentos , Modelos de Riscos Proporcionais , Biobanco do Reino UnidoRESUMO
The degree of anaemia in sickle cell disease (SCD) is a well-known contributor to morbidity and mortality. We aimed to explore the factors affecting haemoglobin (Hb) level in African SCD patients, considering haemolysis biomarkers (LDH and bilirubin level, and reticulocyte count), leucocyte and platelet counts and socio-demographic characteristics (gender, age group, country of residence and BMI). The research was part of the CADRE multinational cohort and involved 3699 SCD patients living in Mali, Senegal, Ivory Coast, Democratic Republic of Congo, Gabon and Cameroon: 2936 SS/Sß0, 587 SC and 176 Sß + patients with median Hb level of 8, 11.3 and 11.2 g/dL respectively (p < 0.001). In multivariate analysis conducted in 1394 SS/Sß0 patients, living in Cameroon, female gender, lower BMI, higher haemolysis markers (especially LDH) and higher leucocyte and platelet counts were independently associated with lower Hb level (all p < 0.05). In 497 SC and 156 Sß + patients, female gender (p < 0.001), lower BMI (p < 0.05) and higher platelet counts (p < 0.001) were independently associated with lower Hb level. Anaemia in African SCD patients is not only associated with haemolysis but also with the country of residence, lower BMI and leucocyte or platelet counts which might reflect inflammation related to infectious burden in the region.
Assuntos
Anemia Falciforme , Hemoglobinas , Hemólise , Humanos , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/epidemiologia , Masculino , Feminino , Adulto , Hemoglobinas/análise , Adolescente , Contagem de Plaquetas , África Subsaariana/epidemiologia , Criança , Contagem de Leucócitos , Adulto Jovem , Pré-Escolar , Pessoa de Meia-Idade , Biomarcadores/sangueRESUMO
BACKGROUND: Outcomes in children and adolescents with recurrent or progressive high-grade glioma are poor, with a historical median overall survival of 5.6 months. Pediatric high-grade gliomas are largely immunologically silent or "cold," with few tumor-infiltrating lymphocytes. Preclinically, pediatric brain tumors are highly sensitive to oncolytic virotherapy with genetically engineered herpes simplex virus type 1 (HSV-1) G207, which lacks genes essential for replication in normal brain tissue. METHODS: We conducted a phase 1 trial of G207, which used a 3+3 design with four dose cohorts of children and adolescents with biopsy-confirmed recurrent or progressive supratentorial brain tumors. Patients underwent stereotactic placement of up to four intratumoral catheters. The following day, they received G207 (107 or 108 plaque-forming units) by controlled-rate infusion over a period of 6 hours. Cohorts 3 and 4 received radiation (5 Gy) to the gross tumor volume within 24 hours after G207 administration. Viral shedding from saliva, conjunctiva, and blood was assessed by culture and polymerase-chain-reaction assay. Matched pre- and post-treatment tissue samples were examined for tumor-infiltrating lymphocytes by immunohistologic analysis. RESULTS: Twelve patients 7 to 18 years of age with high-grade glioma received G207. No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigators. Twenty grade 1 adverse events were possibly related to G207. No virus shedding was detected. Radiographic, neuropathological, or clinical responses were seen in 11 patients. The median overall survival was 12.2 months (95% confidence interval, 8.0 to 16.4); as of June 5, 2020, a total of 4 of 11 patients were still alive 18 months after G207 treatment. G207 markedly increased the number of tumor-infiltrating lymphocytes. CONCLUSIONS: Intratumoral G207 alone and with radiation had an acceptable adverse-event profile with evidence of responses in patients with recurrent or progressive pediatric high-grade glioma. G207 converted immunologically "cold" tumors to "hot." (Supported by the Food and Drug Administration and others; ClinicalTrials.gov number, NCT02457845.).
Assuntos
Neoplasias Encefálicas/terapia , Glioma/terapia , Terapia Viral Oncolítica , Adolescente , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Criança , Pré-Escolar , Terapia Combinada , Feminino , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/radioterapia , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais , Contagem de Leucócitos , Masculino , Terapia Viral Oncolítica/efeitos adversos , Linfócitos TRESUMO
The accurate and efficient measurement of white blood cell (WBC) counts is vital for monitoring general patient health and can aid in the diagnosis of a range of possible infections or diseases. Even with their importance universally acknowledged, access to WBC counts is largely limited to those with access to phlebotomists and centralized clinical laboratories, which house the instruments that perform the tests. As a result, large populations of people (e.g., those that are home-bound or live in remote locations) lack facile access to testing. Dried blood spot (DBS) cards are often used to bridge these gaps in access to testing by offering the ability to collect blood at home for ambient shipping to laboratories. However, it is well understood that these cards, which are prepared from cellulose cardstocks without further modification, suffer from variabilities in accuracy and precision due to uncontrolled sample spreading and hematocrit effects, which have hindered their use to determine WBC counts. In this paper, we present a method to obtain an accurate WBC count using a patterned dried blood spot (pDBS) card, which comprises collection zones that meter volumes of dried blood. Using an input volume of 75 µL of whole blood, we demonstrate that, unlike the gold standard DBS card (Whatman 903), our pDBS design allows for the collection of replicate zones containing a reproducible, average volume of dried blood (12.1 µL, 7.8% CV) over the range of hematocrits from 25 to 55%. We then used qPCR to quantify the 18S rRNA gene to determine WBC counts from the volumes of blood that are metered in pDBS zones. We observe that WBC counts generated from our method are comparable to those measured with a HemoCue point-of-care WBC analyzer. Our approach to using pDBS cards as a blood collection device has the potential to support at-home sampling and other patient populations that need WBC counts but lack access to clinical facilities.
