Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit

Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe

The Extragalactic Background Light (EBL) includes photons with wavelengths from ultraviolet to infrared, which are effective at attenuating gamma rays with energy above ~10 GeV during propagation from sources at cosmological distances. This results in a redshift- and energy-dependent attenuation of the gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts (GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using photons above 10 GeV collected by Fermi over more than one year of observations for these sources, we investigate the effect of gamma-ray flux attenuation by the EBL. We place upper limits on the gamma-ray opacity of the Universe at various energies and redshifts, and compare this with predictions from well-known EBL models. We find that an EBL intensity in the optical-ultraviolet wavelengths as great as predicted by the "baseline" model of Stecker et al. (2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A. Reimer, L.C. Reye

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Eaten out of house and home:impacts of grazing on ground-dwelling reptiles in Australian grasslands and grassy woodlands

Large mammalian grazers can alter the biotic and abiotic features of their environment through their impacts on vegetation. Grazing at moderate intensity has been recommended for biodiversity conservation. Few studies, however, have empirically tested the benefits of moderate grazing intensity in systems dominated by native grazers. Here we investigated the relationship between (1) density of native eastern grey kangaroos, Macropus giganteus, and grass structure, and (2) grass structure and reptiles (i.e. abundance, richness, diversity and occurrence) across 18 grassland and grassy Eucalyptus woodland properties in south-eastern Australia. There was a strong negative relationship between kangaroo density and grass structure after controlling for tree canopy cover. We therefore used grass structure as a surrogate for grazing intensity. Changes in grazing intensity (i.e. grass structure) significantly affected reptile abundance, reptile species richness, reptile species diversity, and the occurrence of several ground-dwelling reptiles. Reptile abundance, species richness and diversity were highest where grazing intensity was low. Importantly, no species of reptile was more likely to occur at high grazing intensities. Legless lizards (Delma impar, D. inornata) were more likely to be detected in areas subject to moderate grazing intensity, whereas one species (Hemiergis talbingoensis) was less likely to be detected in areas subject to intense grazing and three species (Menetia greyii, Morethia boulengeri, and Lampropholis delicata) did not appear to be affected by grazing intensity. Our data indicate that to maximize reptile abundance, species richness, species diversity, and occurrence of several individual species of reptile, managers will need to subject different areas of the landscape to moderate and low grazing intensities and limit the occurrence and extent of high grazing

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Behavioural and educational outcomes following extremely preterm birth : current controversies and future directions

As a consequence of improved survival rates for extremely preterm (EP; <28 weeks of gestation) births, there is a growing body of evidence detailing the impact of extreme prematurity on outcomes throughout childhood and adolescence. Historically, attention first focused on documenting rates of sensory impairments and severe neurodevelopmental disabilities. However, over recent years, there has been growing interest in the impact of EP birth on long term mental health and educational outcomes. In this chapter we review literature relating to the impact of EP birth on attention, social and emotional problems, psychiatric disorders and educational outcomes. We also outline current controversies in the field. In particular, we present emergent research exploring developmental trajectories to determine whether the sequelae associated with EP birth represent a developmental delay or persistent deficit, and we consider what approaches to intervention may be most fruitful in improving behavioural and educational outcomes in this population

Clinical Perspectives on Targeting of Myeloid Derived Suppressor Cells in the Treatment of Cancer

Tumors escape immune recognition by several mechanisms, and induction of myeloid derived suppressor cells (MDSC) is thought to play a major role in tumor mediated immune evasion. MDSC arise from myeloid progenitor cells that do not differentiate into mature dendritic cells, granulocytes, or macrophages, and are characterized by the ability to suppress T cell and natural killer cell function. They are increased in patients with cancer including renal cell carcinoma (RCC), and their levels have been shown to correlate with prognosis and overall survival. Multiple methods of inhibiting MDSCs are currently under investigation. These can broadly be categorized into methods that (a) promote differentiation of MDSC into mature, non-suppressive cells (all trans retinoic acid, vitamin D), (b) decrease MDSC levels (sunitinib, gemcitabine, 5-FU, CDDO-Me), or (c) functionally inhibit MDSC (PDE-5 inhibitors, cyclooxygenase 2 inhibitors). Recently, several pre-clinical tumor models of combination therapy involving sunitinib plus vaccines and/or adoptive therapy have shown promise in MDSC inhibition and improved outcomes in the tumor bearing host. Current clinical trials are underway in RCC patients to assess not only the impact on clinical outcome, but how this combination can enhance anti-tumor immunity and reduce immune suppression. Decreasing immune suppression by MDSC in the cancer host may improve outcomes and prolong survival in this patient population