| 1. |
|
|
| 2. |
|
|
| 3. |
- Svenningsson, A., et al.
(author)
-
Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3, randomised controlled trial
- 2022
-
In: Lancet Neurology. - : Elsevier BV. - 1474-4422. ; 21:8, s. 693-703
-
Journal article (peer-reviewed)abstract
- Background B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines. Methods RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744. Findings Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0.19 (95% CI 0.06-0.62; p=0.0060). Infusion reactions (105 events [40.9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47.4 per 100 patient-years]) and flush (65 events [47.4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns. Interpretation RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Herrera, M, et al.
(author)
-
Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer
- 2020
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 12:11
-
Journal article (peer-reviewed)abstract
- Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
- Sjoblom, A, et al.
(author)
-
The Role of Human Chorionic Gonadotropin Beta (hCGβ) in HPV-Positive and HPV-Negative Oropharyngeal Squamous Cell Carcinoma
- 2022
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 14:12
-
Journal article (peer-reviewed)abstract
- Background: This study was carried out to observe the upregulation of the free β-subunit of human chorionic gonadotropin (hCGβ) and its prognostic significance in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCC). Materials and methods: A total of 90 patients with OPSCC treated with curative intent at the Helsinki University Hospital (HUS), Helsinki, Finland, during 2012–2016 were included. Serum samples were collected prospectively, and their hCGβ concentrations (S-hCGβ) were determined by an immunofluorometric assay. The expression of hCGβ in tumor tissues was defined by immunohistochemistry (IHC). HPV determination was performed by combining p16-INK4 IHC and HPV DNA PCR genotyping. Overall survival (OS) and disease-specific survival (DSS) were used as survival endpoints. Results: S-hCGβ positivity correlated with poor OS in the whole patient cohort (p < 0.001) and in patients with HPV-negative OPSCC (p < 0.001). A significant correlation was seen between S-hCGβ and poor DSS in the whole cohort (p < 0.001) and in patients with HPV-negative OPSCC (p = 0.007). In a multivariable analysis, S-hCGβ was associated with poor DSS. Of the clinical characteristics, higher cancer stage and grade were associated with S-hCGβ positivity. No statistically significant correlation with tissue positivity of hCGβ was seen in these analyses. Conclusion: S-hCGβ may be a potential independent factor indicating poor prognosis, notably in HPV-negative OPSCC.
|
|
| 17. |
- Sjoblom, A, et al.
(author)
-
Tumor-Associated Trypsin Inhibitor (TATI) as a Biomarker of Poor Prognosis in Oropharyngeal Squamous Cell Carcinoma Irrespective of HPV Status
- 2021
-
In: Cancers. - : MDPI AG. - 2072-6694. ; 13:11
-
Journal article (peer-reviewed)abstract
- Background: We studied the role of tumor-associated trypsin inhibitor (TATI) in serum and in tumor tissues among human papillomavirus (HPV)-positive and HPV-negative OPSCC patients. Materials and methods: The study cohort included 90 OPSCC patients treated at the Helsinki University Hospital (HUS), Helsinki, Finland, in 2012–2016. TATI serum concentrations (S-TATIs) were determined by an immunofluorometric assay. Immunostaining was used to assess tissue expression. HPV status was determined with a combination of p16 immunohistochemistry and HPV DNA PCR genotyping. The survival endpoints were overall survival (OS) and disease-specific survival (DSS). Results: A significant correlation was found between S-TATI positivity and poor OS (p < 0.001) and DSS (p = 0.04) in all patients. In HPV-negative cases, S-TATI positivity was linked to poor OS (p = 0.01) and DSS (p = 0.05). In HPV-positive disease, S-TATI positivity correlated with poor DSS (p = 0.01). S-TATI positivity was strongly associated with HPV negativity. TATI serum was negatively linked to a lower cancer stage. TATI expression in peritumoral lymphocytes was associated with favorable OS (p < 0.025) and HPV positivity. TATI expression in tumor and in peritumoral lymphocytes correlated with lower cancer stages. Conclusion: Our results suggest that S-TATI positivity may be a biomarker of poor prognosis in both HPV-positive and HPV-negative OPSCC.
|
|
| 18. |
- Wu, D., et al.
