Immune evasion in cancer: mechanistic basis and therapeutic strategies

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re- emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, deregulated metabolism etc. In this review, we will discuss the advances made towards understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection

NuSTAR ground calibration: The Rainwater Memorial Calibration Facility (RaMCaF)

The Nuclear Spectroscopic Telescope Array (NuSTAR) is a NASA Small Explorer mission that will carry the first focusing hard X-ray (5-80 keV ) telescope to orbit. The ground calibration of the three flight optics was carried out at the Rainwater Memorial Calibration Facility (RaMCaF) built for this purpose. In this article we present the facility and its use for the ground calibration of the three optics

Production and calibration of the first HEFT hard x-ray optics module

Complete hard X-ray optics modules are currently being produced for the High Energy Focusing Telescope (HEFT), a balloon born mission that will observe a wide range of objects including young supernova remnants, active galactic nuclei, and galaxy clusters at energies between 20 and 70 keV. Large collecting areas are achieved by tightly nesting layers of grazing incidence mirrors in a conic approximation Wolter-I design. The segmented layers are made of thermally-formed glass substrates coated with depth-graded multilayer films for enhanced reflectivity. Our novel mounting technique involves constraining these mirror segments to successive layers of precisely machined graphite spacers. We report the production and calibration of the first HEFT optics module

X-ray scatter measurements from thermally slumped thin glass substrates for the HEFT hard x-ray telescopes

We have performed x-ray specular reflectivity and scattering measurements of thermally slumped glass substrates on x-ray diffractometers utilizing a rotating anode x-ray source at the Danish Space Research Institute (DSRI) and synchrotron radiation at the European Synchrotron Radiation Facility (ESRF) optics Bending Magnet beamline. In addition, we tested depth graded W/Si multilayer-coated slumped glass using x-ray specular reflectivity measurements at 8.048 keV and 28 keV and energy-dispersive measurements in the 20-50 keV rang at a double-axis diffractometer at the Orsted Laboratory, University of Copenhagen. The thermally slumped glass substrates will be used to fabricate the hard x-ray grazing incidence optics for the High-Energy Focusing Telescope. We compared the measurements to the SODART- mirrors from the SRG telescope mission program. The surface scatter measurement of the thermally slumped glass substrates yields Half Power Diameters (HPD's) of single- bounce mirrors of full-illuminated lengths of ~ 40 arcseconds for typical substrates and as low as ~ 10 arcseconds for the best substrates, whereas the SODART mirrors yields HPD's of ~ 80 arcseconds with very little variation. Both free-standing glass substrates and prototype mounted and multilayer-coated optics were tested. The result demonstrate that the surface scatter contribution, plus any contribution from the mounting procedure, to the Half Power Diameter from a telescope using the slumped glass optics will be in the subarcminute range.In addition we measured low surface microroughness, yielding high reflectivity, from the glass substrates, as well as from the depth graded W/Si multilayer-coated glass glass (interfacial width 4.2 Å)

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Hard x-ray optics: from HEFT to NuSTAR

Focusing optics are now poised to dramatically improve the sensitivity and angular resolution at energies above 10 keV to levels that were previously unachievable by the past generation of background limited collimated and coded-aperture instruments. Active balloon programs (HEFT), possible Explorer-class satellites (NuSTAR - currently under Phase A study), and major X-ray observatories (Con-X HXT) using focusing optics will play a major role in future observations of a wide range of objects including young supernova remnants, active galactic nuclei, and galaxy clusters. These instruments call for low cost, grazing incidence optics coated with depth-graded multilayer films that can be nested to achieve large collecting areas. Our approach to building such instruments is to mount segmented mirror shells with our novel error-compensating, monolithic assembly and alignment (EMAAL) procedure. This process involves constraining the mirror segments to successive layers of graphite rods that are precisely machined to the required conic-approximation Wolter-I geometry. We present results of our continued development of thermally formed glass substrates that have been used to build three HEFT telescopes and are proposed for NuSTAR. We demonstrate how our experience in manufacturing complete HEFT telescopes, as well as our experience developing higher performance prototype optics, will lead to the successful production of telescopes that meet the NuSTAR design goals

Autobiographical memory and hierarchical search strategies in depressed and non-depressed participants

Background: There is a growing body of literature showing individuals with depression and other trauma-related disorders (e.g., posttraumatic stress disorder) recall more overgeneral and less specific autobiographical memories compared to normal participants. Although the mechanisms underlying overgeneral memory are quite clear, the search strategy operated within the autobiographical knowledge base, at time of recollection, requires further exploration. The current study aimed to examine the hierarchical search sequence used to recall autobiographical memories in depressed and non-depressed participants, with a view to determining whether depressed participants exhibited truncated search strategies. Methods: Thirteen depressed and an equal number of non-depressed participants retrieved 15 memories each, in response to 15 commonly used cue words. Participants reported the first memory that entered in their mind. All memory descriptions were recorded and later transcribed verbatim for content analysis.Results: Depressed participants retrieved autobiographical memories faster, produced shorter memory descriptions and were less likely to recall positive memories than non-depressed participants. Non-depressed participants were more likely to commence retrieval by accessing lifetime period knowledge followed by general event and event specific knowledge, whereas depressed participants showed a tendency to terminate retrieval at the general event level. Conclusions: It is concluded that depressed participants do adhere to the same hierarchical search strategy as non-depressed participants when retrieving specific autobiographical memories, but that they terminate their search early, resulting in overgeneral memories

Imaging Long-Term Fate of Intramyocardially Implanted Mesenchymal Stem Cells in a Porcine Myocardial Infarction Model

The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [18F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [18F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33–35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC–associated [18F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [18F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI