Neither increased chemotactic activity in the airways nor increased chemotactic responsiveness of neutrophils explains the increased number of these cells in subjects with stable COPD. The implications of the observed reduction in neutrophil chemotactic activity remain to be established.

No abstract

Autophagy plays a critical role in tumorigenesis, but how autophagy contributes to cancer cells’ responses to chemotherapeutics remains controversial. To investigate the roles of autophagy in malignant gliomas, we used CRISPR/CAS9 to knock out the ATG5 gene, which is essential for autophagosome formation, in tumor cells derived from patients with glioblastoma. While ATG5 disruption inhibited autophagy, it did not change the phenotypes of glioma cells and did not alter their sensitivity to temozolomide, an agent used for glioblastoma patient therapy. Screening of an anticancer drug library identified compounds that showed greater efficacy to ATG5‐knockout glioma cells compared to control. While several selected compounds, including nigericin and salinomycin, remarkably induced autophagy, potent autophagy inducers by mTOR inhibition did not exhibit the ATG5‐dependent cytoprotective effects. Nigericin in combination with ATG5 deficiency synergistically suppressed spheroid formation by glioma cells in a manner mitigated by Ca2+ chelation or CaMKK inhibition, indicating that, in combination with autophagy inhibition, calcium‐mobilizing compounds contribute to efficient anticancer therapeutics. ATG5‐knockout cells treated with nigericin showed increased mitochondria‐derived reactive oxygen species and apoptosis compared to controls, indicating that autophagy protects glioma cells from mitochondrial reactive oxygen species‐mediated damage. Finally, using a patient‐derived xenograft model, we demonstrated that chloroquine, a pharmacological autophagy inhibitor, dramatically enhanced the efficacy of compounds selected in this study. Our findings propose a novel therapeutic strategy in which calcium‐mobilizing compounds are combined with autophagy inhibitors to treat patients with glioblastoma.

1Hematopoietic stem cells (HSCs) in a steady state can be efficiently purified by selecting for a combination of several cell surface markers; however, such markers do not consistently reflect HSC activity. In this study, we successfully enriched HSCs with a unique stemness-monitoring system using a transgenic mouse in which green florescence protein (GFP) is driven by the promoter/enhancer region of the nucleostemin (NS) gene. We found that the phenotypically defined long-term (LT)-HSC population exhibited the highest level of NS-GFP intensity, whereas NS-GFP intensity was strongly downregulated during differentiation in vitro and in vivo. Within the LT-HSC population, NS-GFP high cells exhibited significantly higher repopulating capacity than NS-GFP low cells. Gene expression analysis revealed that nine genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFP high cells and may represent a signature of HSCs, i.e., a stemness signature. When LT-HSCs suffered from remarkable stress, such as transplantation or irradiation, NS-GFP intensity was downregulated. Finally, we found that high levels of NS-GFP identified HSC-like cells even among CD34 + cells, which have been considered progenitor cells without long-term reconstitution ability. Thus, high NS-GFP expression represents stem cell characteristics in hematopoietic cells, making this system useful for identifying previously uncharacterized HSCs.Hematopoietic stem cells (HSCs) perpetuate undifferentiated status through self-renewal, but also give rise to progenitors, which no longer possess the capacity for self-renewal but can differentiate into committed lineages 1 . Accumulating evidence supports the presence of "stemness" signals, that is, molecules and signaling pathways that play critical roles in maintaining the undifferentiated properties of HSCs. HSCs are maintained in a quiescent status in the bone marrow niches, and cooperative networks of intrinsic and extrinsic factors contribute to stem cell homeostasis in vivo 2 . To date, numerous factors involved in microenvironments, the cell cycle, metabolism, and epigenetics have been identified as regulators of HSC homeostasis 3, 4 ; however, it remains unclear how the stemness is regulated to maintain homeostasis.The identification of an HSC population is based on differential expression of cell surface markers. Positive selection for c-Kit (a receptor for stem cell factor; also known as CD117) and Sca-1 in combination with negative selection of mature hematopoietic markers (Lineage markers) efficiently enrich HSC/progenitor cells (Lineage − Sca-1 + c-Kit + ; LSK) 5 . Additional markers, including CD34, CD150, Flt3, and CD48, have been used to isolate HSCs that have long-term (LT) reconstitution activity (LT-HSCs, e.g. CD150− LSK cells) 6,7 .

No abstract

Our results suggest a clear dissociation between IL-5 and AHR. ICS therapy improves AHR at least in part through decrease in airway vascular permeability.

Autophagy is a cellular degradation system contributing to homeostasis of tissue stem cells including haematopoietic stem cells (HSCs). It plays pleiotropic roles in HSC characteristics throughout life, but its stage-specific roles in HSC self-renewal are unclear. To investigate the effects of Atg5 deletion on stage-specific HSC functions, we compared the repopulating capacity of HSCs in Atg5f/f;Vavi-cre mice from postnatal day (P) 0–7 weeks of age. Interestingly, Atg5 deficiency led to no remarkable abnormality in the HSC self-renewal capacity at P0, but significant defects at P7, followed by severe defects. Induction of Atg5 deletion at P5 by tamoxifen administration to Atg5f/f;Rosa26-Cre-ERT2 mice resulted in normal haematopoiesis, including the HSC population, until around 1 year, suggesting that Atg5 in the early neonatal period was critical for haematopoiesis in adults. Mitochondrial oxidative stress was increased by Atg5 loss in neonatal HSC/progenitor cells. Although p62 had accumulated in immature bone marrow cells of Atg5f/f;Vavi-cre mice, p62 deletion did not restore defective HSC functions, indicating that Atg5-dependent haematopoietic regulation in the developmental period was independent of p62. This study proposes a critical role of autophagy in HSC protection against harsh environments in the early neonatal stage, which is essential for healthy long-term haematopoiesis.

In young adult atopic subjects with asymptomatic BHR, airway inflammation does not necessarily play a determining role in the development of BHR to methacholine itself, though it might be an important factor in the onset of asthma.