Peptide-Based Cancer Vaccine Delivery via the STINGΔTM-cGAMP Complex.

With the advent of bioinformatic tools in efficiently predicting neo-antigens, peptide vaccines have gained tremendous attention in cancer immunotherapy. However, the delivery of peptide vaccines remains a major challenge, primarily due to ineffective transport to lymph nodes and low immunogenicity. Here, a strategy for peptide vaccine delivery is reported by first fusing the peptide to the cytosolic domain of the stimulator of interferon genes protein (STINGΔTM), then complexing the peptide-STINGΔTM protein with STING agonist 2'3' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). The process results in the formation of self-assembled cGAMP-peptide-STINGΔTM tetramers, which enables efficient lymphatic trafficking of the peptide. Moreover, the cGAMP-STINGΔTM complex acts not only as a protein carrier for the peptide, but also as a potent adjuvant capable of triggering STING signaling independent of endogenous STING protein-an especially important attribute considering that certain cancer cells epigenetically silence their endogenous STING expression. With model antigen SIINFEKL, it is demonstrated that the platform elicits effective STING signaling in vitro, draining lymph node targeting in vivo, effective T cell priming in vivo as well as antitumoral immune response in a mouse colon carcinoma model, providing a versatile solution to the challenges faced in peptide vaccine delivery.

Pathways to program entry: Factors promoting entry and participation in veteran peer-support programs.

Given the documented underutilization of community-based services by veterans, this study aims to identify factors promoting engagement in programs. Qualitative data from interviews with 154 veterans in peer support programs were analyzed to identify factors promoting program entry and participation. Findings confirm the importance of both internal and external factors for program engagement. Internal factors included feeling a sense of disconnection, dissatisfaction with other programs, emotional needs, concrete needs, and a desire to serve others. External factors included encouragement from others, program culture, and program climate. Implications for program development and evaluation are discussed. While much of the current literature on veterans focuses on individual characteristics promoting or impeding service use, this study provides insight into programmatic features such as culture and climate which foster participation and meaningful engagement. Ultimately, programs serving veterans need input and influence by veterans, and should emphasize peer support and other opportunities for social connection.

Self-assembled cGAMP-STINGΔTM signaling complex as a bioinspired platform for cGAMP delivery.

The stimulator of interferon (IFN) genes (STING) pathway constitutes a highly important part of immune responses against various cancers and infections. Consequently, administration of STING agonists such as cyclic GMP-AMP (cGAMP) has been identified as a promising approach to target these diseases. In cancer cells, STING signaling is frequently impaired by epigenetic silencing of STING; hence, conventional delivery of only its agonist cGAMP may be insufficient to trigger STING signaling. In this work, while expression of STING lacking the transmembrane (TM) domain is known to be unresponsive to STING agonists and is dominant negative when coexpressed with the full-length STING inside cells, we observed that the recombinant TM-deficient STING protein complexed with cGAMP could effectively trigger STING signaling when delivered in vitro and in vivo, including in STING-deficient cell lines. Thus, this bioinspired method using TM-deficient STING may present a universally applicable platform for cGAMP delivery.

Cost-effectiveness of meningococcal polysaccharide serogroups A, C, W-135 and Y conjugate vaccine in Australian adolescents.

OBJECTIVES: The incidence of invasive meningitis disease (IMD) is increasing in Australia. A conjugate vaccine of meningococcal polysaccharide serogroups A, C, W and Y (MenACWY) is currently indicated for infants aged 12 months on the Australian National Immunisation Program. This study sought to determine the cost-effectiveness of a broader MenACWY vaccination program for Australians aged 15 to 19 years. METHODS: A Markov model was constructed to simulate the incidence and consequences of IMD in Australians aged 0-84 years, with follow up until age 85 years. The model comprised four health states: 'Alive with no previous IMD', 'Alive, post IMD without long-term complications', 'Alive, post IMD with long-term complications' and 'Dead'. Decision analysis compared the clinical consequences and costs of a vaccination program versus no vaccination from the perspective of the Australian health care system. Age-specific incidence of IMD and fatality rates were derived from Australian surveillance data. Vaccine coverage, vaccine efficacy and herd immunity were based on published data. The total cost for MenACWY vaccination was AU$56 per dose. Costs and health outcomes were discounted by 5% per annum (in the base-case analysis). RESULTS: Compared to no vaccination, a MenACWY vaccination program targeted at Australians aged 15-19 years was expected to prevent 1664 IMD cases in the Australian population aged 0-84 years followed up until age 85 years. The program would lead to 1131 life years (LYs) and 2058 quality adjusted life years (QALYs) gained at a total cost of AU$115 million (all discounted values). These equated to incremental cost-effectiveness ratios of AU$101,649 per LY gained and AU$55,857 per QALY gained. A probabilistic sensitivity analysis demonstrated a likelihood of cost-effectiveness of 34.6%, assuming a willingness to pay threshold of AU$50,000 per QALY gained. CONCLUSION: The likelihood of this program being cost-effective under a willingness to pay threshold AU$50,000 per QALY gained is 35%.

