Synthesis of waterborne degradable polyester nanoparticles

Waterborne degradable nanoparticles are of interest for many applications, such as drug delivery, temporary coatings or adhesives. The aim of this project is to achieve degradability of waterborne polymeric adhesive dispersions by introducing polyesters in the polymer particles due to their simple decomposition through hydrolysis. Two approaches were followed to introduce polyesters into the polymer matrix. On the one hand the usage of acrylated oligoesters as macromonomers to form degradable side chains and on the other hand the usage of diacrylated oligoesters as crosslinker for degradability in the crosslinking points of the polymeric network (Figure 1). Please click Additional Files below to see the full abstract

Triggering MSR1 promotes JNK-mediated inflammation in IL-4 activated macrophages

Alternatively activated M2 macrophages play an important role in maintenance of tissue homeostasis by scavenging dead cells, cell debris and lipoprotein aggregates via phagocytosis. Using proteomics, we investigated how alternative activation, driven by IL-4, modulated the phagosomal proteome to control macrophage function. Our data indicate that alternative activation enhances homeostatic functions such as proteolysis, lipolysis and nutrient transport. Intriguingly, we identified the enhanced recruitment of the TAK1/MKK7/JNK signalling complex to phagosomes of IL-4-activated macrophages. The recruitment of this signalling complex was mediated through K63 polyubiquitylation of the macrophage scavenger receptor 1 (MSR1). Triggering of MSR1 in IL-4-activated macrophages leads to enhanced JNK activation, thereby promoting a phenotypic switch from an anti-inflammatory to a pro-inflammatory state, which was abolished upon MSR1 deletion or JNK inhibition. Moreover, MSR1 K63 polyubiquitylation correlated with the activation of JNK signalling in ovarian cancer tissue from human patients, suggesting that it may be relevant for macrophage phenotypic shift in vivo Altogether, we identified that MSR1 signals through JNK via K63 polyubiquitylation and provides evidence for the receptor's involvement in macrophage polarization

Treatment of bulky lymph nodes in locally advanced cervical cancer:boosting versus debulking

Objective: Treatment strategies for bulky lymph nodes in patients with locally advanced cervical cancer scheduled for definitive chemoradiation include nodal boosting with radiotherapy, surgical debulking, or both. The aim of this retrospective cohort study was to compare survival and toxicity in patients receiving these treatments and to compare them with a group that received neither form of treatment. Methods: Women diagnosed between January 2009 and January 2017 with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IB2, IIA2-IVA cervical cancer with lymph nodes ≥1.5 cm without upper limit on pretreatment imaging and treated with definitive chemoradiation were selected from the Netherlands Cancer Registry. Patients were categorized by intention-to-treat strategy: boosting, debulking, or neither treatment, with subgroup analysis for patients receiving both treatments, that is, debulking with boosting. Overall and relapse-free survival outcomes were compared by Kaplan-Meier and Cox regression analyses and toxicity by logistic regression analysis. Results: Of 190 patients, 101 (53%) received only nodal boosting, 31 (16%) debulking alone, 29 (15%) debulking combined with boosting, and 29 (15%) received neither treatment. The 5 year overall and relapse-free survival for the treatment groups were 58%, 45% and 45% (p=0.19), and 47%, 44% and 46% (p=0.87), respectively. Multivariable Cox regression analyses demonstrated no differences in overall and relapse-free survival. Combination of debulking with boosting was associated with decreased overall and relapse-free survival compared with debulking alone (HR 2.47, 95% CI 1.22 to 5.00; and HR 2.37, 95% CI 1.14 to 4.93). Nodal boosting was independently associated with a decreased toxicity risk compared with debulking strategy (OR 0.37, 95% CI 0.16 to 0.83). Conclusions: This study showed no survival benefit from either nodal boosting or debulking strategy in patients with suspicious bulky nodes. Nodal boosting might, however, be associated with less toxicity. Dual treatment with debulking and boosting showed a worse survival outcome because this group probably represents patients with poor prognostic factors

Short-term surgical complications after radical hysterectomy—A nationwide cohort study

Introduction: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. Material and methods: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also

Short-term surgical complications after radical hysterectomy - a nationwide cohort study

