Up-regulation of Bcl-2 during adipogenesis mediates apoptosis resistance in human adipocytes

Targeting apoptotic pathways in adipocytes has been suggested as a pharmacological approach to treat obesity. However, adipocyte apoptosis was identified as a cause for macrophage infiltration into adipose tissue. Previous studies suggest that mature adipocytes are less sensitive to apoptotic stimuli as compared to preadipocytes. Here, we aimed to identify proteins mediating apoptosis resistance in adipocytes.     

Circulating haematopoietic progenitors during treatment of renal anaemia with recombinant human erythropoietin

The effect of recombinant human erythropoietin (rhEPO) and interleukin 3 (IL3) on circulating haematopoietic progenitors consisting mainly of immature burst-forming-units-erythrocytes (BFU-E), was investigated in ten paediatric patients treated by regular haemodialysis. During a 30-week study rhEPO treatment resulted in a rise of median haemoglobin levels from 6.7 g/dl to >10 g/dl in all patients. Before initiating rhEPO treatment the number of circulating BFU-E in chronic renal failure patients responded to grading doses of rhEPO in vitro similar to that in control children; however, the dose-response curves were not predictive for the in vivo response to rhEPO. After an initial rise in five patients BFU-E numbers declined by week 30 of rhEPO treatment. BFU-E numbers decreased to 35% of pretreatment values. The number of granulocyte-macrophage colony forming cells (GM-CFC) also decreased during rhEPO treatment. Addition of IL3 to the culture medium containing saturating concentrations of granulocyte-macrophage colony stimulating factor did not stimulate BFU-E numbers of patients before rhEPO treatment or those of controls. However, 2 weeks after start of rhEPO treatment IL3 increased the growth of patient's BFU-E in vitro to 220% of pretreatment levels, followed by a gradual decrease of stimulation until the end of observation. These findings indicate that: (1) long-term recruitment of circulating haematopoietic progenitors during rhEPO treatment is low in children with renal anaemia; (2) rhEPO sensitivity of circulating BFU-E is not predictive for the in vivo response; (3) rhEPO treatment results in enhanced sensitivity of BFU-E to IL3.     

Life satisfaction in adult survivors of cancer during adolescence: what contributes to the latter satisfaction with life?

Purpose  

To compare the general and health-related life satisfaction (LS) in long-term survivors of adolescent cancer with a community sample and to identify medical and psychosocial factors associated with LS.     

Association between lymph node silicosis and lung silicosis in 4,384 German uranium miners with lung cancer

This study investigates the association between lymph node-only and lung silicosis in uranium miners with lung cancer and exposure to quartz dust. Tissue slides of 4,384 German uranium miners with lung cancer were retrieved from an autopsy archive and reviewed by 3 pathologists regarding silicosis in the lungs and lymph nodes. Cumulative exposure to quartz dust was assessed with a quantitative job-exposure matrix. The occurrence of silicosis by site was investigated with regression models for exposure to quartz dust. Miners with lung silicosis had highest cumulative quartz exposure, followed by lymph node-only silicosis and no silicosis. At a cumulative quartz exposure of 40 mg/m(3) × years, the probability of lung silicosis was above 90% and the likelihood of lymph node-only silicosis and no silicosis do not differ anymore. The results support that lymph node silicosis can precede lung silicosis, at least in a proportion of subjects developing silicosis, and that lung silicosis strongly depends on the cumulative quartz dose.     

Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand-independent growth and is responsive to a synergistic effect of imatinib and rapamycin

Activating mutations of c-KIT lead to ligand-independent growth. Internal tandem duplications (ITDs) of exon 11, which encodes the juxtamembrane domain (JMD), are constitutively activating mutations found in 7% of gastrointestinal stromal tumors (GISTs) but have not been described in childhood acute myeloid leukemia (AML). DNA and cDNA from 60 children with AML were screened by polymerase chain reaction (PCR) for mutations of the JMD. A complex ITD (kit cITD) involving exon 11 and exon 12 was identified with a relative frequency of 7% (4/60). The human kit cITDs were inserted into the murine c-Kit backbone and expressed in Ba/F3 cells. KIT cITD induced factorindependent growth and apoptosis resistance, and exhibited constitutive autophosphorylation. KIT cITD constitutively activated the PI3K/AKT pathway and phosphorylated STAT1, STAT3, STAT5, and SHP-2. Imatinib (IM) or rapamycin (Rap) led to complete inhibition of growth, with IC50 values at nanomolar levels. IM and Rap synergistically inhibited growth and surmounted KIT cITD-induced apoptosis resistance. IM but not LY294002 inhibited phosphorylation of STAT3 and STAT5, suggesting aberrant cross talk between PI3K- and STAT-activating pathways. The findings presented may have immediate therapeutic impact for a subgroup of childhood AML-expressing c-KIT mutations.     

Modulation of apoptosis signaling for cancer therapy

Apoptosis, the cell’s intrinsic death program, plays a central role in regulating tissue homeostasis. Also, most cytotoxic therapies used for cancer treatment, such as chemotherapy, γ-irradiation, suicide genes, or immunotherapy, predominantly act by triggering apoptosis in target cells. Thus, understanding the molecular events that regulate apoptosis and how tumor cells evade apoptotic deletion have provided a paradigm to link cancer genetics and response to cancer therapy. Therefore, insights into the mechanisms regulating drug-induced apoptosis provide rational targets for novel therapeutic interventions.     

Residual CD95-pathway function in children with autoimmune lymphoproliferative syndrome is independent from clinical state and genotype of CD95 mutation

Human autoimmune lymphoproliferative syndrome (ALPS) is caused by defective CD95-mediated apoptosis of lymphocytes. In most patients, heterozygous mutations within the CD95 gene are found. Mutated proteins interfere with CD95-signaling in a dominant-negative way. However, the penetrance of clinical disease is variable. We describe 13 patients out of nine families with the clinical presentation of ALPS. Eight different mutations were detected. Sensitivity to CD95-induced cell-death, assembly of the CD95-death-inducing signaling complex (DISC), and activity of initiator caspases-8 and -10 were compared in EBV-transformed B-lymphoblastoid cells of these patients. All CD95-mutations led to a reduced DISC formation and diminished initiator caspase activity upon CD95-stimulation, whereas a marked heterogeneity in sensitivity to CD95-induced killing was found. Residual apoptosis sensitivity to almost normal levels could be achieved upon cross-linking by addition of protein A. Thus, no correlation between residual CD95 sensitivity and clinical phenotype or genotype of ALPS was found. This observation is only partially explained by the variable effects of the CD95-mutations themselves. It also points to a pronounced influence of additional factors, such as modifier pathways or exogenous effects apart from the CD95 pathway in the pathogenesis of ALPS.