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- Leja, Justyna, et al.
(author)
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A novel chromogranin-A promoter-driven oncolytic adenovirus for midgut carcinoid therapy
- 2007
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 13:8, s. 2455-2462
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Journal article (peer-reviewed)abstract
- Purpose: The use of replication-selective oncolytic adenoviruses is an emerging therapeutic approach for cancer, which thus far has not been employed for carcinoids. We therefore constructed Ad[CgA-E1A], a novel replication-selective oncolytic adenovirus, where the chromogranin A (CgA) promoter controls expression of the adenoviral E1A gene. Experimental Design: The Ad[CgA-E1A] virus was evaluated for E1A protein expression, replication ability, and cytolytic activity in various cell lines. It was also evaluated for treatment of xenografted human carcinoid tumors in nude mice. To use Ad[CgA-E1A] for the treatment of carcinoid liver metastases, it is important that normal hepatocytes do not support virus replication to minimize hepatotoxicity. We therefore evaluated CgA protein expression in normal hepatocytes. We also evaluated CgA gene expression in normal hepatocytes and microdissected tumor cells from carcinoid metastases. Results: We found that Ad[CgA-E1A] replicates similarly to wild-type virus in tumor cells with neuroendocrine features, including the BON carcinoid cell line and the SH-SY-5Y neuroblastoma cell lines, whereas it is attenuated in other cell types. Thus, cells where the CgA promoter is active are selectively killed. We also found that Ad[CgA-E1A] is able to suppress fast-growing human BON carcinoid tumors in nude mice. Furthermore, CgA is highly expressed in microdissected cells from carcinoid metastases, whereas it is not expressed in normal hepatocytes. Conclusion: Ad[CgA-E1A] is an interesting agent for the treatment of carcinoid liver metastases in conjunction with standard therapy for these malignancies.
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- Leja, Justyna, et al.
(author)
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Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains neuroendocrine cell killing ability
- 2010
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 5:1, s. e8916-
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Journal article (peer-reviewed)abstract
- BACKGROUND:We have previously developed an oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression, Ad[CgA-E1A], with the intention to treat neuroendocrine tumors, including carcinoids. Since carcinoids tend to metastasize to the liver it is important to fully repress viral replication in hepatocytes to avoid adenovirus-related liver toxicity. Herein, we explore miRNA-based regulation of E1A expression as a complementary mechanism to promoter-based transcriptional control.METHODOLOGY/PRINCIPAL FINDINGS: Ad[CgA-E1A-miR122], where E1A expression is further controlled by six tandem repeats of the target sequence for the liver-specific miR122, was constructed and compared to Ad[CgA-E1A]. We observed E1A suppression and replication arrest of the miR122-detargeted adenovirus in normal hepatocytes, while the two viruses killed carcinoid cells to the same degree. Repeated intravenous injections of Ad[CgA-E1A] induced liver toxicity in mice while Ad[CgA-E1A-miR122] injections did not. Furthermore, a miR122-detargeted adenovirus with the wild-type E1A promoter showed reduced replication in hepatic cells compared to wild-type Ad5 but not to the same extent as the miR122-detargeted adenovirus with the neuroendocrine-selective CgA promoter.CONCLUSIONS/SIGNIFICANCE:A combination of transcriptional (promoter) and post-transcriptional (miRNA target) regulation to control virus replication may allow for the use of higher doses of adenovirus for efficient tumors treatment without liver toxicity.
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- Mak, Jonathan K. L., et al.
(author)
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Development of an Electronic Frailty Index for Hospitalized Older Adults in Sweden
- 2022
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In: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press. - 1079-5006 .- 1758-535X. ; 77:11, s. 2311-2319
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Journal article (peer-reviewed)abstract
- Background Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its association with adverse outcomes in hospitalized older adults. Methods EHRs were extracted for 18 225 patients with unplanned admissions between 1 March 2020 and 17 June 2021 from 9 geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modeled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression. Results Thirteen thousand one hundred and eighty-eight patients were included in analyses (mean age 83.1 years). A 0.03 increment in the eFI was associated with higher risks of in-hospital (odds ratio: 1.65; 95% confidence interval: 1.54-1.78), 30-day (hazard ratio [HR]: 1.43; 1.38-1.48), and 6-month mortality (HR: 1.34; 1.31-1.37) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the highest area under receiver operating characteristic curve for in-hospital mortality of 0.813. Higher eFI was associated with longer length of stay, but had a rather poor discrimination for 30-day readmission. Conclusions An EHR-based eFI has robust associations with adverse outcomes, suggesting that it can be used in risk stratification in hospitalized older adults.