Introduction: Centralization has, among other aspects, been argued to have an impact on quality of care in terms of surgical morbidity. Next, monitoring quality of care is essential in identifying areas of improvement. This nationwide cohort study was conducted to determine the rate of short-term surgical complications and to evaluate its possible predictors in women with early-stage cervical cancer. Material and methods: Women diagnosed with early-stage cervical cancer, 2009 FIGO stages IB1 and IIA1, between 2015 and 2017 who underwent radical hysterectomy with pelvic lymphadenectomy in 1 of the 9 specialized medical centers in the Netherlands, were identified from the Netherlands Cancer Registry. Women were excluded if primary treatment consisted of hysterectomy without parametrial dissection or radical trachelectomy. Women in whom radical hysterectomy was aborted during the procedure, were also excluded. Occurrence of intraoperative and postoperative complications and type of complications, developing within 30 days after surgery, were prospectively registered. Multivariable logistic regression analysis was used to identify predictors of surgical complications. Results: A total of 472 women were selected, of whom 166 (35%) developed surgical complications within 30 days after radical hysterectomy. The most frequent complications were urinary retention with catheterization in 73 women (15%) and excessive perioperative blood loss >1000 mL in 50 women (11%). Open surgery (odds ratio [OR] 3.42; 95% CI 1.73-6.76), chronic pulmonary disease (OR 3.14; 95% CI 1.45-6.79), vascular disease (OR 1.90; 95% CI 1.07-3.38), and medical center (OR 2.83; 95% CI 1.18-6.77) emerged as independent predictors of the occurrence of complications. Body mass index (OR 0.94; 95% CI 0.89-1.00) was found as a negative predictor of urinary retention. Open surgery (OR 36.65; 95% CI 7.10-189.12) and body mass index (OR 1.15; 95% CI 1.08-1.22) were found to be independent predictors of excessive perioperative blood loss. Conclusions: Short-term surgical complications developed in 35% of the women after radical hysterectomy for early-stage cervical cancer in the Netherlands, a nation with centralized surgical care. Comorbidities predict surgical complications, and open surgery is associated with excessive perioperative blood loss

Diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT in detecting lymph node metastases in clinically early-stage cervical cancer: a nationwide Dutch cohort study

Objectives: Imaging is increasingly used to assess lymph node involvement in clinically early-stage cervical cancer. This retrospective study aimed to evaluate the diagnostic accuracy of MRI, CT, and [18F]FDG-PET-CT. Methods: Women with International Federation of Gynaecology and Obstetrics (FIGO) 2009 stage IA2-IIA cervical cancer and pretreatment imaging between 2009 and 2017 were selected from the Netherlands Cancer Registry. Patient-based and region-based (i.e. pelvic and common iliac) nodal status was extracted from radiology reports. Pathology results were considered the reference standard for calculating accuracy indices. Multiple imputation was used for missing pathology to limit verification bias risk. Results: Nodal assessment was performed in 1676 patients with MRI, 926 with CT, and 379 with [18F]FDG-PET-CT, with suspicious nodes detected in 17%, 16%, and 48%, respectively. [18F]FDG-PET-CT was used to confirm MRI/CT results in 95% of patients. Pathology results were imputed for 30% of patients. [18F]FDG-PET-CT outperformed MRI and CT in detecting patient-based nodal metastases with sensitivities of 80%, 48%, and 40%, and AUCs of 0.814, 0.706, and 0.667, respectively, but not in specificity: 79%, 92%, and 92%. Region-based analyses showed similar indices in the pelvic region, but worse performance in the common iliac region with AUCs of 0.575, 0.554, and 0.517, respectively. Conclusions: [18F]FDG-PET-CT outperformed MRI and CT in detecting nodal metastases, which may be related to its use as a verification modality. However, MRI and CT had the highest specificity. As MRI is generally performed routinely to assess local and regional spread of cervical cancer, [18F]FDG-PET-CT can be used to confirm suspicious nodes. Critical relevance statement: Accurate assessment of the nodal status in clinically early-stage cervical cancer is essential for tumour staging, treatment decision making and prognosis. Key points: • The accuracy of MRI, CT or [18F]FDG-PET-CT for nodal staging in early cervical cancer is a subject of discussion. • Overall, [18F]FDG-PET-CT outperformed MRI, followed by CT, when used as a verification modality. • Staging with MRI and the addition of [18F]FDG-PET-CT to verify high-risk cases seems to be a good approach. Graphical Abstract: (Figure presented.

