Targeting and inhibition of tumor-associated macrophages in breast cancer

Breast cancer is a disease which affects 1 in 7 women during their lifetime. With 464.000 new cases and 131.000 deaths, it is the most occurring cancer type and leading cause of cancer related deaths in women in Europe. As the overall age of the population is predicted to increase, these numbers will rise as well. Cytotoxic agents, hormone treatment, radiation and small molecule inhibitors are the current therapies used in the treatment of breast cancer. Although these therapies work well towards the primary tumor, they do not affect the surrounding stromal cells. Tumor growth and survival depend greatly on the support of the tumor micro-environment (TME), where stromal cells promote neo-angiogenesis, matrix remodeling and cause suppression of the adaptive immune system. Macrophages play a major role in these processes. Tumor-associated macrophages (TAM), present in the TME, have been shown to play a crucial role in tumor growth and progression. Therefore, effective treatment of TAM might prove to be a successful treatment strategy in breast cancer therapy. This thesis project aimed to develop a novel nanoparticle-based strategy to target TAM and inhibit their tumor growth promoting activities. A novel drug candidate (AS1517499) was identified for such inhibition, and incorporated into a newly designed nanoparticle delivery system, which was able to selectively deliver TAM-modulating drugs to TA

Respiratory Function after Spinal Cord Injury

__Abstract__ Survival rates and medical care following spinal cord injury (SCI) have improved largely over the last decades and have resulted in a decline of mortality during the first 2 years after injury. The mortality rates in the period thereafter have not changed substantially. Respiratory diseases, particularly lower tract respiratory infections, remain a common cause of early death and hospitalization in persons with chronic SCI. Therefore, in this thesis we focused on respiratory function after SCI. We studied changes in respiratory function, the prevalence of impaired respiratory function and consequences in the early years after inpatient rehabilitation. In addition, we studied the effects of a specific respiratory training program added to the usual inpatient rehabilitation treatment. For the first part of this thesis we used data of a Dutch multicenter prospective cohort study (the Umbrella and SPIQUE project). For the second part we conducted a multicenter randomized controlled trial (RCT) on the effects of resistive inspiratory muscle training (RIMT)

Respiratory function and respiratory complications in spinal cord injury: protocol for a prospective, multicentre cohort study in high-income countries

Introduction Pneumonia is one of the leading complications and causes of death after a spinal cord injury (SCI). After a cervical or thoracic lesion, impairment of the respiratory muscles decreases respiratory function, which increases the risk of respiratory complications. Pneumonia substantially reduces patient’s quality of life, may prolong inpatient rehabilitation time, increase healthcare costs or at worse, lead to early death. Respiratory function and coughing can be improved through various interventions after SCI, but the available evidence as to which as

Physical Activity and Sedentary Behavior From Discharge to 1 Year After Inpatient Rehabilitation in Ambulatory People With Spinal Cord Injury:A Longitudinal Cohort Study

Objective: To evaluate changes in duration of physical activity (PA) and sedentary behavior (SB) from discharge to 1 year after inpatient rehabilitation in ambulatory people with spinal cord injury (SCI). Design: Longitudinal cohort study with objective measurements of physical behavior at discharge and at 6 and 12 months post discharge. Setting: Three rehabilitation centers and the participant's home environment. Participants: Participants (N= 47) with ambulatory function were consecutively recruited from the self-management and self-efficacy in patients with SCI cohort (age 18 years or older, recent SCI, expected inpatient stay >4wk). Mean age was 54.5 +/- 12.9 years, all had incomplete lesions, 53% were men, 49% had tetraplegia, and 51% were community ambulators at discharge. Interventions: Not applicable. Main Outcome Measures: Duration (min) of PA (summed duration of walking, cycling, running, and wheeling) and SB (sitting/lying). Results: Mean duration of PA increased by 21 min/d (95% confidence interval, 7-35) and SB decreased by 64 min/d (95% confidence interval, -94 to -35) from discharge to 6 months after inpatient rehabilitation. No changes were found in the second half-year. One year after discharge mean PA was 116 +/- 59 min/d and mean SB was 665 +/- 121 min/d. The increase in PA was the result of an almost doubling of time spent walking. Variability in physical behavior and its change was large. Older age and lower ambulation level were associated with lower PA, lower ambulation level with higher SB, and tetraplegia was associated with a reduced increase in PA. Conclusions: At group level, duration of PA and SB improved following inpatient rehabilitation in ambulatory people with SCI. However, there were large differences between individuals. Levels 1 year after discharge were still unfavorable, particularly regarding SB. (C) 2020 by the American Congress of Rehabilitation Medicin

Longitudinal association between respiratory muscle strength and cough capacity in persons with spinal cord injury::An explorative analysis of data from a randomized controlled trial