Assuntos
Coleta de Amostras Sanguíneas , Teste em Amostras de Sangue Seco , Humanos , Hematócrito , Teste em Amostras de Sangue Seco/métodos , Contagem de Leucócitos , CeluloseRESUMO
BACKGROUND: Accelerated lung function decline is characteristic of COPD. However, the association between blood eosinophil counts and lung function decline, accounting for current smoking status, in young individuals without prevalent lung disease is not fully understood. METHODS: This is a cohort study of 629 784 Korean adults without COPD or a history of asthma at baseline who participated in health screening examinations including spirometry and differential white blood cell counts. We used a linear mixed-effects model to estimate the annual change in forced expiratory volume in 1â s (FEV1) (mL) by baseline blood eosinophil count, adjusting for covariates including smoking status. In addition, we performed a stratified analysis by baseline and time-varying smoking status. RESULTS: During a mean follow-up of 6.5â years (maximum 17.8â years), the annual change in FEV1 (95% CI) in participants with eosinophil counts <100, 100-199, 200-299, 300-499 and ≥500â cells·µL-1 in the fully adjusted model were -23.3 (-23.9--22.7) mL, -24.3 (-24.9--23.7) mL, -24.8 (-25.5--24.2) mL, -25.5 (-26.2--24.8) mL and -26.8 (-27.7--25.9) mL, respectively. When stratified by smoking status, participants with higher eosinophil count had a faster decline in FEV1 than those with lower eosinophil count in both never- and ever-smokers, which persisted when time-varying smoking status was used. CONCLUSIONS: Higher blood eosinophil counts were associated with a faster lung function decline among healthy individuals without lung disease, independent of smoking status. The findings suggest that higher blood eosinophil counts contribute to the risk of faster lung function decline, particularly among younger adults without a history of lung disease.
Assuntos
Eosinófilos , Fumar , Espirometria , Humanos , Masculino , Feminino , Volume Expiratório Forçado , Adulto , República da Coreia , Pessoa de Meia-Idade , Contagem de Leucócitos , Estudos de Coortes , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Modelos Lineares , Pulmão/fisiopatologia , Asma/sangue , Asma/fisiopatologiaRESUMO
This paper developed an electrical micro flow cytometry to realize leukocyte differentials leveraging a constrictional microchannel and a deep neural network. Firstly, purified granulocytes, lymphocytes or monocytes traveled through the constrictional microchannel with a cross-sectional area marginally larger than individual cells and produced large impedance variations by blocking focused electric field lines. By optimizing key elements (e.g., normalization, learning rate, batch size and neuron number) of the recurrent neural network (RNN), electrical results of purified leukocytes were analyzed to establish a leukocyte differential system with a classification accuracy of 95.2%. Then the leukocyte mixtures were forced to travel through the same constrictional microchannel, producing mixed impedance profiles which were classified into granulocytes, lymphocytes and monocytes based on the aforementioned differential system. As to the classification results, two leukocyte mixtures from the same donor were processed, producing comparable classification results, which were 57% versus 59% of granulocytes, 37% versus 34% of lymphocytes and 6% versus 7% of monocytes. These results validated the established classification system based on the constrictional microchannel and the recurrent neural network, providing a new perspective of differentiating white blood cells by electrical flow cytometry.
Assuntos
Leucócitos , Monócitos , Citometria de Fluxo , Granulócitos , Linfócitos , Contagem de LeucócitosRESUMO
OBJECTIVE: The role of inflammation and neuroimmune mechanisms, which have been documented in various neuropsychiatric disorders including the seizure subtype of functional neurological disorder, remains unclear in functional movement disorders (FMD). To explore these mechanisms, we analyzed selected inflammatory markers in cerebrospinal fluid (CSF) in patients with FMD. METHODS: We compared CSF markers in 26 patients with clinically established FMD (20 females; mean [SD] age = 43.3 [10.9], disease duration = 3.9 [3], range = 0.1-11 years; mean follow-up after lumbar puncture = 4.3 [2] years, range = 0.5-7 years) and 26 sex- and age-matched clinical controls with noninflammatory nonneurodegenerative neurological disorders, mostly sleep disorders. RESULTS: Sixty-five percent of FMD patients versus 15% of controls showed cytological abnormalities (i.e., increased white blood cells [WBC] count, signs of WBC activation, or both; odds ratio [OR] = 9.85, 95% confidence interval = 2.37-52.00, p < .01, corrected), with a significantly higher frequency of an isolated lymphocytic activation, 35% versus 0% (OR = ∞, 95% confidence interval = 2.53-∞, p < .05, corrected). There were no differences in CSF protein and albumin levels, quotient albumin, IgG index, and oligoclonal bands. CSF abnormalities were not associated with more severe motor symptoms or a higher frequency of depression in FMD. CONCLUSIONS: Our results suggest a possible involvement of immune mechanisms in the pathophysiology of (at least a subtype of) FMD that deserves further investigation.