Antimicrobial peptides as novel anti-tuberculosis therapeutics

"Available online 24 May 2016"Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, has recently joined HIV/AIDS as the world's deadliest infectious disease, affecting around 9.6 million people worldwide in 2014. Of those, about 1.2 million died from the disease. Resistance acquisition to existing antibiotics, with the subsequent emergence of Multi-Drug Resistant mycobacteria strains, together with an increasing economic burden, has urged the development of new anti-TB drugs. In this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that make part of the innate immune system, now arise as promising candidates for TB treatment. In this review, we analyze the potential of AMPs for this application. We address the mechanisms of action, advantages and disadvantages over conventional antibiotics and how problems associated with its use may be overcome to boost their therapeutic potential. Additionally, we address the challenges of translational development from benchside to bedside, evaluate the current development pipeline and analyze the expected global impact from a socio-economic standpoint. The quest for more efficient and more compliant anti-TB drugs, associated with the great therapeutic potential of emerging AMPs and the rising peptide market, provide an optimal environment for the emergence of AMPs as promising therapies. Still, their pharmacological properties need to be enhanced and manufacturing-associated issues need to be addressed.Portuguese Foundation for Science and Technology (FCT) - UID/ BIO/04469/2013 unit ; COMPETE 2020 (POCI-01-0145-FEDER- 006684) ; SFRH/BPD/64958/2010Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462

Learning for Purpose: Researching the Social Return on Education and Training in the Australian Not-for-Profit Sector

Executive Summary Training and professional development are key tools for strategically enhancing the leadership and technical competence of any workforce. Research shows that formal learning experiences that are well aligned, designed, delivered, and applied do improve individual and organisational performance. Indeed, the development of human capital is now globally heralded as fundamental to individual, organisational, and societal sustainability and progress. Yet, the continuous and professional development of leaders, managers, directors, employees, and volunteers is repetitively admonished for its absence in the Not-for-Profit (NFP) sector. Despite the need for an informed conversation, there is a profound absence of systematic information on the state of professional development in Australian NFP organisations: how they develop their people, the consequences of their efforts, and what might be holding them back. This research begins to fill that gap. The Australian Not-for-Profit sector is extensive and operates across most aspects of our lives and communities. It provides services and support that are diverse and complicated, and in domains that business and public sector organisations are not able or willing to address. With over 600,000 organisations, the NFP sector is the fastest growing part of the Australian economy. Notably, the Australian NFP Sector makes a substantial economic contribution by generating 55 billion toward the nation’s GDP; employs more than 1 million people, who represent about 9% of the overall workforce; and engages over 5 million volunteers, who contribute an additional 15 billion in unpaid work. Every Australian benefits from NFP services that address social disadvantage, civic awareness, community cohesion, education, employment, emergency relief, cultural heritage, biodiversity, artistic creation, sports, well-being, and thus shape and sustain an attractive and functional society. Meanwhile, challenging times give rise to NFP leaders being pessimistic about their organisations’ ability to match heightened expectations. The Australian NFP sector is under severe strain to meet the many obligations, challenges, and goals for making a sustained social impact.  And so is its workforce. Most people working for NFP organisations are dedicated and motivated. They work long hours and are paid less for their efforts when compared with the private and public sector. Even more people volunteer their time and energy. The challenge is not to make them work harder, but smarter. This report draws on robust theory and integrates rich empirical evidence to inform leaders, funders, policy makers, and scholars about workforce development in the Australian NFP sector. It reviews pertinent literature and juxtaposes debates that usually take place within different communities and discipline fields. The report summarises key findings from field research conducted in Australia from 2012 to 2015. The report is for all those interested in the state of ‘Learning for Purpose’ and how it affects NFP organisations’ success in realising their mission and community objectives. The potential to rise from good to great hinges on the people and capabilities within the Australian NFP sector. The findings in this report establish support for professional development as necessary to systematically facilitate Australian NFP workers’ knowledge, skills, and abilities. And for these, in turn, to significantly contribute to organisational viability and the generation of positive social change.   Key Findings #1 Training intensity in the Australian NFP sector is highly variable across organisational size, job role and sub-sector. #2 NFP organisations that systematically develop their people do better. #3 Training for NFP key competencies works. #4 Training NFP key competencies leads to multiple positive outcomes. #5 Training can deliver positive economic returns. #6 The lack of money and time prevent needed professional development opportunities. #7 The needs for developing NFP key competencies vary considerably. &nbsp