Synthetic Double-Stranded RNAs Are Adjuvants for the Induction of T Helper 1 and Humoral Immune Responses to Human Papillomavirus in Rhesus Macaques

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or without dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC—but not CpG-C given at the same dose—also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell–activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell–attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates

Second Language Processing Shows Increased Native-Like Neural Responses after Months of No Exposure

Although learning a second language (L2) as an adult is notoriously difficult, research has shown that adults can indeed attain native language-like brain processing and high proficiency levels. However, it is important to then retain what has been attained, even in the absence of continued exposure to the L2—particularly since periods of minimal or no L2 exposure are common. This event-related potential (ERP) study of an artificial language tested performance and neural processing following a substantial period of no exposure. Adults learned to speak and comprehend the artificial language to high proficiency with either explicit, classroom-like, or implicit, immersion-like training, and then underwent several months of no exposure to the language. Surprisingly, proficiency did not decrease during this delay. Instead, it remained unchanged, and there was an increase in native-like neural processing of syntax, as evidenced by several ERP changes—including earlier, more reliable, and more left-lateralized anterior negativities, and more robust P600s, in response to word-order violations. Moreover, both the explicitly and implicitly trained groups showed increased native-like ERP patterns over the delay, indicating that such changes can hold independently of L2 training type. The results demonstrate that substantial periods with no L2 exposure are not necessarily detrimental. Rather, benefits may ensue from such periods of time even when there is no L2 exposure. Interestingly, both before and after the delay the implicitly trained group showed more native-like processing than the explicitly trained group, indicating that type of training also affects the attainment of native-like processing in the brain. Overall, the findings may be largely explained by a combination of forgetting and consolidation in declarative and procedural memory, on which L2 grammar learning appears to depend. The study has a range of implications, and suggests a research program with potentially important consequences for second language acquisition and related fields

The prognostic significance of tumour-stroma ratio in endometrial carcinoma.

Background: High tumour stromal content has been found to predict adverse clinical outcome in a range of epithelial tumours. The aim of this study was to assess the prognostic significance of tumour-stroma ratio (TSR) in endometrial adenocarcinomas and investigate its relationship with other clinicopathological parameters. Methods: Clinicopathological and 5-year follow-up data were obtained for a retrospective series of endometrial adenocarcinoma patients (n = 400). TSR was measured using a morphometric approach (point counting) on digitised histologic hysterectomy specimens. Inter-observer agreement was determined using Cohen’s Kappa statistic. TSR cut-offs were optimised using log-rank functions and prognostic significance of TSR on overall survival (OS) and disease-free survival (DFS) were determined using Cox Proportional Hazards regression analysis and Kaplan-Meier curves generated. Associations of TSR with other clinicopathological parameters were determined using non-parametric tests followed by Holm-Bonferroni correction for multiple comparisons. Results: TSR as a continuous variable associated with worse OS (P = 0.034) in univariable Cox-regression analysis. Using the optimal cut-off TSR value of 1.3, TSR-high (i.e. low stroma) was associated with worse OS (HR = 2.51; 95 % CI = 1.22–5.12; P = 0.021) and DFS (HR = 2.19; 95 % CI = 1.15–4.17; P = 0.017) in univariable analysis. However, TSR did not have independent prognostic significance in multivariable analysis, when adjusted for known prognostic variables. A highly significant association was found between TSR and tumour grade (P < 0.001) and lymphovascular space invasion (P < 0.001), both of which had independent prognostic significance in this study population. Conclusions: Low tumour stromal content associates with both poor outcome and with other adverse prognostic indicators in endometrial cancer, although it is not independently prognostic. These findings contrast with studies on many - although not all - cancers and suggest that the biology of tumour-stroma interactions may differ amongst cancer types

Network analysis of coronary artery disease risk genes elucidates disease mechanisms and druggable targets

Genome-wide association studies (GWAS) have identified over two hundred chromosomal loci that modulate risk of coronary artery disease (CAD). The genes affected by variants at these loci are largely unknown and an untapped resource to improve our understanding of CAD pathophysiology and identify potential therapeutic targets. Here, we prioritized 68 genes as the most likely causal genes at genome-wide significant loci identified by GWAS of CAD and examined their regulatory roles in 286 metabolic and vascular tissue gene-protein sub-networks ("modules"). The modules and genes within were scored for CAD druggability potential. The scoring enriched for targets of cardiometabolic drugs currently in clinical use and in-depth analysis of the top-scoring modules validated established and revealed novel target tissues, biological processes, and druggable targets. This study provides an unprecedented resource of tissue-defined gene-protein interactions directly affected by genetic variance in CAD risk loci