Association between Variants in Atopy-Related Immunologic Candidate Genes and Pancreatic Cancer Risk

<div><p>Background</p><p>Many epidemiology studies report that atopic conditions such as allergies are associated with reduced pancreas cancer risk. The reason for this relationship is not yet understood. This is the first study to comprehensively evaluate the association between variants in atopy-related candidate genes and pancreatic cancer risk.</p><p>Methods</p><p>A population-based case-control study of pancreas cancer cases diagnosed during 2011-2012 (via Ontario Cancer Registry), and controls recruited using random digit dialing utilized DNA from 179 cases and 566 controls. Following an exhaustive literature review, SNPs in 180 candidate genes were pre-screened using dbGaP pancreas cancer GWAS data; 147 SNPs in 56 allergy-related immunologic genes were retained and genotyped. Logistic regression was used to estimate age-adjusted odd ratio (AOR) for each variant and false discovery rate was used to adjust Wald p-values for multiple testing. Subsequently, a risk allele score was derived based on statistically significant variants.</p><p>Results</p><p>18 SNPs in 14 candidate genes (<i>CSF2</i>, <i>DENND1B</i>, <i>DPP10</i>, <i>FLG</i>, <i>IL13</i>, <i>IL13RA2</i>, <i>LRP1B</i>, <i>NOD1</i>, <i>NPSR1</i>, <i>ORMDL3</i>, <i>RORA</i>, <i>STAT4</i>, <i>TLR6</i>, <i>TRA</i>) were significantly associated with pancreas cancer risk. After adjustment for multiple comparisons, two <i>LRP1B</i> SNPs remained statistically significant; for example, <i>LRP1B</i> rs1449477 (AA vs. CC: AOR=0.37, 95% CI: 0.22-0.62; p (adjusted)=0.04). Furthermore, the risk allele score was associated with a significant reduction in pancreas cancer risk (p=0.0007).</p><p>Conclusions</p><p>Preliminary findings suggest certain atopy-related variants may be associated with pancreas cancer risk. Further studies are needed to replicate this, and to elucidate the biology behind the growing body of epidemiologic evidence suggesting allergies may reduce pancreatic cancer risk.</p></div

Auranofin Is an Apoptosis-Simulating Agent with <i>in Vitro</i> and <i>in Vivo</i> Anti-leishmanial Activity

Cutaneous leishmaniasis remains ignored in therapeutic drug discovery programs worldwide. This is mainly because cutaneous leishmaniasis is frequently a disease of impoverished populations in countries where funds are limited for research and patient care. However, the health burden of individuals in endemic areas mandates readily available, effective, and safe treatments. Of the existing cutaneous leishmaniasis therapeutics, many are growth inhibitory to <i>Leishmania</i> parasites, potentially creating dormant parasite reservoirs that can be activated when host immunity is compromised, enabling the reemergence of cutaneous leishmaniasis lesions or worse spread of <i>Leishmania</i> parasites to other body sites. To accelerate the identification and development of novel cutaneous leishmaniasis therapeutics, we designed an integrated <i>in vitro</i> and <i>in vivo</i> screening platform that incorporated multiple <i>Leishmania</i> life cycles and species and probed a focused library of pharmaceutically active compounds. The objective of this phenotypic drug discovery platform was the identification and prioritization of <i>bona fide</i> cytotoxic chemotypes toward <i>Leishmania</i> parasites. We identified the Food and Drug Administration-approved drug auranofin, a known inhibitor of <i>Leishmania</i> promastigote growth, as a potent cytotoxic anti-leishmanial agent and inducer of apoptotic-like death in promastigotes. Significantly, the anti-leishmanial activity of auranofin transferred to cell-based amastigote assays as well as <i>in vivo</i> murine models. With appropriate future investigation, these data may provide the foundation for potential exploitation of gold­(I)-based complexes as chemical tools or the basis of therapeutics for leishmaniasis. Thus, auranofin may represent a prototype drug that can be used to identify signaling pathways within the parasite and host cell critical for parasite growth and survival

Additional file 1: of Immune oncology, immune responsiveness and the theory of everything

List of individual genes and corresponding models related to immune suppression used for the Theory of Everything (TOE). (TXT 11 kb