Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Low-density neutrophils”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Hyperprogression Upon Cemiplimab Alone or With Short Course Chemotherapy in PD-L1 ≥ 50% Non-small Cell Lung Cancer: A Biomarker Guided Multicenter International Phase 2 Trial-HYPERBOLIC Study.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS: HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION: to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

CD10↗
PubMed1990

Chemiluminescence by polymorphonuclear leucocyte subpopulations in chronic inflammatory bowel disease. Influence of the cell separation procedure.

Chemiluminescence (CL) is a simple quantitative assay of polymorphonuclear leucocyte (PMNL) oxidative metabolism. PMNL CL was found to be significantly higher in patients with chronic inflammatory bowel disease than in normal controls (167 +/- 60 vs. 139 +/- 50 mV/10(5) cells, p less than 0.05). There were no significant differences between patients with ulcerative colitis and Crohn's disease. Disease controls with rheumatoid arthritis and with bronchiectasis also demonstrated elevated CL. These results were obtained using a two-step gelatin/Ficoll-Hypaque procedure for PMNL separation. However when PMNLs were prepared using a one-step Ficoll-Hypaque procedure PMNL CL was found to be depressed in chronic inflammatory bowel disease (CIBD). It was demonstrated that this disparity was caused by the elimination of low-density neutrophils with high CL production by the one-step procedure. These data indicate that reports of abnormal in vitro neutrophil function in CIBD should be interpreted with caution since separation techniques which are satisfactory in normal individuals may significantly influence results in patients with inflammatory diseases. Furthermore these data indicate the presence of a subpopulation of activated low-density PMNL in patients with CIBD.

Cell Separation↗
PubMed1989

Separation of human neutrophils in self-generated continuous density gradients of Percoll.

Human neutrophils were separated into two fractions using a continuous density gradient of Percoll solution. A marked decrease in O2- production was observed in the low-density neutrophil fraction. There was little erythrocyte contamination in the high-density neutrophil fraction (less than 0.5%), and thus the hypotonic or ammonium chloride lysis of erythrocytes was not necessary.

Cell Separation↗
PubMed1991

Free-radical generation by monocytes and neutrophils: a possible cause of plasma lipoprotein modification.

The activation of freshly isolated human blood monocytes and neutrophils monitored by oxidized human plasma lipoproteins (LP) was measured by detecting luminol-amplified chemiluminescence. The activation was accompanied by production of superoxide radicals. This finding was confirmed by measuring superoxide dismutase-sensitive reduction of cytochrome c. Incubation of monocytes or neutrophils with low-density lipoproteins (LDL) resulted in the accumulation of lipid peroxidation (LPO) products which were assayed by the 2-thiobarbituric acid test. Data from inhibitory analysis suggest that the hydroxyl radical scavenger, mannitol, had no appreciable effect on the accumulation of LPO products during the incubation of LDL with either cell type. However, catalase, superoxide dismutase, the metal ion chelators desferrioxamine and EDTA, as well as the free radical scavenger, butylated hydroxytoluene, markedly decreased the accumulation of LPO products in the medium--by 88%, 67%, 38%, 52%, and 47%, respectively, after incubation of LDL with monocytes, and by 65%, 47%, 41%, 65%, and 100% after incubation of LDL with neutrophils. These results indicate that activation of monocytes and neutrophils by oxidized LP intensifies LPO which proceeds via a free-radical mechanism that is superoxide-dependent and is catalyzed by transition metals.

Adult↗
PubMed1990

IgG-dependent generation of platelet-activating factor by normal and low density human eosinophils.

