The role of the tissue microenvironment in the regulation of cancer cell motility and invasion

During malignant neoplastic progression the cells undergo genetic and epigenetic cancer-specific alterations that finally lead to a loss of tissue homeostasis and restructuring of the microenvironment. The invasion of cancer cells through connective tissue is a crucial prerequisite for metastasis formation. Although cell invasion is foremost a mechanical process, cancer research has focused largely on gene regulation and signaling that underlie uncontrolled cell growth. More recently, the genes and signals involved in the invasion and transendothelial migration of cancer cells, such as the role of adhesion molecules and matrix degrading enzymes, have become the focus of research. In this review we discuss how the structural and biomechanical properties of extracellular matrix and surrounding cells such as endothelial cells influence cancer cell motility and invasion. We conclude that the microenvironment is a critical determinant of the migration strategy and the efficiency of cancer cell invasion

Physiological basis and image processing in functional magnetic resonance imaging: Neuronal and motor activity in brain

Functional magnetic resonance imaging (fMRI) is recently developing as imaging modality used for mapping hemodynamics of neuronal and motor event related tissue blood oxygen level dependence (BOLD) in terms of brain activation. Image processing is performed by segmentation and registration methods. Segmentation algorithms provide brain surface-based analysis, automated anatomical labeling of cortical fields in magnetic resonance data sets based on oxygen metabolic state. Registration algorithms provide geometric features using two or more imaging modalities to assure clinically useful neuronal and motor information of brain activation. This review article summarizes the physiological basis of fMRI signal, its origin, contrast enhancement, physical factors, anatomical labeling by segmentation, registration approaches with examples of visual and motor activity in brain. Latest developments are reviewed for clinical applications of fMRI along with other different neurophysiological and imaging modalities

Functional MRI and Diffusion Tensor Imaging of Brain Reorganization After Experimental Stroke

The potential of the adult brain to reorganize after ischemic injury is critical for functional recovery and provides a significant target for therapeutic strategies to promote brain repair. Despite the accumulating evidence of brain plasticity, the interaction and significance of morphological and physiological modifications in post-stroke brain tissue remain mostly unclear. Neuroimaging techniques such as functional MRI (fMRI) and diffusion tensor imaging (DTI) enable in vivo assessment of the spatial and temporal pattern of functional and structural changes inside and outside ischemic lesion areas. This can contribute to the elucidation of critical aspects in post-stroke brain remodeling. Task/stimulus-related fMRI, resting-state fMRI, or pharmacological MRI enables direct or indirect measurement of neuronal activation, functional connectivity, or neurotransmitter system responses, respectively. DTI allows estimation of the structural integrity and connectivity of white matter tracts. Together, these MRI methods provide an unprecedented means to (a) measure longitudinal changes in tissue structure and function close by and remote from ischemic lesion areas, (b) evaluate the organizational profile of neural networks after stroke, and (c) identify degenerative and restorative processes that affect post-stroke functional outcome. Besides, the availability of MRI in clinical institutions as well as research laboratories provides an optimal basis for translational research on stroke recovery. This review gives an overview of the current status and perspectives of fMRI and DTI applications to study brain reorganization in experimental stroke models

Functional diversity and co-operativity between subclonal populations of paediatric glioblastoma and diffuse intrinsic pontine glioma cells

The failure to develop effective therapies for pediatric glioblastoma (pGBM) and diffuse intrinsic pontine glioma (DIPG) is in part due to their intrinsic heterogeneity. We aimed to quantitatively assess the extent to which this was present in these tumors through subclonal genomic analyses and to determine whether distinct tumor subpopulations may interact to promote tumorigenesis by generating subclonal patient-derived models in vitro and in vivo. Analysis of 142 sequenced tumors revealed multiple tumor subclones, spatially and temporally coexisting in a stable manner as observed by multiple sampling strategies. We isolated genotypically and phenotypically distinct subpopulations that we propose cooperate to enhance tumorigenicity and resistance to therapy. Inactivating mutations in the H4K20 histone methyltransferase KMT5B (SUV420H1), present in <1% of cells, abrogate DNA repair and confer increased invasion and migration on neighboring cells, in vitro and in vivo, through chemokine signaling and modulation of integrins. These data indicate that even rare tumor subpopulations may exert profound effects on tumorigenesis as a whole and may represent a new avenue for therapeutic development. Unraveling the mechanisms of subclonal diversity and communication in pGBM and DIPG will be an important step toward overcoming barriers to effective treatments

A Peer-Reviewed Journal on Nutraceuticals and Nutrition Editor-in-Chief Pilot Study: Orally-Administered Yeast β β1,3-glucan Prophylactically Protects Against Anthrax Infection and Cancer in Mice Yeast β β1,3-glucan and Its Use Against Anthrax Infection a