Cross-sectional study of HPV testing in self-sampled urine and comparison with matched vaginal and cervical samples in women attending colposcopy for the management of abnormal cervical screening.

OBJECTIVES: Human papillomavirus (HPV) testing in cervical screening offers the potential for self-sampling to improve uptake among non-attenders. High-risk (HR) HPV detection in urine shows promise, but few studies have examined its sensitivity for cervical intraepithelial neoplasia (CIN2+) detection compared with standard cervical samples. The aims of this cross-sectional study were to optimise conditions for urine testing for HPV detection; to determine concordance for HR-HPV detection in matched urine, vaginal and cervical samples; to compare the sensitivity of HR-HPV testing for the detection of CIN2+ in matched samples; and to determine the acceptability of urine testing for cervical screening. DESIGN: Cross-sectional study. SETTING: Secondary care colposcopy clinic in North West England. PARTICIPANTS: Women aged 25 years of age or older, attending colposcopy clinic for management of abnormal cervical screening results or a suspicious-looking cervix. In total, 104 women took part in the study. Triple matched samples were available for 79 and 66 women using Abbott RealTime (ART) and Roche Cobas 4800 (RC), respectively. INTERVENTION: Self-collected urine and vaginal samples and practitioner-obtained cervical samples were tested for HR-HPV by ART and RC assays, including comparison of neat and preservative-fixed urine. Colposcopic opinion was recorded and directed cervical biopsies taken if clinically indicated. The acceptability of self-testing was evaluated by questionnaire. PRIMARY OUTCOME MEASURE: The sensitivity of urine to detect underlying CIN2+. SECONDARY OUTCOME MEASURES: The comparative sensitivity of vaginal and cervical samples to detect CIN2+; the acceptability of urine sampling. RESULTS: Preservative-fixed, but not neat urine, showed good concordance with vaginal samples for the detection of HR-HPV. The sensitivity for detecting CIN2+ was 15/18 (83%) for urine and 16/18 (89%) for cervical and vaginal samples by ART, and 15/17 (88%) for all samples by RC. Urine-based testing was broadly acceptable to women. CONCLUSIONS: Urinary HR-HPV detection offers an alternative strategy of cervical screening. Larger studies to determine its clinical utility are warranted.

Non-animal approaches for consumer safety risk assessments: Unilever's scientific research programme.

Non-animal based approaches to risk assessment are now routinely used for assuring consumer safety for some endpoints (such as skin irritation) following considerable investment in developing and applying new methods over the past 20 years. Unilever's research programme into non-animal approaches for safety assessment is currently focused on the application of new technologies to risk assessments in the areas of skin allergy, cancer and general toxicity (including inhalation toxicity). In all of these areas, a long-term investment is essential to increase the scientific understanding of the underlying biological and chemical processes that we believe will ultimately form a sound basis for novel risk assessment approaches. Our research programme in these priority areas consists of in-house research as well as Unilever-sponsored academic research, involvement with EU-funded projects (e.g. Sens-it-iv, carcinoGENOMICS), participation in cross-industry collaborative research (e.g. COLIPA, EPAA) and ongoing involvement with other scientific initiatives on non-animal approaches to risk assessment (e.g. UK NC3Rs, US 'Human Toxicology Project' consortium).

Transcriptomic and histopathology changes in rat lung after intratracheal instillation of polymers.

The lung toxicity of inhalable polymer materials is normally carried out by evaluation of the histopathology responses of rat lungs to repeat, nose-only, exposures of an inhalable aerosol of material in a 13-wk subchronic repeat dose toxicity study. The introduction of transcriptomics into toxicology has allowed the comparison of histopathological responses in target organs, after exposure, with the "signature" of gene expression ( Waters et al., 2003 ), characteristic of the pathology processes known to be involved in the response to inhaled particulates. The transcriptomic and histopathological changes have been examined in a dose response study of the rat lung to intratracheally administered acrylate polymer solutions at time points equivalent to those used in a 13-wk inhalation study with an additional 13-wk recovery period. The doses administered in the intratracheal study were equivalent to the total doses achieved in a comparable 13-wk inhalation study. The changes in gene expression were found to be dose dependent, as was the histopathology. The changes in regulation of the genes expressed were also consistent with the histopathological responses, such as acute and chronic inflammation, commonly observed with inhalation exposure of the rat lungs to polymers. Functional classification of the genes affected highlight changes in inflammatory and immune response combined with macrophage recruitment, as well as cell adhesion and matrix formation. This would suggest a degree of tissue remodeling and is consistent with the histopathology observed. With further confirmation of the consistency of this response, the use of a transcriptomic approach in toxicology may be valuable in defining "signature" markers for the acute and chronic inflammation induced by polymers, or other inhalables, deposited in the lung. Osteopontin, in particular, a gene implicated in granuloma formation during chronic tissue damage, was significantly upregulated at high levels of exposure to polymer.