We have compared normal and low density human eosinophils for their ability to generate platelet activating factor (PAF) in response to IgG-dependent and nonimmunologic stimulation. After 45 min incubation with IgG-coated Sepharose beads the concentrations of cell-associated PAF recovered from normal density eosinophils were significantly greater than from low-density eosinophils or neutrophils. Moreover, eosinophils stimulated with calcium ionophore A23187 had a considerably greater capacity to generate PAF than had previously been described. Although the quantities of cell-associated PAF recovered from normal and low density eosinophils and neutrophils after A23187 stimulation were similar, the amounts of extracellular PAF recovered from both eosinophil populations were significantly greater than from neutrophils. The amounts of PAF recovered from the low density eosinophils may not reflect the full synthetic capacity of these cells, because PAF-turnover was found to be more rapid than that observed with normal density eosinophils. When exogenous [3H]PAF was added to the two stimulated eosinophil populations subsequent analysis of the [3H]PAF metabolites by DIOL-HPLC revealed that low density eosinophils incorporated PAF into the phosphatidylcholine (PC) pool more rapidly than did normal density eosinophils or neutrophils. Alkaline hydrolysis of the PC fraction from whole cell extracts followed by treatment with acetic anhydride resulted in all the PC-associated radioactivity being converted to [3H]PAF, confirming PAF incorporation to PC via this pathway. These findings suggest that the contribution of eosinophils to inflammatory processes through the generation of PAF may be greater than previously appreciated, and that Ig-mediated stimulation may be important in initiating generation of the mediator. Low density eosinophils, that are presumed to be similar to tissue eosinophils, may have a role in regulating PAF concentrations in tissues through their enhanced rate of metabolism.

Calcimycin↗
PubMed2026

Dysregulation of U12-Type Splicing in Lupus Neutrophils.

OBJECTIVE: Neutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and posttranscriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing. METHODS: LDGs and normal-density granulocytes (NDGs) were isolated from patients with SLE and healthy controls (HCs). CYBA (p22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing (RNA-seq) and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes. RESULTS: CYBA expression was reduced in SLE LDGs (n = 11) compared to SLE and HC NDGs (n = 6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n = 7 SLE, n = 12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad down-regulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-including exon skipping and mutually exclusive exon use-in genes such as GBP5, MAEA, and STX10. These abnormalities were validated in an independent long-read RNA-seq data set from SLE peripheral blood mononuclear cells. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles. CONCLUSION: Impaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.

Humans↗
PubMed1990

Fc gamma and CD11/CD18 receptor expression on normal density and low density human eosinophils.

We have studied the expression of Fc gamma receptors and leucocyte integrins (CD11/CD18 family) on human eosinophils using specific monoclonal antibodies (mAb) and flow cytometric analysis. Peripheral blood eosinophils of normal density and low density were compared with neutrophils and monocytes. Several properties of the human eosinophil were established. These were (i) that the eosinophil expressed Fc gamma RII (CDw32) only (unlike monocytes which bear Fc gamma RI and Fc gamma RII and neutrophils which bear Fc gamma RII and Fc gamma RIII); (ii) that the absence of Fc gamma RIII (CD16) on eosinophils served as a basis for distinguishing eosinophil and neutrophil populations by immunofluorescence; (iii) that the leucocyte adhesion glycoproteins, LFA-1 alpha (CD11a), CR3-alpha (CD11b), p150, 95-alpha (CD11c) and the common beta-chain (CD18), were expressed on the eosinophil as well as the neutrophil; (iv) that CD18 expression was significantly reduced on low-density eosinophils from the hypereosinophilic syndrome. Thus, our findings emphasize the unique phenotype of the human eosinophil in terms of Fc gamma receptor expression, the similarity of the eosinophil and neutrophil with regard to the leucocyte integrins and that eosinophils of low density do not differ greatly from those of normal density in terms of receptor expression.

Antigens, Differentiation↗
PubMed1990

Superoxide generation by hypodense eosinophils from patients with asthma.

