Novel Chemokine-Based Immunotoxins for Potent and Selective Targeting of Cytomegalovirus Infected Cells

Immunotoxins as antiviral therapeutics are largely unexplored but have promising prospective due to their high selectivity potential and their unparalleled efficiency. One recent example targeted the virus-encoded G protein-coupled receptor US28 as a strategy for specific and efficient treatment of human cytomegalovirus (HCMV) infections. US28 is expressed on virus-infected cells and scavenge chemokines by rapid internalization. The chemokine-based fusion-toxin protein (FTP) consisted of a variant (F49A) of CX3CL1 specifically targeting US28 linked to the catalytic domain of Pseudomonas exotoxin A (PE). Here, we systematically seek to improve F49A-FTP by modifications in its three structural domains; we generated variants with (1) altered chemokine sequence (K14A, F49L, and F49E), (2) shortened and elongated linker region, and (3) modified toxin domain. Only F49L-FTP displayed higher selectivity in its binding to US28 versus CX3CR1, the endogenous receptor for CX3CL1, but this was not matched by a more selective killing of US28-expressing cells. A longer linker and different toxin variants decreased US28 affinity and selective killing. Thereby, F49A-FTP represents the best candidate for HCMV treatment. Many viruses encode internalizing receptors suggesting that not only HCMV but also, for instance, Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus may be targeted by FTPs

A Psychometric Evaluation of the Danish Version of the Theory of Mind Storybook for 8-14 Year-Old Children

Background: Theory-of-Mind (ToM) keeps on developing in late childhood and early adolescence, and the study of ToM development later in childhood had to await the development of sufficiently sensitive tests challenging more mature children. The current study aimed to investigate the psychometric properties of the Danish version of the Theory-of-Mind Storybook Frederik (ToM-Frederik). Methods: We assessed whether ToM-Frederik scores differed between a group of 41 typically developing (TD) children and a group of 33 children with High Functioning Autism Spectrum Disorder (HFASD). A lower mean ToM Frederik score was expected in the HFASD group. To determine the convergent validity of ToM-Frederik, potential associations with Strange Stories and Animated Triangles (AT) were analyzed. Furthermore, potential associations between ToM-Frederik and the Social Responsiveness Scale (SRS) and between ToM Frederik and the Social Emotional Evaluation (SEE) Total score were analyzed. Results: A significantly higher ToM-Frederik score was observed in the TD group compared to the HFASD group. Furthermore, the convergent validity of ToM-Frederik as a measure of ToM was supported by significant and positive associations with the Strange Stories and the AT scores in the HFASD group, whereas ToM-Frederik was significantly correlated with Strange Stories, but not with AT in the TD group. ToM-Frederik was not significantly associated with SRS in neither the HFASD nor the TD group. Conclusion: The findings are supportive of ToM-Frederik as a valid indicator of deficits at the group level in children with HFASD between 7 and 14 years of age. Furthermore, the convergent validity is supported

The effect of five years versus two years of specialised assertive intervention for first episode psychosis - OPUS II: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The Danish OPUS I trial randomized 547 patients with first-episode psychosis to a two-year early-specialised assertive treatment programme (OPUS) versus standard treatment. The two years OPUS treatment had significant positive effects on psychotic and negative symptoms, secondary substance abuse, treatment adherence, lower dosage of antipsychotic medication, and a higher treatment satisfaction. However, three years after end of the OPUS treatment, the positive clinical effects were not sustained, except that OPUS-treated patients were significantly less likely to be institutionalised compared with standard-treated patients. The major objective of the OPUS II trial is to evaluate the effects of five years of OPUS treatment versus two years of OPUS treatment.</p> <p>Methods</p> <p>The OPUS II trial is designed as a randomized, open label, parallel group trial with blinded outcome assessment. Based on our sample size estimation, 400 patients treated in OPUS for two years will be randomized to further three years of OPUS treatment versus standard treatment. The specialized assertive OPUS treatment consists of three core elements: assertive community treatment, psycho-educational family treatment, and social skills training.</p> <p>Discussion</p> <p>It has been hypothesized that there is a critical period from onset up to five years, which represents a window of opportunity where a long-term course can be influenced. Extending the specialized assertive OPUS treatment up to five years may allow the beneficial effects to continue beyond the high-risk period, through consolidation of improved social and functional outcome.</p> <p>Trial registration</p> <p>Clinical Trial.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00914238">NCT00914238</a></p

What is the prevalence of fear of cancer recurrence in cancer survivors and patients? A systematic review and individual participant data meta-analysis

This study was supported by the Dutch Cancer Society (KWF) grant number 10936.Objective Care for fear of cancer recurrence (FCR) is considered the most common unmet need among cancer survivors. Yet the prevalence of FCR and predisposing factors remain inconclusive. To support targeted care, we provide a comprehensive overview of the prevalence and severity of FCR among cancer survivors and patients, as measured using the short form of the validated Fear of Cancer Recurrence Inventory (FCRI-SF). We also report on associations between FCR and clinical and demographic characteristics. Methods This is a systematic review and individual participant data (IPD) meta-analysis on the prevalence of FCR. In the review, we included all studies that used the FCRI-SF with adult (≥18 years) cancer survivors and patients. Date of search: 7 February 2020. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tool. Results IPD were requested from 87 unique studies and provided for 46 studies comprising 11,226 participants from 13 countries. 9311 respondents were included for the main analyses. On the FCRI-SF (range 0–36), 58.8% of respondents scored ≥13, 45.1% scored ≥16 and 19.2% scored ≥22. FCR decreased with age and women reported more FCR than men. FCR was found across cancer types and continents and for all time periods since cancer diagnosis. Conclusions FCR affects a considerable number of cancer survivors and patients. It is therefore important that healthcare providers discuss this issue with their patients and provide treatment when needed. Further research is needed to investigate how best to prevent and treat FCR and to identify other factors associated with FCR. The protocol was prospectively registered (PROSPERO CRD42020142185).Publisher PDFPeer reviewe

