Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

15 years of processing and dissemination of SPOT-VEGETATION products

Throughout the VEGETATION programme, the Flemish Institute for Technological Research (VITO) uninterruptedly hosted the prime user segment of both VEGETATION 1 and VEGETATION 2 multispectral instruments on board the Satellite Pour l’Observation de la Terre 4 (SPOT 4) and SPOT 5 satellites. Operational since the launch of SPOT 4 in March 1998, and foreseen to continue at least until the end of the SPOT 5 mission (anticipated in spring 2014), this user segment comprises a processing facility (PF), actively receiving, processing, correcting, archiving, and distributing the VEGETATION data and derived added-value products. First and foremost, the VEGETATION programme has been serving the needs of operational users – both institutional and commercial – requesting data in near-real time. However, scientific and educational users too benefited significantly, in particular from VEGETATION’s unique time series of the Earth’s land cover, and more specifically the vegetation cover. Over the years, the centralized archive houses processed data covering the equivalent of 11,000 times the Earth’s surface, and delivered more than 50 terapixels to around 10.000 users. As such, VEGETATION’s mission is a prime example of what Europe wants to achieve through the Global Monitoring for Environment and Security (GMES) initiative: truly operational services providing reliable and up-to-date information.

This article describes the processing facility, the way the data and products are archived, the different dissemination channels as well as the data policy adopted and the users served. One of the recent evolutions, the development of an entirely new product distribution facility (PDF), implemented as part of the Project for On-Board Autonomy – Vegetation (PROBA-V) user segment is discussed.     

Physical Maltreatment Victim to Antisocial Child: Evidence of an Environmentally Mediated Process.

The well-documented finding that child physical maltreatment predicts later antisocial behavior has at least 2 explanations: (a) Physical maltreatment causes antisocial behavior, and (b) genetic factors transmitted from parents to children influence the likelihood that parents will be abusive and that children will engage in antisocial behavior. The authors tested these hypotheses in the representative Environmental-Risk cohort of 1,116 twin pairs and their families, who were assessed when the twins were 5 and 7 years old. Mothers reported on children's experience of physical maltreatment, and mothers and teachers reported on children's antisocial behavior. The findings support the hypothesis that physical maltreatment plays a causal role in the development of children's antisocial behavior and that preventing maltreatment can prevent its violent sequelae. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Improvement of Glycaemia and Endothelial Function by a New Low-Dose Curcuminoid in an Animal Model of Type 2 Diabetes

Curcumin has been suggested as a promising treatment for metabolic diseases, but the high doses required limit its therapeutic use. In this study, a new curcuminoid is synthesised to increase curcumin anti-inflammatory and antioxidant potential and to achieve hypoglycaemic and protective vascular effects in type 2 diabetic rats in a lower dose. In vitro, the anti-inflammatory effect was determined through the Griess reaction, and the antioxidant activity through ABTS and TBARS assays. In vivo, Goto-Kakizaki rats were treated for 2 weeks with the equimolar dose of curcumin (40 mg/kg/day) or curcuminoid (52.4 mg/kg/day). Fasting glycaemia, insulin tolerance, plasma insulin, insulin signalling, serum FFA, endothelial function and several markers of oxidative stress were evaluated. Both compounds presented a significant anti-inflammatory effect. Moreover, the curcuminoid had a marked hypoglycaemic effect, accompanied by higher GLUT4 levels in adipose tissue. Both compounds increased NO-dependent vasorelaxation, but only the curcuminoid exacerbated the response to ascorbic acid, consistent with a higher decrease in vascular oxidative and nitrosative stress. SOD1 and GLO1 levels were increased in EAT and heart, respectively. Altogether, these data suggest that the curcuminoid developed here has more pronounced effects than curcumin in low doses, improving the oxidative stress, endothelial function and glycaemic profile in type 2 diabetes.     

First-Void Urine Microbiome in Women with Chlamydia trachomatis Infection

Background: Chlamydia trachomatis (CT) is the agent of the most common bacterial sexually transmitted infection worldwide. Until now, little information is available about the microbial composition of urine samples during CT urethritis. Therefore, in this study, we characterized the microbiome and metabolome profiles of first-void urines in a cohort of women with CT urethral infection attending an STI clinic. Methods: Based on CT positivity by nucleic acid amplification techniques on urine samples, the enrolled women were divided into two groups, i.e., “CT-negative” (n = 21) and “CT-positive” (n = 11). Urine samples were employed for (i) the microbiome profile analysis by means of 16s rRNA gene sequencing and (ii) the metabolome analysis by ¹H-NMR. Results: Irrespective of CT infection, the microbiome of first-void urines was mainly dominated by Lactobacillus, L. iners and L. crispatus being the most represented species. CT-positive samples were characterized by reduced microbial biodiversity compared to the controls. Moreover, a significant reduction of the Mycoplasmataceae family—in particular, of the Ureaplasma parvum species—was observed during CT infection. The Chlamydia genus was positively correlated with urine hippurate and lactulose. Conclusions: These data can help elucidate the pathogenesis of chlamydial urogenital infections, as well as to set up innovative diagnostic and therapeutic approaches.     

Therapeutic Vaccines for HPV-Associated Oropharyngeal and Cervical Cancer: The Next De-Intensification Strategy?

The rise in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has prompted a quest for further understanding of the role of high-risk HPV in tumor initiation and progression. Patients with HPV-positive OPSCC (HPV+ OPSCC) have better prognoses than their HPV-negative counterparts; however, current therapeutic strategies for HPV+ OPSCC are overly aggressive and leave patients with life-long sequalae and poor quality of life. This highlights a need for customized treatment. Several clinical trials of treatment de-intensification to reduce acute and late toxicity without compromising efficacy have been conducted. This article reviews the differences and similarities in the pathogenesis and progression of HPV-related OPSCC compared to cervical cancer, with emphasis on the role of prophylactic and therapeutic vaccines as a potential de-intensification treatment strategy. Overall, the future development of novel and effective therapeutic agents for HPV-associated head and neck tumors promises to meet the challenges posed by this growing epidemic.     

A Second Life for MAP,a Model Amphipathic Peptide

Cell-penetrating peptides (CPP) have been shown to be efficient in the transport of cargoes into the cells, namely siRNA and DNA, proteins and peptides, and in some cases, small therapeutics. These peptides have emerged as a solution to increase drug concentrations in different tissues and various cell types, therefore having a relevant therapeutic relevance which led to clinical trials. One of them, MAP, is a model amphipathic peptide with an α-helical conformation and both hydrophilic and hydrophobic residues in opposite sides of the helix. It is composed of a mixture of alanines, leucines, and lysines (KLALKLALKALKAALKLA). The CPP MAP has the ability to translocate oligonucleotides, peptides and small proteins. However, taking advantage of its unique properties, in recent years innovative concepts were developed, such as in silico studies of modelling with receptors, coupling and repurposing drugs in the central nervous system and oncology, or involving the construction of dual-drug delivery systems using nanoparticles. In addition to designs of MAP-linked vehicles and strategies to achieve highly effective yet less toxic chemotherapy, this review will be focused on unique molecular structure and how it determines its cellular activity, and also intends to address the most recent and frankly motivating issues for the future.