Low density, or hypodense eosinophils (HE) are found in increased numbers in asthma. Since HE have been reported to have increased inflammatory potential and correlate with the severity of airway obstruction, it has been suggested that this subpopulation of eosinophils may contribute to the asthma process. However, investigations to define the function of HE in asthma have been limited. In this study, pure populations of both HE and normal dense eosinophils were isolated from the peripheral blood of seven patients with asthma, and functional activity of these cells was determined by measuring superoxide (O2-) generation to several activators. Compared to normal dense eosinophils, HE generated significantly more O2- when activated with the chemotactic peptide FMLP or opsonized zymosan; however, these differences were small. In contrast, no difference was observed in O2- production between normal- and low-density eosinophils from asthma patients when stimulated by phorbol myristate acetate (PMA) or the calcium ionophore A23187. Furthermore, both eosinophil populations, and corresponding neutrophil isolates, from asthma patients generated significantly more O2- than control granulocytes when activated by PMA. When stimulated by calcium ionophore, all three eosinophil populations released equivalent amounts of O2-, which were, however, higher than from both neutrophil suspensions. Compared to increased activity found in some other hypereosinophilic conditions, blood HE in asthma do not necessarily have enhanced function. This suggests that eosinophil heterogeneity extends not only to cell density but is also reflected in cell function and that these cell variations are dependent on many factors, including the function assessed, source of cells (normal versus patients with some diseases), and stimulus used.

Adult↗
PubMed1992

Vulnerability of intestinal interstitial fluid to oxidant stress.

The objective of this study was to quantify free radical-mediated lipid, protein, and sulfhydryl oxidation in intestinal interstitial fluid (lymph) and plasma of fasted rats. Free radicals and oxidants were generated either by thermal decomposition of 2,2'-azobis(2-amidinopropane)hydrochloride (AAPH), which yields peroxyl radicals, or by activated polymorphonuclear neutrophils (PMNs). Incubation of intestinal lymph with AAPH resulted in a time-dependent increase in the formation of thiobarbituric acid-reactive substances (TBARS; lipid peroxidation) and carbonyl content (protein oxidation). TBARS formation was completely inhibited by removal of the apo B-containing lipoproteins in lymph suggesting that very low-density lipoprotein is the major substrate for lipid peroxidation in fasted interstitial fluid. The sulfhydryl content of lymph was reduced significantly on exposure to the peroxyl radical generator. Incubation with activated PMNs revealed qualitatively similar changes in protein and sulfhydryl oxidation; however, there was no detectable TBARS formation. Exposure of plasma to AAPH produced similar increases in protein and sulfhydryl oxidation when plasma protein concentration was adjusted to that of lymph; however, TBARS formation was significantly lower compared with lymph. Incubation of dialyzed plasma with AAPH produced significantly greater amounts of TBARS. Taken together, our data suggest that plasma is more resistant to AAPH-induced lipid peroxidation than interstitial fluid and the substrate for TBARS formation in intestinal interstitial fluid is different from that of plasma.

Amidines↗
PubMed1991

The function of human NK cells is enhanced by beta-glucan, a ligand of CR3 (CD11b/CD18).

Cells responsible for the natural killer (NK) effect in the human blood can be collected in the low-density lymphocyte subset and the majority of them express CR3. In addition to the iC3b binding site the CR3 molecules possess an epitope which binds beta-glucan. Ligands of this site can deliver activation signals to CR3-carrying monocytes and neutrophils. We found that the function of NK cells was also potentiated by preincubation with beta-glucan. The treatment increased the proportion of target-binding lymphocytes and of the damaged target cells in the conjugates. The monoclonal antibody OKM-1, directed to the beta-glucan-binding site of CR3, abrogated this effect. Another CR3-reactive monoclonal antibody, M522, known to activate monocytes and neutrophils, enhanced the NK function.

Antibodies, Monoclonal↗
PubMed1992

Smooth muscle cell elastase, atherosclerosis, and abdominal aortic aneurysms.