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| 9. |
- Mak, Jonathan K. L., et al.
(author)
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Two Years with COVID-19 : The Electronic Frailty Index Identifies High-Risk Patients in the Stockholm GeroCovid Study
- 2023
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In: Gerontology. - : S. Karger. - 0304-324X .- 1423-0003. ; 69:4, s. 396-405
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Journal article (peer-reviewed)abstract
- Introduction: Frailty, a measure of biological aging, has been linked to worse COVID-19 outcomes. However, as the mortality differs across the COVID-19 waves, it is less clear whether a medical record-based electronic frailty index (eFI) that we have previously developed for older adults could be used for risk stratification in hospitalized COVID-19 patients. Objectives: The aim of the study was to examine the association of frailty with mortality, readmission, and length of stay in older COVID-19 patients and to compare the predictive accuracy of the eFI to other frailty and comorbidity measures. Methods: This was a retrospective cohort study using electronic health records (EHRs) from nine geriatric clinics in Stockholm, Sweden, comprising 3,980 COVID-19 patients (mean age 81.6 years) admitted between March 2020 and March 2022. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the Clinical Frailty Scale, and the Hospital Frailty Risk Score. Comorbidity was measured using the Charlson Comorbidity Index. We analyzed in-hospital mortality and 30-day readmission using logistic regression, 30-day and 6-month mortality using Cox regression, and the length of stay using linear regression. Predictive accuracy of the logistic regression and Cox models was evaluated by area under the receiver operating characteristic curve (AUC) and Harrell's C-statistic, respectively. Results: Across the study period, the in-hospital mortality rate decreased from 13.9% in the first wave to 3.6% in the latest (Omicron) wave. Controlling for age and sex, a 10% increment in the eFI was significantly associated with higher risks of in-hospital mortality (odds ratio = 2.95; 95% confidence interval = 2.42-3.62), 30-day mortality (hazard ratio [HR] = 2.39; 2.08-2.74), 6-month mortality (HR = 2.29; 2.04-2.56), and a longer length of stay (beta-coefficient = 2.00; 1.65-2.34) but not with 30-day readmission. The association between the eFI and in-hospital mortality remained robust across the waves, even after the vaccination rollout. Among all measures, the eFI had the best discrimination for in-hospital (AUC = 0.780), 30-day (Harrell's C = 0.733), and 6-month mortality (Harrell's C = 0.719). Conclusion: An eFI based on routinely collected EHRs can be applied in identifying high-risk older COVID-19 patients during the continuing pandemic.
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- Malmberg, Milijana, 1977, et al.
(author)
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Experiences of an Internet-based aural rehabilitation (IAR) program for hearing aid users : a qualitative study
- 2018
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In: International Journal of Audiology. - : Taylor & Francis. - 1499-2027 .- 1708-8186. ; 57:8, s. 570-576
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Journal article (peer-reviewed)abstract
- Objective: Internet interventions for hearing aid (HA) users have been shown to be effective in helping persons with hearing problems. As earlier research refers to objective data on these effects, little is known about how participants experience the Internet interventions subjectively. The aim of the present study was to explore participants' experiences of an Internet-based aural rehabilitation (IAR) program for HA-users, and to explore the possible subjective benefits of such a program. Design: A qualitative exploratory design was implemented involving semi-structured telephone interviews. The interviews were transcribed and analysed using content analysis. Study sample: Interviews were conducted with 20 participants (9 men and 11 women) who had completed an IAR program for HA-users. The participants were 57-81 years old and had used HAs for 2-25 years. Results: The results are organised in three main categories: general experiences associated with participating in the program, knowledge obtained from the program and perceived impact of taking part in the program. Conclusions: The overall results indicate positive experiences of the IAR program, and an overreaching theme of increased self-esteem was identified. The findings provide some valuable information for developers of future IAR programs.
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