Neutrophil functions in patients with myelodysplasia : implications of impaired

Mensen met myelodysplasie (MDS) hebben een tekort aan verschillende types bloedcellen in het bloed. Bovendien functioneren de bloedcellen die er wél zijn niet naar behoren. Dat laatste is het geval bij granulocyten, een bepaald type witte bloedcellen dat een rol speelt in de afweer. MDS-patiënten zijn daardoor erg gevoelig voor bacteriële infecties. Gwenny Fuhler ontrafelde een aantal cellulaire en moleculaire mechanismen die hierbij een rol spelen. Normaal trekken granulocyten bij een infectie het weefsel binnen, waar ze de bacteriën opsporen en vervolgens 'opeten'. Bovendien produceren ze zuurstofradicalen die giftig zijn voor de bacteriën. Voordat de granulocyten tot actie overgaan, moeten ze een signaal krijgen waar de infectie precies plaatsvindt. Deze signaalstoffen worden afgegeven door de bacteriën en weefselcellen rondom de infectie. Fuhler ontdekte dat de granulocyten van MDS-patiënten minder goed reageren op deze signaleringsstoffen. Daardoor kunnen ze de infectie minder goed bereiken en produceren ze minder zuurstofradicalen. Ook de activatie van de signaleringsmoleculen in granulocyten blijkt verstoord.

Drug Discovery in Liver Disease Using Kinome Profiling

The liver is one of the most important organs, playing critical roles in maintaining biochemical homeostasis. Accordingly, disease of the liver is often debilitating and responsible for un-told human misery. As biochemical nexus, with kinases being master regulators of cellular biochem-istry, targeting kinase enzymes is an obvious avenue for treating liver disease. Development of such therapy, however, is hampered by the technical difficulty of obtaining comprehensive insight into hepatic kinase activity, a problem further compounded by the often unique aspects of hepatic kinase activities, which makes extrapolations from other systems difficult. This consideration prompted us to review the current state of the art with respect to kinome profiling approaches towards the hepatic kinome. We observe that currently four different approaches are available, all showing significant promise. Hence we postulate that insight into the hepatic kinome will quickly increase, leading to rational kinase-targeted therapy for different liver diseases.</p

The immune system and microbiome in pregnancy

Hormonal changes during pregnancy instigate numerous physiological changes aimed at the growth and delivery of a healthy baby. A careful balance between immunological tolerance against fetal antigens and immunity against infectious agents needs to be maintained. A three-way interaction between pregnancy hormones, the immune system and our microbiota is now emerging. Recent evidence suggests that microbial alterations seen during pregnancy may help maintain homeostasis and aid the required physiological changes occurring in pregnancy. However, these same immunological and microbial alterations may also make women more vulnerable during pregnancy and the post-partum period, especially regarding immunological and infectious diseases. Thus, a further understanding of the host-microbial interactions taking place during pregnancy may improve identification of populations at risk for adverse pregnancy outcomes

Widespread Deregulation of Phosphorylation-Based Signaling Pathways in Multiple Myeloma Cells:Opportunities for Therapeutic intervention

Multiple myeloma (MM) is a neoplasm of plasma cell origin that is largely confined to the bone marrow (BM). Chromosomal translocations and other genetic events are known to contribute to deregulation of signaling pathways that lead to transformation of plasma cells and progression to malignancy. However, the tumor stroma may also provide trophic support and enhance resistance to therapy. Phosphorylation of proteins on tyrosine, serine and threonine residues plays a pivotal role in cell growth and survival. Therefore, knowing the status of phosphorylation-based signaling pathways in cells may provide key insights into how cell growth and survival is promoted in tumor cells, To provide a more comprehensive molecular analysis of signaling disruptions in MM, we conducted a kinome profile comparison of normal plasma cells and MM plasma cells as well as their surrounding cells from normal BM and diseased BM. Integrated pathway analysis of the profiles obtained reveals deregulation of multiple signaling pathways in MM cells but also in surrounding bone marrow blood cells compared to their normal counterparts. The deregulated kinase activities identified herein, which include the mTOR (mammalian target of rapamycin)/p70S6K and ERK1/2 (extracellular signal-regulated kinases 1 and 2) pathways, are potential novel molecular targets in this lethal disease. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.or

Action and function of Wnt/β-catenin signaling in the progression from chronic hepatitis C to hepatocellular carcinoma

Hepatitis C virus (HCV) infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide but the mechanistic basis as to how chronic HCV infection furthers the HCC process remains only poorly understood. Accumulating evidence indicates that HCV core and nonstructural proteins provoke activation of the Wnt/β-catenin signaling pathway, and the evidence supporting a role of Wnt/β-catenin signaling in the onset and progression of HCC is compelling. Convincing molecular explanations as to how expression of viral effectors translates into increased activity of the Wnt/β-catenin signaling machinery are still largely lacking, hampering the design of rational strategies aimed at preventing HCC. Furthermore, how such increased signaling is especially associated with HCC oncogenesis in the context of HCV infection remains obscure as well. Here we review the body of contemporary biomedical knowledge on the role of the Wnt/β-catenin pathway in the progression from chronic hepatitis C to cirrhosis and HCC and explore potential hypotheses as to the mechanisms involved