Smooth muscle cells (SMC) were obtained by outgrowth of human aortic explants from abdominal aortic aneurysm (AAA) patients, aortic occlusive disease (AOD) patients, and transplant donors (controls). Specimens were incubated with medium alone or medium with either elastin-derived peptides (EDP, 5 micrograms/mL) or low-density lipoproteins (LDL, 5 micrograms/mL). Elastase activity (ng/mg total protein) was assayed from 4-week-old cultures. Control aortas obtained from patients significantly younger secrete an increased amount of elastase at baseline compared with AOD and AAA patients (p less than 0.05). Elastin-derived peptides caused a significant increase in elastase secretion in all groups. The increase in elastase secretion in response to EDP in AAA patients was significantly higher compared with AOD or control. Low-density lipoprotein had no effect on SMC elastase secretion. These data suggest that (1) aortic SMCs secrete elastase in response to EDP, (2) SMC elastase is age dependent, and (3) AAA SMC secrete an abnormally high amount of elastase compared with AOD and control aortas in response to EDP. Like the neutrophil, the SMC is highly responsive to the degradation products of elastin and in AAA patients secrete significantly increased amounts of elastase in response to the breakdown products of atherosclerosis.

Adult↗
PubMed1992

Plasma lipid levels and platelet and neutrophil function in patients with vascular disease following fish oil and olive oil supplementation.

This double-blind study was designed to examine and compare the effects of supplementing the existing diet with fish oil or olive oil on lipids and cell function in patients with peripheral vascular disease. Thirty-two patients with symptomatic and angiographically demonstrated peripheral vascular disease were screened, matched, and randomly allocated to take either 15 g/d fish oil or olive oil for 4 weeks. Fish oil reduced serum triglyceride levels by 26%, but increased total cholesterol levels due to a significant increase in both low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein-2 cholesterol (HDL2-C). There was a nonsignificant decrease in HDL3-C levels. Olive oil reduced total cholesterol levels, accountable to a significantly decrease in LDL-C levels. Serum thromboxane B2 (TXB2) levels remained unchanged following fish oil, but were significantly increased by olive oil. Urinary excretion of TXB2 and 6-keto-PGF1 alpha was unaffected by either oil supplement. Platelet aggregation, which was measured in platelet-rich plasma in response to two doses of collagen or platelet-activating factor (PAF), was significantly reduced after fish oil, but was increased by olive oil. Following fish oil, there was a significant increase in eicosapentaenoic acid (EPA, 20:5) and docosahexaenoic acid (DHA, 22:6) levels and a decrease in arachidonic acid content of platelet phospholipids. The platelet fatty acid composition after olive oil was unchanged. Fish oil decreased neutrophil leukotriene B4 (LTB4) generation following calcium ionophore stimulation by 33%, while leukotriene B5 levels increased significantly. Neutrophil PAF production and plasma lyso-PAF were unaffected by either oil.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1978

NADPH-oxidation activities in subcellular fractions isolated from resting or phagocytozing human polymorphonuclears.

Using a fluorometric assay for the determination of oxidized pyridine nucleotides (NAD[P]+), total and cyanide-resistant NADPH-oxidative activities have been measured in subcellular fractions isolated from resting and phagocytosing human polymorphonuclears. Enzymatic activies responsible for the oxidation of the NADPH have been recovered in the heavy particles (15,000g/15 min), the low-density particles (100,000g/30 min), and the cytosolic fraction. Stimulation of the cells with opsonized zymosan had a different effect on the NADPH-oxidative activities of these subcellular fractions, which suggests the involvement of various types of enzymatic systems in the oxidation of NADPH. The cytosolic fraction interacted strongly with the enzymatic activities occurring in the sedimentable fractions and is therefore thought to play a central role in the regulation of the activation of the oxidative metabolism associated with phagocytosis.

Cell Fractionation↗
PubMed1991

Ascorbic acid protects lipids in human plasma and low-density lipoprotein against oxidative damage.

We exposed human blood plasma and low-density lipoprotein (LDL) to many different oxidative challenges and followed the temporal consumption of endogenous antioxidants in relation to the initiation of oxidative damage. Under all types of oxidizing conditions, ascorbic acid completely protects lipids in plasma and LDL against detectable peroxidative damage as assessed by a specific and highly sensitive assay for lipid peroxidation. Ascorbic acid proved to be superior to the other water-soluble plasma antioxidants bilirubin, uric acid, and protein thiols as well as to the lipoprotein-associated antioxidants alpha-tocopherol, ubiquinol-10, lycopene, and beta-carotene. Although these antioxidants can lower the rate of detectable lipid peroxidation, they are not able to prevent its initiation. Only ascorbic acid is reactive enough to effectively intercept oxidants in the aqueous phase before they can attack and cause detectable oxidative damage to lipids.

