Development of a Potential Facility Risk Index for Radiological Security.

Given the threat of radiological and nuclear terrorism, it is imperative to understand and evaluate the security risk of radioactive sources. In this context, risk assessment is a function of threat, vulnerability, and consequences. Currently, no broad risk index exists for radiological facilities, such as healthcare centers and universities. This study aims to develop and demonstrate a methodology to compute a potential facility risk index (PFRI) based on a probable loss event (LE) and loss magnitude (LM) resulting from a radiological dispersal device (RDD) attack. The threat component of the PFRI is devised as a utility function weighing the threat group attributes and RDD radioactive material preference. The principles of probabilistic risk assessment and pathway analysis are implemented to account for RDD radioactive material theft probabilities in different attack scenarios. Locational hazards and nuclear security culture are measured as a function of radiological facility vulnerability for LE. The LM of the attack, in the form of loss of life and economic damage, is then estimated to construct the PFRI. The methodology is applied to a hypothetical healthcare facility with a single radioactive material asset. For this example, the PFRI resulted in a value of 2.0 (on a scale of 1-10), showing low risk to the facility. The development of the PFRI provides a risk analysis tool that may be useful in making decisions for radiological security improvements.

Impact of a Heat Shock Protein Impurity on the Immunogenicity of Biotherapeutic Monoclonal Antibodies.

PURPOSE: Anti-drug antibodies can impair the efficacy of therapeutic proteins and, in some circumstances, induce adverse health effects. Immunogenicity can be promoted by aggregation; here we examined the ability of recombinant mouse heat shock protein 70 (rmHSP70) - a common host cell impurity - to modulate the immune responses to aggregates of two therapeutic mAbs in mice. METHODS: Heat and shaking stress methods were used to generate aggregates in the sub-micron size range from two human mAbs, and immunogenicity assessed by intraperitoneal exposure in BALB/c mice. RESULTS: rmHSP70 was shown to bind preferentially to aggregates of both mAbs, but not to the native, monomeric proteins. Aggregates supplemented with 0.1% rmHSP70 induced significantly enhanced IgG2a antibody responses compared with aggregates alone but the effect was not observed for monomeric mAbs. Dendritic cells pulsed with mAb aggregate showed enhanced IFNγ production on co-culture with T cells in the presence of rmHSP70. CONCLUSION: The results indicate a Th1-skewing of the immune response by aggregates and show that murine rmHSP70 selectively modulates the immune response to mAb aggregates, but not monomer. These data suggest that heat shock protein impurities can selectively accumulate by binding to mAb aggregates and thus influence immunogenic responses to therapeutic proteins.

Novel prostate acid phosphatase-based peptide vaccination strategy induces antigen-specific T-cell responses and limits tumour growth in mice.

Treatment options for patients with advanced prostate cancer remain limited and rarely curative. Prostatic acid phosphatase (PAP) is a prostate-specific protein overexpressed in 95% of prostate tumours. An FDA-approved vaccine for the treatment of advanced prostate disease, PROVENGE® (sipuleucel-T), has been shown to prolong survival, however the precise sequence of the PAP protein responsible for the outcome is unknown. As the PAP antigen is one of the very few prostate-specific antigens for which there is a rodent equivalent with high homology, preclinical studies using PAP have the potential to be directly relevant to clinical setting. Here, we show three PAP epitopes naturally processed and presented in the context of HHDII/DR1 (114-128, 299-313, and 230-244). The PAP-114-128 epitope elicits CD4(+) and CD8(+) T-cell-specific responses in C57BL/6 mice. Furthermore, when immunised in a DNA vector format (ImmunoBody®), PAP-114-128 prevents and reduces the growth of transgenic adenocarcinoma of mouse prostate-C1 prostate cancer cell-derived tumours in both prophylactic and therapeutic settings. This anti-tumour effect is associated with infiltration of CD8(+) tumour-infiltrating lymphocytes and the generation of high avidity T cells secreting elevated levels of IFN-γ. PAP-114-128 therefore appears to be a highly relevant peptide on which to base vaccines for the treatment of prostate cancer.

Functional Genomics and Insights into the Pathogenesis and Treatment of Psoriasis.

