CD34+ cells home, proliferate, and participate in capillary formation, and in combination with

Objective - Emerging evidence suggests that human blood contains bone marrow (BM)-derived endothelial progenitor cells that contribute to postnatal neovascularization. Clinical trials demonstrated that administration of BM-cells can enhance neovascularization. Most studies, however, used crude cell populations. Identifying the role of different cell populations is important for developing improved cellular therapies. Methods and Results - Effects of the hematopoietic stem cell-containing CD34+ cell population on migration, proliferation, differentiation, stimulation of, and participation in capillary-like tubule formation were assessed in an in vitro 3-dimensional matrix model using human microvascular endothelial cells. During movement over the endothelial monolayer, CD34+ cells remained stuck at sites of capillary tube formation and time- and dose-dependently formed cell clusters. Immunohistochemistry confirmed homing and proliferation of CD34+ cells in and around capillary sprouts. CD34+ cells were transduced with the LNGFR marker gene to allow tracing. LNGFR gene-transduced CD34 + cells integrated in the tubular structures and stained positive for CD31 and UEA-1. CD34+ cells alone stimulated neovascularization by 17%. Coculture with CD34- cells led to 68% enhancement of neovascularization, whereas CD34- cells displayed a variable response by themselves. Cell-cell contact between CD34+ and CD34- cells facilitated endothelial differentiation of CD34+ cells. Conclusions - Our data suggest that administration of CD34+-enriched cell populations may significantly improve neovascularization and point at an important supportive role for (endogenous or exogenous) CD34- cells. © 2005 American Heart Association, Inc. Chemicals / CAS: nitric oxide, 10102-43-9; Antigens, CD34; Biological Marker

Dutch Oncology COVID-19 consortium:Outcome of COVID-19 in patients with cancer in a nationwide cohort study

Aim of the study: Patients with cancer might have an increased risk for severe outcome of coronavirus disease 2019 (COVID-19). To identify risk factors associated with a worse outcome of COVID-19, a nationwide registry was developed for patients with cancer and COVID-19. Methods: This observational cohort study has been designed as a quality of care registry and is executed by the Dutch Oncology COVID-19 Consortium (DOCC), a nationwide collaboration of oncology physicians in the Netherlands. A questionnaire has been developed to collect pseudonymised patient data on patients' characteristics, cancer diagnosis and treatment. All patients with COVID-19 and a cancer diagnosis or treatment in the past 5 years are eligible. Results: Between March 27th and May 4th, 442 patients were registered. For this first analysis, 351 patients were included of whom 114 patients died. In multivariable analyses, age ≥65 years (p < 0.001), male gender (p = 0.035), prior or other malignancy (p = 0.045) and active diagnosis of haematological malignancy (p = 0.046) or lung cancer (p = 0.003) were independent risk factors for a fatal outcome of COVID-19. In a subgroup analysis of patients with active malignancy, the risk for a fatal outcome was mainly determined by tumour type (haematological malignancy or lung cancer) and age (≥65 years). Conclusion: The findings in this registry indicate that patients with a haematological malignancy or lung cancer have an increased risk of a worse outcome of COVID-19. During the ongoing COVID-19 pandemic, these vulnerable patients should avoid exposure to severe acute respiratory syndrome coronavirus 2, whereas treatment adjustments and prioritising vaccination, when available, should also be considered

Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2-specific CD8(+) T cell responses following COVID-19

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates(1-6). Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c(+) natural killer (NK) cells and CD4(+) T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38(+)PD1(+)CD4(+) T effector (T-eff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127(+) granulocytes and CD38(+)CD8(+) tissue-resident memory T cells (T-RM). SARS-CoV-2-specific CD8(+) T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Wnt signalling and cancer stem cells

[Abstract] Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefly reviewed.Ministerio de Ciencia e Innovación; SAF2008-0060

Tales of the unexpected: tcf1 functions as a tumor suppressor for leukemias

The Wnt-responsive transcription factors Tcf1 and Lef1 are well-known for their roles in lymphocyte development. In this issue of Immunity, Yu et al. (2012) report that Tcf1-deficient mice develop aggressive T cell lymphomas that are characterized by high Lef1 expression

Wnt signals are transmitted through N-terminally dephosphorylated {beta}-catenin

beta-catenin mediates Wnt signaling by acting as the essential co-activator for TCF transcription factors. Wnt signaling increases the half-life and therefore the absolute level of beta-catenin in responding cells. The current model states that these changes in beta-catenin stability set the threshold for Wnt signaling. However, we find that pharmacological inhibition of proteasome activity by ALLN leads to accumulation of cytosolic beta-catenin but not to increased TCF-mediated transcription. In addition, in temperature-sensitive ubiquitylation mutant CHO cells inhibition of ubiquitylation increases beta-catenin levels, but does not induce transcriptional activation of TCF reporter genes. Using an antibody specific for beta-catenin dephosphorylated at residues Ser37 and Thr41, we show that Wnt signals specifically increase the levels of dephosphorylated beta-catenin, whereas ALLN does not. We conclude that changes in the phosphorylation status of the N-terminus of beta-catenin that occur upon Wnt signaling independently affect the signaling properties and half-life of beta-catenin. Hence, Wnt signals are transduced via N-terminally dephosphorylated beta-catenin

Modulation of gene expression and DNA adduct formation in HepG2 cells by polycyclic aromatic hydrocarbons with different carcinogenic potencies

Polycyclic aromatic hydrocarbons (PAHs) can occur in relatively high concentrations in the air, and many PAHs are known or suspected carcinogens. In order to better understand differences in carcinogenic potency between PAHs, we investigated modulation of gene expression in human HepG2 cells after 6 h incubation with varying doses of benzo[a]pyrene (B[a]P), benzo[b]fluoranthene (B[b]F), fluoranthene (FA), dibenzo[a,h]anthracene (DB[a,h]A), 1-methylphenanthrene (1-MPA) or dibenzo[a,l]pyrene (DB[a,l]P), by using cDNA microarrays containing 600 toxicologically relevant genes. Furthermore, DNA adduct levels induced by the compounds were assessed with P-32-post-labeling, and carcinogenic potency was determined by literature study. All tested PAHs, except 1-MPA, induced gene expression changes in HepG2 cells, although generally no dose-response relationship could be detected. Clustering and principal component analysis showed that gene expression changes were compound specific, since for each compound all concentrations grouped together. Furthermore, it showed that the six PAHs can be divided into three groups, first FA and 1-MPA, second B[a]P, B[b]F and DB[a,h]A, and third DB[a,l]P. This grouping corresponds with the carcinogenic potencies of the individual compounds. Many of the modulated genes are involved in biological pathways like apoptosis, cholesterol biosynthesis and fatty acid synthesis. The order of DNA adduct levels induced by the PAHs was: B[a]P >> DB[a,l]P > B[b]F > DB[a,h]A > 1-MPA >= FA. When comparing the expression change of individual genes with DNA adduct levels, carcinogenic potency or Ah-receptor antagonicity (the last two were taken from literature), several highly correlated genes were found, of which CYP1A1, PRKCA, SLC22A3, NFKB1A, CYP1A2 and CYP2D6 correlated with all parameters. Our data indicate that discrimination of high and low carcinogenic PAHs by gene expression profiling is feasible. Also, the carcinogenic PAHs induce several pathways that were not affected by the least carcinogenic PAHs