Apoptosis In Peripheral Blood Monocytes Research Articles

An overview of lurbinectedin as a new second-line treatment option for small cell lung cancer.

Small cell lung cancer (SCLC) is a highly proliferative, aggressive form of lung cancer that carries a poor prognosis. Recent approvals with new therapeutic options represent the first in more than a decade for SCLC. Lurbinectedin, a newly approved second-line option, is a synthetic alkaloid that covalently binds DNA, generating double-strand breaks, and disrupts DNA-protein interactions and RNA transcription. Lurbinectedin may also modulate the tumor microenvironment by inducing apoptosis of peripheral blood monocytes and tumor associated macrophages, decreasing expression of the inflammatory chemokine (C-C motif) ligand 2 (CCL2) and reducing tumor angiogenesis. A single-arm, open-label, basket trial included 105 patients with SCLC that had received one prior line of therapy. Patients received lurbinectedin 3.2 mg/m2 as an intravenous infusion every 3 weeks, resulting in a response rate of 35.2% and a disease control rate of 68.6%. The response rate was 45% among those with >90 days chemotherapy free interval (CTFI) and 22% in the resistant group (CTFI < 90 days). The median overall survival was 9.3 months. Myelosuppression is the most frequent clinically significant adverse event, particularly neutropenia; however, neutropenic fever occurred in only 5% of those in the SCLC cohort of the basket trial. Nausea and fatigue were also noted. The side effect profile compares favorably to topotecan, while a direct comparison of tolerability can be made between lurbinectedin versus topotecan or pegylated-liposomal doxorubicin from CORAIL, a randomized study for platinum-resistant/refractory ovarian cancer. A press release has reported the ongoing clinical trial for SCLC including combination lurbinectedin and doxorubicin versus topotecan or cyclophosphamide, doxorubicin, and vinblastine to be negative. The details may provide more insight at publication, and future trials will be important to further define the clinical utility of lurbinectedin. Lurbinectedin represents a new option in second-line SCLC.

TNF-α-elicited miR-29b potentiates resistance to apoptosis in peripheral blood monocytes from patients with rheumatoid arthritis.

CD14-positive monocytes from patients with rheumatoid arthritis (RA) are more resistant to apoptosis, which promotes their persistence at the inflammatory site and thereby contributes crucially to immunopathology. We sought to elucidate one mechanism underlying this unique pathogenesis: resistance to apoptosis and the potential involvement of miR-29b in this process. CD14-positive peripheral blood monocytes (PBMs) from RA patients were observed to be resistant to spontaneous apoptosis compared to PBMs from healthy volunteers. Intriguingly, expression of miR-29b was significantly upregulated in PBMs from RA patients than those from healthy volunteers, and this upregulation was correlated with RA disease activity. Functionally, forced expression of the exogenous miR-29b in CD14-positive Ctrl PBMs conferred resistance to spontaneous apoptosis and Fas-induced death, thereafter enhancing the production of major proinflammatory cytokines in there cells. Following identification of the potential miR-29b target transcripts using bioinformatic algorithms, we showed that miR-29b could directly bind to the 3'-UTR of the high-mobility group box-containing protein 1 (HBP1) and inhibited its transcription in PBMs. Importantly, stable expression of the exogenous HBP1 in differentiated THP-1 monocytes effectively abolished miR-29b-elicited resistance to Fas-induced apoptosis. Finally, among patients with RA and good clinical responses to immunotherapy, expression levels of miR-29b were significantly compromised in those treated with infliximab (a TNF-α inhibitor) but not in those treated with tocilizumab (a humanized mAb against the IL-6 receptor), pointing to a potential association between miR-29b activation and TNF-α induction. The available data collectively suggest that TNF-α-elicited miR-29b potentiates resistance to apoptosis in PBMs from RA patients via inhibition of HBP1 signaling, and testing patients for miR-29b/HBP1 expression ratios may provide more accurate prognostic information and could influence the recommended course of immunotherapy.

Accelerated apoptosis of peripheral blood monocytes in Cebpb-deficient mice

The CCAAT/enhancer-binding protein β (C/EBPβ) transcription factor is required for granulopoiesis under stress conditions. However, little is known about its roles in steady state hematopoiesis. Here, we analyzed the peripheral blood and bone marrow of Cebpb−/− mice at steady state by flow cytometry and unexpectedly found that the number of peripheral blood monocytes was severely reduced, while the number of bone marrow monocytes was maintained. The ability of Cebpb−/− bone marrow cells to give rise to macrophages/monocytes in vitro was comparable to that of wild-type bone marrow cells. Apoptosis of monocytes was enhanced in the peripheral blood, but not in the bone marrow of Cebpb−/− mice. These results indicate that C/EBPβ is required for the survival of monocytes in peripheral blood.

Neonatal monocytes express antiapoptotic pattern of Bcl-2 proteins and show diminished apoptosis upon infection with Escherichia coli.