Psoriasis is a lifelong, systemic, immune mediated inflammatory skin condition, affecting 1-3% of the world's population, with an impact on quality of life similar to diseases like cancer or diabetes. Genetics are the single largest risk factor in psoriasis, with Genome-Wide Association (GWAS) studies showing that many psoriasis risk genes lie along the IL-23/Th17 axis. Potential psoriasis risk genes determined through GWAS can be annotated and characterised using functional genomics, allowing the identification of novel drug targets and the repurposing of existing drugs. This review is focused on the IL-23/Th17 axis, providing an insight into key cell types, cytokines, and intracellular signaling pathways involved. This includes examination of currently available biological treatments, time to relapse post drug withdrawal, and rates of primary/secondary drug failure, showing the need for greater understanding of the underlying genetic mechanisms of psoriasis and how they can impact treatment. This could allow for patient stratification towards the treatment most likely to reduce the burden of disease for the longest period possible.

TYK2 as a novel therapeutic target in psoriasis.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease affecting approximately 60 million people worldwide. Genome-wide association studies (GWAS) have allowed identification of novel therapeutic targets in psoriasis including tyrosine kinase 2 (TYK2) where an exonic variant within the gene increases the risk of developing psoriasis. AREAS COVERED: This review discusses the role of TYK2 in psoriasis pathogenesis, how that relates to genetic variants and recently published ground-breaking clinical trials of novel TYK2 inhibitors. Keyword searches of PubMed were made until January 2023, using the terms: 'TYK2 inhibitor,' 'TYK2 inhibitor AND psoriasis' and 'TYK2 AND GWAS.' Articles and references have been thoroughly reviewed by the authors. EXPERT OPINION: The TYK2 inhibitor deucravacitinib shows promise as an effective oral agent for treating psoriasis. Longer term data are needed to know if thrombotic risk/cancer risk is distinct from other Janus kinase (JAK) inhibitors. Psoriasis is a complex genetic disease for which risk is influenced by genes and environmental factors. GWAS studies have identified several regions of DNA associated with increased risk of disease. We believe that pathway analysis by genetic and genomic means will be key to optimizing TYK2 therapy for the right person at the right time.

Quantification of a Facility Radiological Security Risk Index With a Graphical User Interface Tool.

ABSTRACT: Healthcare facilities around the world routinely use radioactive sources to diagnose and treat illness. To effectively manage the security of radioactive sources, these facilities need to understand the risk, which is comprised of threat, vulnerability, and consequences. The threat component of risk requires knowledge of potential adversaries and understanding their capabilities and intentions. To help articulate the multiple layers of threat and support better informed decisions, the research developed a risk-based methodology to evaluate radiological security at the facility level. The methodology is applied to a radiological dispersal device (RDD) incident from three radionuclides of concern: 137Cs, 60Co, and 192Ir. The results of the research have led to the creation of a potential facility risk index (PFRI). The PFRI is mathematically represented as the exponential product of the maximum expected utility among the threat groups, the sum of geographic vulnerability and cultural vulnerability, and net consequences. The PFRI is a novel risk index that quantifies the facility risk on a scale of 1 to 10, 1 being "very low risk" and 10 being "very high risk." A MATLAB-based graphical user interface (GUI) tool was also developed to enable the radiological facility (i.e., healthcare facility) staff to conduct self-assessments and manage their most valuable assets. The PFRI methodology is a useful starting point for any healthcare facility risk assessment and is a valuable input for decision makers considering potential investments in security upgrades.

Adaptation of an ELISA assay for detection of IgG2a responses against therapeutic monoclonal antibodies in a mouse immunization model.

Biotherapeutic monoclonal antibodies (mAb) play important roles in clinical medicine but their potential to elicit immune responses in patients remains a major issue. In a study designed to investigate the effect of aggregation on immunogenic responses, mice were immunized with two monoclonal antibodies (mAb1 and mAb2). Serum levels of total IgG, IgG1, and IgG2a were measured by ELISA. An anti-mouse IgG2a monoclonal detection antibody cross-reacted with mAb2 but not mAb1, leading to high background when the ELISA plate was coated with mAb2. The problem was solved by use of a goat anti-mouse IgG2a polyclonal antibody that demonstrated the required specificity. IgG2a responses were similar for monomer- or aggregate-coated ELISA plates. The results demonstrate the importance of assessment of the specificity of individual reagents when measuring antibody responses against therapeutic antibodies by ELISA.

