Current status of therapeutic targeting of developmental signalling pathways in oncology

Signalling pathways such as Hedgehog (Hh), Wnt, Notch, bone morphogenetic protein (BMP) and transforming growth factor-β (TGF-β) hold a central position in regulation of vertebrate development by controlling vital processes such as migration, differentiation and proliferation. Insights into the mechanistic aspects of cancer initiation and progression have pointed to striking similarities between tumourigenesis and embryonic development. These observations can partly be explained by the fact that similar cellular signalling mechanisms are employed in both situations. This review focuses on the role and therapeutic potential of Hh, Wnt, Notch and BMP/TGF-β signalling and discusses i) their signal transduction mechanisms during development and tumourigenesis, ii) evidence of pathway activation in different types of cancers, and, iii) strategies for pharmacological targeting. Numerous studies have demonstrated a crucial role of developmental signalling in a variety of tumours, where their signalling mechanisms contribute to oncogenic properties such as tumour cell proliferation, apoptosis inhibition and / or metastatic migration. From the literature available, it is obvious that the relative importance and the oncogenic mechanisms of developmental pathways vary with the tumour type, the stage of the disease as well as the interaction with the tumour microenvironment, thus highlighting the complexity of cellular signalling strategies employed during tumourigenesis. Intensive research activities are devoted to identification of drugs that interfere with oncogenic signalling by developmental pathways. First clinical data for such compounds--e.g. GDC-0449 for the Hh pathway--are promising and indicate that targeted therapy of developmental signalling pathways has potential for future anti-cancer therapies.     

Association of stem cell marker expression pattern and survival in human biliary tract cancer

The aim of this study was to investigate the molecular and protein expression pattern of markers of stemness phenotype and its clinicopathological significance in human biliary tract cancer (BTC). Human BTC cell lines (CCLP-1, Egi-1, MzChA-1, MzChA-2, SkChA-1, TFK-1 and GBC) were analyzed in vitro and in xenotransplanted animals for expression of markers of stemness and compared to tissue microarrays (TMA) of 34 cases of human BTC with complete pathomorphological and clinical data (survival). Molecular analyses on the mRNA and protein level included makers of stemness and progenitor (Bmi-1, Sox-2, Nestin, CD133, CD44 and Nanog), proliferation and differentiation (cell cycle proteins, intermediate filaments). The investigated BTC samples showed a low to moderate and partially significantly different expression pattern of the stem cell markers in vitro, in vivo and in TMA. Hierarchical cluster analysis identified subgroups with homogenous expression of stem cell markers significantly differing with respect to cytokeratin expression in xenografts and Ki67 proliferation marker in human TMA, respectively - thus indicating possible heterogeneous carcinogenesis pathways in BTC. Additionally, these stem cell markers could be linked to morphology and molecular markers of proliferation and differentiation on the mRNA and protein level. Finally, survival analysis identified the combination of CD133 and CD44 as an independent prognostic factor yet their value as prognostic factors need testing in prospective study design.     

Central insulin action regulates peripheral glucose and fat metabolism in mice

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.     

Local bioavailability and distribution of systemically (parenterally) administered ibandronate in the infarcted femoral head

Recent studies show that bisphosphonates can decrease the development of femoral head deformity following ischemic osteonecrosis by inhibiting osteoclast-mediated bone resorption. Given the potential new indication, improved understanding of pharmacokinetics of bisphosphonates as it applies to the infarcted head would be beneficial. The purpose of this study was to investigate the local bioavailability and the distribution of ibandronate in the infarcted head at the avascular and vascular phases of the disease process. Ischemic osteonecrosis of the femoral head was surgically induced in 15 piglets. One, 3, and 6 weeks following the induction of ischemia, which represent various stages of revascularization and repair, 14C-labeled ibandronate was administered intravenously. Twenty-four hours following 14C-drug administration, the level of radioactivity and its distribution in the infarcted heads were determined using liquid scintillation analysis and autoradiography. A significant correlation was found between the extent of revascularization and the level of radioactivity measured in the infarcted heads (r=0.80, P<0.05). The radioactivity level in the infarcted heads measured by liquid scintillation was similar to the negative controls at 1 week when revascularization was absent, but it increased significantly at 6 weeks when extensive revascularization was present (P相似文献   

Dynamic changes in right ventricular pressures during haemodialysis recorded with an implantable haemodynamic monitor.

BACKGROUND: Intermittent and chronic volume overload contributes to the development of cardiovascular disease in patients on maintenance haemodialysis (HD). Continuous monitoring of central haemodynamic parameters may provide valuable information to improve volume control, particularly in patients with left ventricular dysfunction. METHODS: Five patients on HD, age 53-76 years, with systolic and/or diastolic dysfunction (EF 20-50%) received an implantable haemodynamic monitor (IHM) (Chronicle model 9520, Medtronic). The IHM consists of a memory device implanted subcutaneously and a transveneous right ventricular (RV) lead carrying a pressure sensor. It continuously records heart rate, RV systolic (RVSP) and diastolic pressures (RVDP), RV dP/dt and an estimate of pulmonary artery diastolic pressure (ePAD). Continuous haemodynamic profiles were recorded in all patients. RESULTS: During dialysis RVSP and ePAD dropped by a mean of 39 and 50%, respectively. RVDP decreased by 6.6 mmHg. The lowest pressures occurred during the first 90 min of dialysis and were partly restored at the end of the procedure. Long-term haemodynamic monitoring unmasked severe volume overload in one patient, when dry weight was kept stable despite a decrease in lean body mass. In another patient with recurrent dyspnea after dialysis, paroxysmal atrial fibrillation, regularly occurring during dialysis, was identified as the cause of symptoms. CONCLUSION: The implanted haemodynamic monitor was a sensitive indicator for changes in volume load. Continuous haemodynamic monitoring may offer a valuable tool to improve volume management in dialysis patients with left ventricular dysfunction.     

Venous thromboembolism 2011–2018 in Stockholm: a demographic study

Journal of Thrombosis and Thrombolysis - Venous thromboembolism (VTE) is an important cause of morbidity and mortality in Western countries. The incidence rate of VTE is estimated at 1–2...     

Pseudomonas aeruginosa cytotoxin: the Asp197-Gly-Asp-Tyr-His-Tyr-His-Tyr202 containing loop is critical for plasma membrane binding

The cytotoxin from Pseudomonas aeruginosa is a pore-forming toxin that binds specifically to water channel-related molecules of the erythrocyte membrane. Here, we have defined a domain, Asp¹⁹⁷-Gly-Asp-Tyr-His-Tyr²⁰² of the cytotoxin, to be essential for receptor binding. Cytotoxin point mutants from the recombinant gene carrying substitutions in the domain were characterized in terms of inhibiting the binding of radioiodinated natural cytotoxin to rat erythrocyte and producing cytotoxic effects in human granulocytes. A synthetic peptide representing residues 191–211 of the cytotoxin acted as a competitive inhibitor at a concentration of 10^–5 M. In contrast, two other cytotoxin-specific peptides were inactive. Structure prediction of the binding sequence shows a loop structure with similarities to the sequence around His³³² in Aeromonas aerolysin essential to receptor binding.     

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.