Highlights • Tumor-infiltrating myeloid cells link angiogenesis and immune tolerance to drive tumor growth. • Hypoxia fuels proangiogenic and immune-suppressive programming of myeloid cells in ...tumors. • Immune-suppressive myeloid cells can drive tumor resistance to antiangiogenic therapy. • Antiangiogenic therapy efficacy may partly depend on promoting an immune-stimulating environment.
Tumor angiogenesis, from foe to friend Rivera, Lee B; Bergers, Gabriele
Science (American Association for the Advancement of Science),
08/2015, Letnik:
349, Številka:
6249
Journal Article
Recenzirano
Treatments that normalize or even promote blood vessel growth may enhance drug delivery to tumors
Targeting the tumor vasculature to “starve a tumor to death” instead of targeting tumor cells with ...chemotherapeutic drugs was conceived over four decades ago and has led to the development of antiangiogenic drugs approved for use against various human malignancies (
1
). So far, however, antiangiogenic therapy has not fulfilled expectations because it aids only a subset of cancer patients and provides only transitory improvements. Vascular-disrupting agents were developed to more rigorously deplete tumor vessels (
2
). However, this approach leads to hypoxia, which promotes neovascularization and tumor regrowth. The sobering realization is that the more we try to exterminate tumor vessels, the more aggressively tumors respond to impede these efforts, sometimes becoming more belligerent tumors. Is manipulating the vasculature to control tumor growth a promising strategy after all?
Inhibitors of VEGF (vascular endothelial growth factor)/VEGFR2 (vascular endothelial growth factor receptor 2) are commonly used in the clinic, but their beneficial effects are only observed in a ...subset of patients and limited by induction of diverse relapse mechanisms. We describe the up-regulation of an adaptive immunosuppressive pathway during antiangiogenic therapy, by which PD-L1 (programmed cell death ligand 1), the ligand of the negative immune checkpoint regulator PD-1 (programmed cell death protein 1), is enhanced by interferon-γ-expressing T cells in distinct intratumoral cell types in refractory pancreatic, breast, and brain tumor mouse models. Successful treatment with a combination of anti-VEGFR2 and anti-PD-L1 antibodies induced high endothelial venules (HEVs) in PyMT (polyoma middle T oncoprotein) breast cancer and RT2-PNET (Rip1-Tag2 pancreatic neuroendocrine tumors), but not in glioblastoma (GBM). These HEVs promoted lymphocyte infiltration and activity through activation of lymphotoxin β receptor (LTβR) signaling. Further activation of LTβR signaling in tumor vessels using an agonistic antibody enhanced HEV formation, immunity, and subsequent apoptosis and necrosis in pancreatic and mammary tumors. Finally, LTβR agonists induced HEVs in recalcitrant GBM, enhanced cytotoxic T cell (CTL) activity, and thereby sensitized tumors to antiangiogenic/anti-PD-L1 therapy. Together, our preclinical studies provide evidence that anti-PD-L1 therapy can sensitize tumors to antiangiogenic therapy and prolong its efficacy, and conversely, antiangiogenic therapy can improve anti-PD-L1 treatment specifically when it generates intratumoral HEVs that facilitate enhanced CTL infiltration, activity, and tumor cell destruction.
Macrophages infiltrate hypoxic tumor regions, where they promote angiogenesis and immunosuppression. In this issue of Cancer Cell, Casazza and colleagues report that tumor-associated macrophage (TAM) ...entry into avascular tumor areas is regulated by Semaphorin 3A/Neuropilin-1 signaling; interference with this pathway entraps TAMs in oxygenated areas, preventing their tumorigenic function.