Amidines↗
PubMed1990

Phagocyte function in familial hypercholesterolaemia: peripheral blood monocytes exposed to lipopolysaccharide show increased tumour necrosis factor production.

We studied functions of polymorphonuclear leucocytes (PMN) and monocytes from peripheral blood of subjects with familial hypercholesterolaemia (FH). FH monocytes exposed to Escherichia coli lipopolysaccharide (LPS) in 10% human AB serum generated tumour necrosis factor (TNF) significantly more than did control monocytes. After lowering of serum low-density lipoprotein (LDL) levels by drug treatment, FH monocytes exposed to LPS in the absence of exogenous lipoproteins generated significantly more TNF than did control monocytes. These findings suggest that increased TNF production is not affected by hypolipidaemic treatment and may not derive from differences between uptake of exogenous LDL by FH monocytes and control cells. Chemotaxis, chemokinesis, and random migration of both FH PMN and FH monocytes were normal, as determined by agarose assay and membrane filter assay. FH PMN showed increased luminol-enhanced chemiluminescence in response to 2.5 x 10(-8) M, but not to 2.5 x 10(-6) M, N-formyl-methionyl-leucyl-phenylalanine, and not to serum-treated zymosan or to phorbol myristate acetate. Luminol- and lucigenin-enhanced chemiluminescence responses of FH monocytes were normal. In summary, the major aberration found in the present study was that FH monocytes stimulated with LPS show enhanced production of TNF. The possibility that exaggerated TNF production contributes to an early development of atherosclerotic lesions in FH subjects warrants further studies.

Adult↗
PubMed1990

Demonstration and characterization of buoyant-density subpopulations of group B Streptococcus type III.

Group B Streptococcus (GBS) type III (18 strains) was investigated for the presence of buoyant-density subpopulations; 10 strains originated from invasive isolates causing early-onset septicemia, and 8 were colonizing isolates from pregnant women. By repeated processing in hypotonic density gradients of Percoll, high- (HD) and low-density (LD) subpopulations were recovered from all strains. Synthesis of type-specific polysaccharide (TPS) was increased in the invasive isolates and their respective LD variants compared with the colonizing strains and their LD subpopulations. Production of capsular TPS correlated directly with synthesis of soluble TPS; there was an inverse exponential relationship between soluble TPS production and buoyant density. LD variants were more resistant to phagocytic killing by human polymorphonuclear leukocytes (PMNL) than were the original strains and HD variants. In a luminol-enhanced chemoluminescence assay, LD variants elicited a weak, slow response. In contrast, the HD subpopulations evoked a prompt, strong respiratory burst in the PMNL.

Centrifugation, Density Gradient↗
PubMed1991

Suppression of bone marrow by low-density lipoproteins in renal disease patients.

Patients with chronic renal disease in whom erythropoietin production is inadequate invariably experience moderate to severe debilitation-induced fatigue. Unlike the direct humeral control of erythropoiesis, neutropenia in the same cohort of patients appears to be under indirect control, very likely brought about by the suppressive effect of increased levels of low-density lipoprotein (LDL) on granulocyte-monocyte colony formation. Markedly elevated LDL levels were identified in plasma samples obtained from a study population of 179 chronic renal disease patients. The effect of the elevated LDL levels in the plasma of these patients resulted in a greater than 60% decrease in granulocyte-macrophage colony-forming unit in comparison with age-matched plasma from normal individuals. Careful review of all nutritional and therapeutic events in these patients did not offer any evidence, other than the elevated LDL levels, in support of the etiology of the chronically low absolute neutrophil counts.

Agranulocytosis↗