Neonates show sustained inflammation after a bacterial infection, which is associated with inflammatory diseases like bronchopulmonary dysplasia or periventricular leucomalacia. Physiologically, inflammation is terminated early after the removal of the invading pathogens by phagocytosis-induced cell death (PICD) of immune effector cells. Earlier results showed reduced PICD in neonatal monocytes. The underlying molecular mechanisms are unknown. We hypothesize that the reduced PICD in neonatal monocytes is regulated through the proteins of the B-cell lymphoma 2 (Bcl-2) protein family. mRNA and protein expression of Bcl-2 family proteins in cord blood and adult peripheral blood monocytes infected with Escherichia coli were analyzed by quantitative real-time PCR and flow cytometry and cytochrome c release by fluorescence microscopy. mRNA expression of antiapopototic Bcl-xL was upregulated in cord blood monocytes (CBMO), whereas proapoptotic Bim tended to be higher in peripheral blood monocytes (PBMO). Upon infection, Bax was more strongly expressed in PBMO compared with CBMO. The pro/antiapoptotic balance was skewed toward survival in CBMO and apoptosis in PBMO. Cytochome c release into the cytosol was enhanced in PBMO compared with CBMO. Bcl-2 proteins are involved in reduced PICD in neonatal monocytes. These findings are another step toward the understanding of sustained inflammation in neonates.

Study of peripheral blood monocytes in patients with hepatitis B virus-related acute-on-chronic liver failure under immune dysfunction state

Objective To study apoptosis and antigen presentation changes of monocytes in HBV-related acute-on-chronic liver failure (ACLF) patients under immune dysfunction state.Methods Peripheral blood samples of 26 HBV-related ACLF patients (ACLF group),20 active chronic hepatitis B patients (CHB group) and 18 healthy individuals (control group) were collected.The changes of apoptosis and proliferation (Ki67) in monocytes and the expression of surface markers including human leukocyte antigen (HLA)-DR and B7 molecules (CD86) of monocytes were analyzed by flow cytometry. Results The percentage of Annexin V expressed monocytes of ACLF group (64％) was significantly higher than that of CHB group (28％) and control group (20％),and the difference was statistically significant (x2 value was 11.75 and 27.23 ; both P＜0.01),which indicated that monocytes apoptosis increased.The Ki67 expression in monocytes of ACLF group was lower than that of CHB group and control group,and the difference was statistically significant (x2 value was 4.71 and 4.83; both P＜ 0.05),which indicated that activated monocytes reduced. The mean fluorescence intensity (MFI) of HLA-DR and CD86 of monocytes in ACLF group was 22.85 and 11.63,which was significantly lower than that of CHB group and control group,indicating the antigen presentation ability of monocytes injured. The percentage of Annexin Ⅴ positive monocytes in survivals (62 ％ ) was significantly higher than that of dead patients (46 ％ ) in ACLF group.Conclusion In HBV-related ACLF patients under immune dysfunction state,the apoptosis of peripheral blood monocytes increased,and the quantity of activated cells reduced,resulting in the decline of the antigen presentation ability of monocytes. Key words: Liver failure; Hepatitis B; Monocytes; Apoptosis; Cell proliferation; Flow cytometry

Severe head injury promotes early caspase-dependent apoptosis in peripheral blood monocytes from multiply injured patients

Severe head injury promotes early caspase-dependent apoptosis in peripheral blood monocytes from multiply injured patients

Severe head injury promotes early caspase-dependent apoptosis in peripheral blood monocytes from multiply injured patients

Objective. To investigate the influence of traumatic brain injury (TBI) on immune function and viability of human peripheral monocytes in polytraumatized patients. Material and methods. This was a prospective, randomized, controlled clinical study conducted in a Level I trauma center. Multiply injured patients (n=42; mean age 42.4±15.5 years) with a mean Injury Severity Score (ISS) of 32.3±9.6 were compared to healthy controls (n=20; mean age 36.3±8.4 years). The methods used were clinical evaluation, scoring of injury severity (ISS, abbreviated injury scores), multiple organ dysfunction score, real-time reverse transcription polymerase chain reaction, Western blotting and fluorescent-activated cell sorting analyses of negatively isolated monocytes. The main outcome measures were overall clinical outcome, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) staining, expression of the Fas and tumor necrosis factor receptor I, expression of the mitochondrial proteins Bax and Bcl-2, ...

The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells

Notch-mediated cellular interactions are known to regulate cell fate decisions in various developmental systems. A previous report indicated that monocytes express relatively high amounts of Notch-1 and Notch-2 and that the immobilized extracellular domain of the Notch ligand, Delta-1 (Delta(ext-myc)), induces apoptosis in peripheral blood monocytes cultured with macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage CSF (GM-CSF). The present study determined the effect of Notch signaling on monocyte differentiation into macrophages and dendritic cells. Results showed that immobilized Delta(ext-myc) inhibited differentiation of monocytes into mature macrophages (CD1a+/-CD14+/- CD64+) with GM-CSF. However, Delta(ext-myc) permitted differentiation into immature dendritic cells (CD1a+CD14-CD64-) with GM-CSF and interleukin 4 (IL-4), and further differentiation into mature dendritic cells (CD1a+CD83+) with GM-CSF, IL-4, and tumor necrosis factor-alpha (TNF-alpha). Notch signaling affected the differentiation of CD1a-CD14+ macrophage/dendritic cell precursors derived in vitro from CD34+ cells. With GM-CSF and TNF-alpha, exposure to Delta(ext-myc) increased the proportion of precursors that differentiated into CD1a+CD14- dendritic cells (51% in the presence of Delta(ext-myc) versus 10% in control cultures), whereas a decreased proportion differentiated into CD1a-CD14+ macrophages (6% versus 65%). These data indicate a role for Notch signaling in regulating cell fate decisions by bipotent macrophage/dendritic precursors.