In this edition of JANA, the paper by Vetvicka et al. makes an important contribution to our scientific understanding of the nutraceutical stimulation of the immune system in the treatment of both infectious disease and cancer. While abundant evidence demonstrates the ability of β1,3-glucans to activate macrophages and neutrophils when given intravenously or intraperitoneally, there has been little information concerning its efficiency when given orally. In their study, Vetvicka et al. used oral β1,3-glucan (Imucell TM WGP Beta Glucan) from a yeast source in mice infected with Bacillus anthracis. With the high incidence of complications associated with anthrax vaccines, an alternative approach is badly needed in this era of bioterrorism threat. Dr. Ken Alibek, a top-ranking scientist at the Russian bioweapons labs, stated that because of the number of possible bioweapon agents available, something other than mass inoculations would be needed. He suggested non-specific immune stimulation. The most effective form of nonspecific immune stimulation is macrophage activation. The anthrax bacillus secretes two toxins, edema toxin and lethal toxin. Edema toxin stimulates an outpouring of fluid, especially into the lungs. Lethal toxin, inhibits neutrophil phagocytosis and triggers destructive intracellular reactions that destroy macrophage cells. Of primary interest is the fact that anthrax lethal toxin inhibits the macrophages from releasing their immune messengers, primarily IL-1, IL-2, IFN-gamma, and TNF-alpha. Of particular importance in combating infection release from the macrophage, apparently overcoming inhibition by anthrax lethal toxin. This would account for the high survival figures in the β1,3-glucan-treated animals. Some previous studies found no increase in TNF-alpha but a significant increase in IL-1β. 1 Other researchers have demonstrated increased TNF-alpha in response to ß-glucan stimulation. 2 My own review of the literature confirms their statement that the most effective source of β1,3-glucan is from Saccharomyces cerevisiae, the one chosen by most researchers. Purity of the product is vital, since protein contaminants, as seen in the earlier-used source Zymosan, can cause untoward immune reactions. β1,3-glucan also stimulates phagocytosis of neutrophils. In one study, the killing efficiency of neutrophils was increased 20-to 50-fold. 3 This is important since the capsular antigen poly-D-glutamic acid from the anthrax organism inhibits neutrophil phagocytosis. It is the two lethal toxins and the capsular antigen that makes the anthrax organism especially deadly. In addition, β1,3-glucan has been shown to increase clearance of bacteria by the reticuloendothelial system. Thus far, no other solutions have solved this problem. As for β1,3-glucan&apos;s effects on tumor growth, several studies have shown a significant effect on tumor growth in animal models. 4,5 Early studies using immune stimulation found occasional tumor growth enhancement. This was later found to be secondary to stimulation of blocking antibody production. A safer and more effective method of immune stimulation is directed at cellular immunity, in particular the stimulation of T-helper cells and NK cells. β1,3-glucan has been shown to increase lymphocyte production, NK cell activation, and activation of macrophages. Several studies have also demonstrated the role played by cytokines in inhibiting tumor growth; again, particular interest is in TNF-alpha release. 6 Of interest also is the role played by IL-1β, which is increased by β1,3-glucan as well. Interleukin 1β has been shown to enhance mobilization of PMLs in the bone marrow and enhance their chemotactic ability. In addition, IL-1β increases the lymphocyte count and increases their activity. 7 The use of β1,3-glucan is of special interest in the cancer patient undergoing chemotherapy and/or radiation treatment, since β-glucans have shown a remarkable ability to accelerate hematopoetic recovery in both sublethally and lethally irradiated mice, even when given after the radiation dose. It can also stimulate recovery of the bone marrow following chemotherapy, something vital to restricting tumor growth and preventing infectious complications during treatment. While data provided in the research by Vetvicka and co-workers is preliminary and needs to be confirmed by a larger controlled trial, this is an important pilot study, in that it demonstrates the effectiveness of oral β1,3-glucan in treating both infectious agents and tumors. ABSTRACT β1,3-glucans from various bacterial, mushroom, yeast, and cereal sources have been established as immunomodulators. In the present paper we demonstrate that orallyadministered yeast β1,3-glucan (WGP Beta Glucan) had significant effects as a prophylactic treatment to reduce the mortality of anthrax infection in mice. In addition, the same type of treatment also inhibited the growth of cancer cells in vivo. The mechanism of action involves the stimulation of three important cytokines: IL-2, IFN-γ, and TNF-α. These results provide preclinical evidence for the beneficial effects of orally-administered yeast β1,3-glucan

The potential role of MR-guided adaptive radiotherapy in pediatric oncology: Results from a SIOPE-COG survey.

Background and purpose Magnetic resonance guided radiotherapy (MRgRT) has been successfully implemented for several routine clinical applications in adult patients. The purpose of this study is to map the potential benefit of MRgRT on toxicity reduction and outcome in pediatric patients treated with curative intent for primary and metastatic sites.Materials and methods Between May and August 2020, a survey was distributed among SIOPE- and COG-affiliated radiotherapy departments, treating at least 25 pediatrics patients annually and being (candidate) users of a MRgRT system. The survey consisted of a table with 45 rows (clinical scenarios for primary (n = 28) and metastatic (n = 17) tumors) and 7 columns (toxicity reduction, outcome improvement, PTV margin reduction, target volume daily adaptation, online re-planning, intrafraction motion compensation and on-board functional imaging) and the option to answer by 'yes/no' . Afterwards, the Dutch national radiotherapy cohort was used to estimate the percentage of pediatric treatments that may benefit from MRgRT.Results The survey was completed by 12/17 (71% response rate) institutions meeting the survey inclusion criteria. Responders indicated an 'expected benefit' from MRgRT for toxicity/outcome in 7% (for thoracic lymphomas and abdominal rhabdomyosarcomas)/0% and 18% (for mediastinal lymph nodes, lymph nodes located in the liver/splenic hilum, and liver metastases)/0% of the considered scenarios for the primary and metastatic tumor sites, respectively, and a 'possible benefit' was estimated in 64%/46% and 47%/59% of the scenarios. When translating the survey outcome into a clinical perspective a toxicity/outcome benefit, either expected or possible, was anticipated for 55%/24% of primary sites and 62%/38% of the metastatic sites.Conclusion Although the benefit of MRgRT in pediatric radiation oncology is estimated to be modest, the potential role for reducing toxicity and improving clinical outcomes warrants further investigation. This fits best within the context of prospective studies or registration trials