Objective: To assess the longitudinal association between respiratory muscle strength and cough capacity in persons with recent spinal cord injury. Design: Longitudinal analyses. Subjects: Forty persons with recent spinal cord injury and impaired pulmonary function. Methods: Measurements were performed 4 weeks after the start of rehabilitation, 9 and 17 weeks after the first measurement, and one year after discharge from inpatient rehabilitation. Peak cough flow was measured with a spirometer. Maximum inspiratory and expiratory pressures (MIP and MEP), expressed in cmH(2)O, were measured at the mouth. Results: Both MIP and MEP were significantly positively associated with peak cough flow. After correction for confounders and time 10 cmH(2)O higher MIP was associated with a 0.32 Us higher peak cough flow, and a 10 cmH(2)O higher MEP was associated with a 0.15 l/s higher peak cough flow. The association between MIP and peak cough flow was mainly based on within-subject variance. The association between MIP and peak cough flow was stronger than between MEP and peak cough flow. Conclusion: Improvement in respiratory muscle strength is associated with improvement in cough capacity in persons with recent spinal cord injury who have impaired pulmonary function

Vaccines as alternatives to antibiotics for food producing animals. Part 1:challenges and needs

Vaccines and other alternative products can help minimize the need for antibiotics by preventing and controlling infectious diseases in animal populations, and are central to the future success of animal agriculture. To assess scientific advancements related to alternatives to antibiotics and provide actionable strategies to support their development, the United States Department of Agriculture, with support from the World Organisation for Animal Health, organized the second International Symposium on Alternatives to Antibiotics. It focused on six key areas: vaccines; microbial-derived products; non-nutritive phytochemicals; immune-related products; chemicals, enzymes, and innovative drugs; and regulatory pathways to enable the development and licensure of alternatives to antibiotics. This article, part of a two-part series, synthesizes and expands on the expert panel discussions regarding opportunities, challenges and needs for the development of vaccines that may reduce the need for use of antibiotics in animals; new approaches and potential solutions will be discussed in part 2 of this series. Vaccines are widely used to prevent infections in food animals. Various studies have demonstrated that their animal agricultural use can lead to significant reductions in antibiotic consumption, making them promising alternatives to antibiotics. To be widely used in food producing animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects. Scientific advancements may allow many of these limitations to be overcome, but progress is funding-dependent. Research will have to be prioritized to ensure scarce public resources are dedicated to areas of potentially greatest impact first, and private investments into vaccine development constantly compete with other investment opportunities. Although vaccines have the potential to improve animal health, safeguard agricultural productivity, and reduce antibiotic consumption and resulting resistance risks, targeted research and development investments and concerted efforts by all affected are needed to realize that potential

Respiratory function and respiratory complications in spinal cord injury: protocol for a prospective, multicentre cohort study in high-income countries

Introduction Pneumonia is one of the leading complications and causes of death after a spinal cord injury (SCI). After a cervical or thoracic lesion, impairment of the respiratory muscles decreases respiratory function, which increases the risk of respiratory complications. Pneumonia substantially reduces patient’s quality of life, may prolong inpatient rehabilitation time, increase healthcare costs or at worse, lead to early death. Respiratory function and coughing can be improved through various interventions after SCI, but the available evidence as to which as

Cancer immune therapy using engineered ‛tail-flipping’ nanoliposomes targeting alternatively activated macrophages

Alternatively-activated, M2-like tumor-associated macrophages (TAM) strongly contribute to tumor growth, invasiveness and metastasis. Technologies to disable the pro-tumorigenic function of these TAMs are of high interest to immunotherapy research. Here we show that by designing engineered nanoliposomes bio-mimicking peroxidated phospholipids that are recognised and internalised by scavenger receptors, TAMs can be targeted. Incorporation of phospholipids possessing a terminal carboxylate group at the sn-2 position into nanoliposome bilayers drives their uptake by M2 macrophages with high specificity. Molecular dynamics simulation of the lipid bilayer predicts flipping of the sn-2 tail towards the aqueous phase, while molecular docking data indicates interaction of the tail with Scavenger Receptor Class B type 1 (SR-B1). In vivo, the engineered nanoliposomes are distributed specifically to M2-like macrophages and, upon delivery of the STAT6 inhibitor (AS1517499), zoledronic acid or muramyl tripeptide, these cells promote reduction of the premetastatic niche and/or tumor growth. Altogether, we demonstrate the efficiency and versatility of our engineered “tail-flipping” nanoliposomes in a pre-clinical model, which paves the way to their development as cancer immunotherapeutics in humans

Fatigue in low-grade glioma

Contains fulltext : 80675.pdf (publisher's version ) (Closed access)The aim of this study was to determine the prevalence and severity of fatigue in long-term survivors with a low-grade glioma (LGG), and to analyze the relationship between fatigue and demographic variables, disease duration, tumor characteristics, former tumor treatment modalities, antiepileptic drug (AED) use, self-reported concentration, motivation, and activity. Fifty-four patients with stable disease (age range, 25-73 years) who were diagnosed and treated more than 8 years ago were included in this study. Fatigue was analyzed with the Checklist Individual Strength (CIS). Thirty-nine percent of the LGG patients were severely fatigued, with older patients being most affected. Severe fatigue was associated with AED use, and with reduced self-reported concentration, motivation, and activity. No relation was found between fatigue and gender, histology, tumor laterality, disease duration, type of neurosurgical intervention and radiation treatment. Fatigue is a severe problem in a large proportion of long-term surviving LGG patients