Rationally designed chemokine-based toxin targeting the viral G protein-coupled receptor US28 potently inhibits cytomegalovirus infection in vivo

The use of receptor–ligand interactions to direct toxins to kill diseased cells selectively has shown considerable promise for treatment of a number of cancers and, more recently, autoimmune disease. Here we move the fusion toxin protein (FTP) technology beyond cancer/autoimmune therapeutics to target the human viral pathogen, human cytomegalovirus (HCMV), on the basis of its expression of the 7TM G protein-coupled chemokine receptor US28. The virus origin of US28 provides an exceptional chemokine-binding profile with high selectivity and improved binding for the CX3C chemokine, CX(3)CL1. Moreover, US28 is constitutively internalizing by nature, providing highly effective FTP delivery. We designed a synthetic CX(3)CL1 variant engineered to have ultra-high affinity for US28 and greater specificity for US28 than the natural sole receptor for CX(3)CL1, CX(3)CR1, and we fused the synthetic variant with the cytotoxic domain of Pseudomonas Exotoxin A. This novel strategy of a rationally designed FTP provided unparalleled anti-HCMV efficacy and potency in vitro and in vivo

The influence of total hysterectomy in a cervical cancer screening population: a register-based cross-sectional study

Abstract Background High coverage of a screening program is essential to program success. Many European screening programs cover only 10–80% of their target population. A possible explanation for the low coverage may be that some women in the screening population have had a total hysterectomy, thus they are not at risk of cervical cancer. The aim of this study was to identify the prevalence of hysterectomy in the target population of the Danish National Cervical Cancer Screening Program (NCCSP) and to recalculate coverage after excluding women with total hysterectomy. Furthermore, to analyze the association between hysterectomy and sociodemographic factors within the screening population. Methods A population-based cross-sectional study using register data on all women in the target population of the NCCSP on January 12, 2012 (women born January 12, 1947, to January 12, 1986). The total coverage included women with hysterectomy in the target population whereas the recalculated coverage was calculated excluding women with total hysterectomy. To test the differences between the total coverage and the recalculated coverage, a two-sample z-test between the proportion of covered hysterectomized women and the proportion of covered non-hysterectomised women were used. A logistic regression model adjusted for age and sociodemographic characteristics was used to analyze the association between sociodemographic factors and total hysterectomy. Results The coverage among women aged 26–49 years and 55–64 years were 77.4% and 72.7%, respectively. The recalculated coverage was 78.2% (26–49 years) and 79.4% (55–64 years). Recalculating the coverage did not result in coverage higher than 82.7% at any age. The effect of excluding women with total hysterectomy increased with age, reaching its maximum of 8 % points for the oldest women. Women with higher socioeconomic status (higher education and higher disposable income) had lower odds of being hysterectomized compared to other women. Also, immigrants and descendants had lower odds of being hysterectomized compared to ethnic Danes. Conclusions Excluding women with total hysterectomy only partly explained the low coverage of the NCCSP. Thus, initiatives must be made to improve acceptability of and accessibility to the NCCSP, especially in the youngest and the oldest women

Data from: Hyper-Theory-of-Mind in children with psychotic experiences

Background: Alterations in Theory-of-Mind (ToM) are associated with psychotic disorder. In addition, studies in children have documented that alterations in ToM are associated with Psychotic Experiences (PE). Our aim was to examine associations between an exaggerated type of ToM (HyperToM) and PE in children. Children with this type of alteration in ToM infer mental states when none are obviously suggested, and predict behaviour on the basis of these erroneous beliefs. Individuals with HyperToM do not appear to have a conceptual deficit (i.e. lack of representational abilities), but rather they apply their theory of the minds of others in an incorrect or biased way. Method: Hypotheses were tested in two studies with two independent samples: (i) a general population sample of 1630 Danish children aged 11–12 years, (ii) a population-based sample of 259 Dutch children aged 12–13 years, pertaining to a case-control sampling frame of children with auditory verbal hallucinations. Multinomial regression analyses were carried out to investigate the associations between PE and ToM and HyperToM respectively. Analyses were adjusted for gender and proxy measures of general intelligence. Results: Low ToM score was significantly associated with PE in sample I (OR = 1.6 95%CI 1.1–2.3 χ2(4) = 12.42 p = 0.010), but not in sample II (OR = 0.9 95%CI 0.5–1.8 χ2(3) = 7.13 p = 0.816). HyperToM was significantly associated with PE both in sample I (OR = 1.8, 95%CI 1.2–2.7 χ2(3) = 10.11 p = 0.006) and II (OR = 4.6, 95%CI 1.3–16.2 χ2(2) = 7.56 p = 0.018). HyperToM was associated particularly with paranoid delusions in both sample I (OR = 2.0, 95%CI: 1.1–3.7% χ2(4) = 9.93 p = 0.021) and II (OR = 6.2 95%CI: 1.7–23.6% χ2(4) = 9.90 p = 0.044). Conclusion: Specific alterations in ToM may be associated with specific types of psychotic experiences. HyperToM may index risk for developing psychosis and paranoid delusions in particular