Liposome-encapsulated prednisolone phosphate inhibits growth of established tumors in mice

Glucocorticoids can inhibit solid tumor growth possibly due to an inhibitory effect on angiogenesis. The antitumor effects of the free drugs have only been observed using treatment schedules based on high and frequent dosing for prolonged periods of time. As long-circulating liposomes accumulate at sites of malignancy, we investigated the tumor-inhibiting potential of liposome-encapsulated prednisolone phosphate. Liposomal prednisolone phosphate could inhibit tumor growth dose-dependently, with 80% to 90% tumor growth inhibition of subcutaneous B16.F10 melanoma and C26 colon carcinoma murine tumor models at 20 mg/kg by single or weekly doses. Prednisolone phosphate in the free form was completely ineffective at this low-frequency treatment schedule, even when administered at a dose of 50 mg/kg. In vitro studies did not show an inhibitory effect of prednisolone (phosphate) on tumor cell, nor on endothelial cell proliferation. Histologic evaluation revealed that liposomal prednisolone phosphate-treated tumors contained a center with areas of picnotic/necrotic cells, which were not apparent in untreated tumors or tumors treated with the free drug. In conclusion, the present study shows potent antitumor effects of liposomal formulations of glucocorticoids in a low dose and low-frequency schedule, offering promise for liposomal glucocorticoids as novel antitumor agents.</p

Renal microvascular endothelial cell responses in sepsis-induced acute kidney injury

Endothelial cells in the kidney microvasculature have an intrinsic molecular and phenotypic heterogeneity and respond to sepsis-induced acute kidney injury conditions in a segment-specific manner. This Review discusses the roles of these cells and the molecular systems that control endothelial functions in the development of sepsis-induced acute kidney injury. Microvascular endothelial cells in the kidney have been a neglected cell type in sepsis-induced acute kidney injury (sepsis-AKI) research; yet, they offer tremendous potential as pharmacological targets. As endothelial cells in distinct cortical microvascular segments are highly heterogeneous, this Review focuses on endothelial cells in their anatomical niche. In animal models of sepsis-AKI, reduced glomerular blood flow has been attributed to inhibition of endothelial nitric oxide synthase activation in arterioles and glomeruli, whereas decreased cortex peritubular capillary perfusion is associated with epithelial redox stress. Elevated systemic levels of vascular endothelial growth factor, reduced levels of circulating sphingosine 1-phosphate and loss of components of the glycocalyx from glomerular endothelial cells lead to increased microvascular permeability. Although coagulation disbalance occurs in all microvascular segments, the molecules involved differ between segments. Induction of the expression of adhesion molecules and leukocyte recruitment also occurs in a heterogeneous manner. Evidence of similar endothelial cell responses has been found in kidney and blood samples from patients with sepsis. Comprehensive studies are needed to investigate the relationships between segment-specific changes in the microvasculature and kidney function loss in sepsis-AKI. The application of omics technologies to kidney tissues from animals and patients will be key in identifying these relationships and in developing novel therapeutics for sepsis

Ligand-targeted liposomes directed against pathological vasculature

The development of liposomes targeted to angiogenic endothelial cells offers exciting prospects for intervention in cancer and inflammation. Several proteins are (strongly) over-expressed on angiogenic endothelial cells as compared to the quiescent endothelium, and could potentially serve as targets for site-specific drug delivery. In this contribution particular attention is given to the design of targeted long-circulating liposomes directed against the alpha v beta 3-integrin protein

Bench-to-bedside review: Angiopoietin signalling in critical illness – a future target?

Multiple organ dysfunction syndrome (MODS) occurs in response to major insults such as sepsis, severe haemorrhage, trauma, major surgery and pancreatitis. The mortality rate is high despite intensive supportive care. The pathophysiological mechanism underlying MODS are not entirely clear, although several have been proposed. Overwhelming inflammation, immunoparesis, occult oxygen debt and other mechanisms have been investigated, and – despite many unanswered questions – therapies targeting these mechanisms have been developed. Unfortunately, only a few interventions, usually those targeting multiple mechanisms at the same time, have appeared to be beneficial. We clearly need to understand better the mechanisms that underlie MODS. The endothelium certainly plays an active role in MODS. It functions at the intersection of several systems, including inflammation, coagulation, haemodynamics, fluid and electrolyte balance, and cell migration. An important regulator of these systems is the angiopoietin/Tie2 signalling system. In this review we describe this signalling system, giving special attention to what is known about it in critically ill patients and its potential as a target for therapy

Perceived barriers and facilitators of the implementation of a combined lifestyle intervention with a financial incentive for chronically ill patients

Background  This study aims to describe barriers and facilitators of the implementation of a combined lifestyle intervention (CLI) in primary care for patients with chronic disease. The aim of CLI to help patients to create a healthy lifestyle and to maintain this healthy lifestyle. During a CLI a patient receives advice and counselling to improve health-related behavior such as physical activity and diet. Special attention was given to the influence of adding a health promoting financial incentive (HPFI) for the participants to the CLI.  Methods  Twenty-four semi-structured interviews within six care groups were performed between July and October 2017. The interviews were transcribed verbatim and coded by two researchers independently.  Results  Respondents mentioned several preferred characteristics of the CLI such as easy accessibility of the intervention site and the presence of health care professionals during exercise sessions. Moreover, factors that could influence implementation (such as attitude of the health care professionals) and preconditions for a successful implementation of a CLI (such as structural funding and good infrastructure) were identified. Overall, positive HPFIs (e.g. a reward) were preferred over negative HPFIs (e.g. a fine). According to the respondents, HPFIs could positively influence the degree of participation, and break down barriers for participating in and finishing the CLI.  Conclusions  Multiple barriers and facilitators for successful implementation of a CLI were identified. For successful implementing CLIs, a positive attitude of all stakeholders is essential and specific preconditions should be fulfilled. With regard to adding a HPFI, more research is needed to identify the attitude of specific target groups towards an HPFI

Snelle meetmethoden als managementinstrument bij de teelt van ruwvoer

Quick measuring methods as management tools in the production of roughage. The most promising technique is spectroscopy, which can be applied in on-line analysis methods for measuring dry matter yield and feed value of silage and grass and which can be available for use within 5 years as a management tool in the production of roughage on dairy farms. Conceptual spectroscopy seems the best technique under the conditions mentioned for measuring feed value. The use of spectroscopy in a dotted measurement seems to be the best technique for measuring dry matter yield