Antiangiogenic therapy is commonly used in the clinic, but its beneficial effects are short-lived, leading to tumor relapse within months. Here, we found that the efficacy of angiogenic inhibitors ...targeting the VEGF/VEGFR pathway was dependent on induction of the angiostatic and immune-stimulatory chemokine CXCL14 in mouse models of pancreatic neuroendocrine and mammary tumors. In response, tumors reinitiated angiogenesis and immune suppression by activating PI3K signaling in all CD11b+ cells, rendering tumors nonresponsive to VEGF/VEGFR inhibition. Adaptive resistance was also associated with an increase in Gr1+CD11b+ cells, but targeting Gr1+ cells was not sufficient to further sensitize angiogenic blockade because tumor-associated macrophages (TAMs) would compensate for the lack of such cells and vice versa, leading to an oscillating pattern of distinct immune-cell populations. However, PI3K inhibition in CD11b+ myeloid cells generated an enduring angiostatic and immune-stimulatory environment in which antiangiogenic therapy remained efficient.
Accurate investigations of quantum-level energies in molecular systems are shown to provide a testing ground to constrain the size of compactified extra dimensions. This is made possible by recent ...progress in precision metrology with ultrastable lasers on energy levels in neutral molecular hydrogen (H2, HD, and D2) and molecular hydrogen ions (H2+, HD+, and D2+). Comparisons between experiment and quantum electrodynamics calculations for these molecular systems can be interpreted in terms of probing large extra dimensions, under which conditions gravity will become much stronger. Molecules are a probe of spacetime geometry at typical distances where chemical bonds are effective (i.e., at length scales of an ). Constraints on compactification radii for extra dimensions are derived within the Arkani-Hamed-Dimopoulos-Dvali framework, while constraints for curvature or brane separation are derived within the Randall-Sundrum framework. Based on the molecular spectroscopy of D2 molecules and HD+ ions, the compactification size for seven extra dimensions (in connection to M-theory defined in 11 dimensions) of equal size is shown to be limited to . While limits on compactification sizes of extra dimensions based on other branches of physics are compared, the prospect of further tightening constraints from the molecular method is discussed.
Background
In order to eliminate tuberculosis (TB) in the USA, primary care providers must take on an expanded role in the diagnosis and management of latent tuberculosis infection (LTBI). Clinical ...practice guidelines and recommendations exist for LTBI management, but there is a need for innovative tools to improve medical students’ and residents’ knowledge of evidence-based practices for LTBI testing and treatment.
Objective
To assess the impact of LTBI-ASSIST, a free online decision support aid, as a novel educational tool and mechanism of delivering clinical practice guidelines for medical trainees.
Design
A single site, randomized controlled trial of trainees delivered by electronic survey.
Interventions
Medical students and Internal Medicine residents at the Johns Hopkins University School of Medicine.
Participants
Participants were randomized in 1:1 ratio to receive the US clinical practice guidelines and recommendations for Latent TB management (control arm) or the guidelines plus an introduction to LTBI-ASSIST (LTBI-ASSIST arm) as they completed a case-based knowledge assessment and reported confidence with domains of LTBI care.
Main Measures
(1) Proportion of questions answered correctly on a case-based knowledge assessment; (2) change in reported confidence with domains of LTBI care.
Key Results
One hundred and thirty participants completed the knowledge assessment. Those randomized to receive the LTBI-ASSIST Tool performed better on the case-based knowledge assessment with a mean score of 75.9% (95% CI: 70.6–81.1), compared to 57.4% (52.8–62.0) in the group that received the guidelines only (
p
<0.001). Similarly, the LTBI-ASSIST group reported a higher change in confidence (measured as post-assessment confidence minus pre-assessment confidence), compared to the control group, in six of the seven domains of LTBI care.
Conclusions
LTBI-ASSIST can be an effective supplement to existing guidelines in educating medical trainees and helping providers find evidence-based, guideline-supported answers for questions encountered in clinical practice.