Eosinophilic Airway Inflammation in Patients with Stable Biomass Smoke- versus Tobacco Smoke-Associated Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease with predominant involvement of neutrophils, macrophages and CD8+ lymphocytes. Eosinophilic airway inflammations are reported in stable state and during acute exacerbations of tobacco smoke-associated COPD (TS-COPD). Women exposed to biomass fuel smoke are known to have eosinophils in sputum. However, little is known about the sputum cellular inflammatory profile in biomass fuel smoke-associated COPD (BMS-COPD). We therefore aimed to compare the sputum cellular inflammatory profile in tobacco smoke- and biomass smoke-associated COPD. METHODS: The study was conducted in a tertiary care hospital in Goa, India. A total of 113 patients with stable COPD reporting to the outpatient pulmonary clinic were recruited. All participants were ≥ 40 years of age. Sputum induction studies were performed by the method of Pizzichini et al. after baseline subject characterization. Significant eosinophilia was defined as induced sputum eosinophils ≥ 3%. RESULTS: There were 85 TS-COPD and 28 BMS-COPD patients. The mean age [standard deviation (SD)] was 64.7 (7.8) and 63.0 years (8.3), p = 0.32 in TS and BMS-COPD, respectively. Eighteen subjects (21.1%) were female smokers. The smoking pack-year median [interquartile range (IQR)] was 36 (20, 58) and hour-years of biomass smoke exposure mean (SD) was 192.4 (61). The TS-COPD and BMS-COPD cases showed a post-bronchodilator forced expiratory volume in one second (FEV1%) mean (SD) of 57.9 (17.1), and 62.6 (19.4), p= 0.22, respectively. Both groups had similar symptoms and severity of disease. Induced sputum total cell count per gram of sputum × 106 mean (SD) was 3.05 (1.53) for TS-COPD, and 2.55(1.37) for BMS-COPD p=0.12. The neutrophils % mean (SD) was 86.4 (16.5) and 87.9 (10.2), p = 0.64; eosinophils % median (IQR) was 2.5 (1, 10) and 8 (2, 12.8), p = 0.07; lymphocytes % median (IQR) was 0 (0, 0.75) and 0 (0, 1) p = 0.13; macrophages % median (IQR) was 2.5 (0.75, 5.7) and 1 (0, 4.7) p = 0.13; and significant eosinophilia (eosinophils ≥3%) was 42 (49.4%) and 20 (71%), p=0.04, for TS-COPD and BMS-COPD, respectively. CONCLUSIONS: For similar severity of disease and clinical symptoms, significant eosinophilic inflammation was observed in stable BMS-COPD, while both groups had similar neutrophilic inflammation. PARTICIPANT CONSENT: Obtained. ETHICS APPROVAL: The study was approved by the Institutional Ethics Committee of the Goa Medical College, Goa, India. COMPETING INTERESTS: The authors declare no competing financial interests.

Nuclear and Radiological Source Security Culture Assessment of Radioactive Material Users at a University.

Securing radioactive sources has become increasingly important given the rising threat of radiological terrorism. While radiation safety has long been established in most applicable industries, the importance of nuclear and radiological source security has lagged behind in nonnuclear material specific industries, such as academic institutions and medical facilities. To evaluate the attitudes and behaviors regarding nuclear security culture, an assessment of nuclear and radiological material practices was developed and conducted on 73 radioactive material users at a university. The survey portion of the assessment was comprised of a series of questions segregated into four categories: policy, enforcement, leadership, and behavior. Nuclear security awareness questions formed a subset of the questionnaire. Users were classified by their radioactive material experience and work classification: student, faculty, or other staff. Of the users surveyed, 9% were also interviewed face-to-face to further expand on their views of nuclear security culture. Results of the assessment showed that students from the work classification group as well as the cohort of radioactive material users with 2-5 y of experience possessed a greater degree of awareness towards nuclear security compared to faculty and other more experienced radioactive material users. Relative to students and faculty, other staff from the work classification group faced some difficulty judging the enforcement of policies, adequacy of inspection, and job performance review related to nuclear security. The response from all three groups emphasized the need to enhance threat-response preparedness and greater communication among stakeholders.

(47)Ca production for (47)Ca/(47)Sc generator system using electron linacs.

In this work we have studied the feasibility of photonuclear production of (47)Ca from (48)Ca for (47)Ca/(47)Sc generators. Photon flux distribution for electron beams of different energies incident on a tungsten converter was calculated using the MCNPX radiation transport code. The (47)Ca production rate dependence on electron beam energy was found and (47)Ca/(47)Sc yields were estimated for a 40MeV electron beam. It was shown that irradiating enriched targets with a 40MeV, 1mA beam will result in tens of MBq g(-1) (few mCi g(-1)) activity of (47)Sc. The results of the simulations were benchmarked by irradiating 22.5g of CaCl2 powder with a 39MeV electron beam incident on a tungsten converter. Measured (47)Ca/(47)Sc activities were found to be in very good agreement with the predictions.