Trial Registration
NIH Clinical Trial Registry No. NCT05772065
Summary
African swine fever (ASF) is an important emerging transboundary animal disease (TAD), which currently has an impact on many countries in Africa, Eastern Europe, the Caucasus and the Russian ...Federation. The current situation in Europe shows the ability of the virus to rapidly spread, which stands to threaten the global swine industry. At present, there is no viable vaccine to minimize spread of the disease and stamping out is the main source of control. In February 2011, Ethiopia had reported its first suspected outbreaks of ASF. Genomic analyses of the collected ASF virus (ASFV) strains were undertaken using 23 tissue samples collected from domestic swine in Ethiopia from 2011 to 2014. The analysis of Ethiopian ASFVs partial p72 gene sequence showed the identification of a new genotype, genotype XXIII, that shares a common ancestor with genotypes IX and X, which comprise isolates circulating in Eastern African countries and the Republic of Congo. Analysis of the p54 gene also followed the p72 pattern and the deduced amino acid sequence of the central variable region (CVR) of the B602L gene showed novel tetramer repeats not previously characterized.
Cancer is understood as a multifactorial disease that involve multiple cell types and phenotypes in the tumor microenvironment (TME). The components of the TME can interact directly or via soluble ...factors (cytokines, chemokines, growth factors, extracellular vesicles, etc.). Among the cells composing the TME, mesenchymal stem cells (MSCs) appear as a population with debated properties since it has been seen that they can both promote or attenuate tumor progression. For various authors, the main mechanism of interaction of MSCs is through their secretome, the set of molecules secreted into the extracellular milieu, recruiting, and influencing the behavior of other cells in inflammatory environments where they normally reside, such as wounds and tumors. Natural products have been studied as possible cancer treatments, appealing to synergisms between the molecules in their composition; thus, extracts obtained from
Petiveria alliacea
(Anamu-SC) and
Caesalpinia spinosa
(P2Et) have been produced and studied previously on different models, showing promising results. The effect of plant extracts on the MSC secretome has been poorly studied, especially in the context of the TME. Here, we studied the effect of Anamu-SC and P2Et extracts in the human adipose-derived MSC (hAMSC)–tumor cell interaction as a TME model. We also investigated the influence of the hAMSC secretome, in combination with these natural products, on tumor cell hallmarks such as viability, clonogenicity, and migration. In addition, hAMSC gene expression and protein synthesis were evaluated for some key factors in tumor progression in the presence of the extracts by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Multiplex, respectively. It was found that the presence of the hAMSC secretome did not affect the cytotoxic or clonogenicity-reducing activities of the natural extracts on cancer cells, and even this secretome can inhibit the migration of these tumor cells, in addition to the fact that the profile of molecules can be modified by natural products. Overall, our findings demonstrate that hAMSC secretome participation in TME interactions can favor the antitumor activities of natural products.
The fusion of different technologies is the base of the fourth industrial revolution. Companies are encouraged to integrate new tools in their production processes in order to improve working ...conditions and increase productivity and production quality. The integration between information, communication technologies and industrial automation can create highly flexible production models for products and services that can be customized through real-time interactions between consumer, production and machinery throughout the production process. The future of production, therefore, depends on increasingly intelligent machinery through the use of digital systems. The key elements for future integrated devices are intelligent systems and machines, based on human–machine interaction and information sharing. To do so, the implementation of shared languages that allow different systems to dialogue in a simple way is necessary. In this perspective, the use of advanced prototyping tools like Open-Source programming systems, the development of more detailed multibody models through the use of CAD software and the use of self-learning techniques will allow for developing a new class of machines capable of revolutionizing our companies. The purpose of this paper is to present a waypoint navigation activity of a custom Wheeled Mobile Robot (WMR) in an available simulated 3D indoor environment by using the Gazebo simulator. Gazebo was developed in 2002 at the University of Southern California. The idea was to create a high-fidelity simulator that gave the possibility to simulate robots in outdoor environments under various conditions. In particular, we wanted to test the high-performance physics Open Dynamics Engine (ODE) and the sensors feature present in Gazebo for prototype development activities. This choice was made for the possibility of emulating not only the system under analysis, but also the world in which the robot will operate. Furthermore, the integration tools available with Solidworks and Matlab-Simulink, well known commercial platforms of modelling and robotics control respectively, are also explored.
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