(author)
-
A novel strained Si0.7Ge0.3 surface-channel pMOSFET with an ALD TiN/Al2O3/HfAlOx/Al2O3 gate stack
- 2003
-
In: IEEE Electron Device Letters. - : Institute of Electrical and Electronics Engineers (IEEE). - 0741-3106 .- 1558-0563. ; 24:3, s. 171-173
-
Journal article (peer-reviewed)abstract
- Proof-of-concept pMOSFETs with a strained-Si0.7Ge0.3 surface-channel deposited by selective epitaxy and a TiN/Al2O3/HfAIO(x)/Al2O3 gate stack grown by atomic layer chemical vapor deposition (ALD) techniques were fabricated. The Si0.7Ge0.3 pMOSFETs exhibited more than 30% higher current drive and peak transconductance than reference Si pMOSFETs with the same gate stack. The effective mobility for the Si reference coincided with the universal hole mobility curve for Si. The presence of a relatively low density of interface states, determined as 3.3x10(11) cm(-2) eV(-1), yielded a subthreshold slope of 75 mV/dec. for the Si reference. For the Si0.7Ge0.3 pMOSFETs, these values were 1.6x10(12) cm(-2) eV(-1) and 110 mV/dec., respectively.
|
|
| 19. |
|
|
| 20. |
- Bergqvist, A, et al.
(author)
-
Production of interleukins 1beta, 6 and 8 and tumor necrosis factor alpha in separated and cultured endometrial and endometriotic stromal and epithelial cells
- 2000
-
In: Gynecologic and obstetric investigation. - : S. Karger AG. - 0378-7346 .- 1423-002X. ; 50:1, s. 1-6
-
Journal article (peer-reviewed)abstract
- The production of IL-1β, IL-6, IL-8 and TNF-α was studied in short-time culture of separated stromal and epithelial cells. The cytokine secretion into culture medium was analyzed using immunoassay to evaluate the cytokine protein levels and bioassay to assess the bioactivity of the cytokines. Tissue samples of endometrium and ovarian endometriomas were obtained from 4 patients operated on for clinical reasons. Only IL-8 was found in all samples. IL-1β and TNF-α were detected in the culture medium from most stromal cell samples, but in fewer media from epithelial cell samples. IL-6 was measurable in a few medium samples. Few of the samples displayed a bioactivity. There was no obvious difference between endometrium and endometriotic cell samples besides the production of IL-8 that seems to be lower in endometriotic tissue.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
- Mairinoja, L., et al.
(author)
-
Deep Learning-Based Image Analysis of Liver Steatosis in Mouse Models
- 2023
-
In: American Journal of Pathology. - 0002-9440. ; 193:8, s. 1072-1080
-
Journal article (peer-reviewed)abstract
- The incidence of nonalcoholic fatty liver disease is a continuously growing health problem worldwide, along with obesity. Therefore, novel methods to both efficiently study the manifestation of nonalco-holic fatty liver disease and to analyze drug efficacy in preclinical models are needed. The present study developed a deep neural network-based model to quantify microvesicular and macrovesicular steatosis in the liver on hematoxylin-eosin-stained whole slide images, using the cloud-based platform, Aiforia Create. The training data included a total of 101 whole slide images from dietary interventions of wild-type mice and from two genetically modified mouse models with steatosis. The algorithm was trained for the following: to detect liver parenchyma, to exclude the blood vessels and any artefacts generated during tissue processing and image acquisition, to recognize and differentiate the areas of micro-vesicular and macrovesicular steatosis, and to quantify the recognized tissue area. The results of the image analysis replicated well the evaluation by expert pathologists and correlated well with the liver fat content measured by EchoMRI ex vivo, and the correlation with total liver triglycerides was notable. In conclusion, the developed deep learning-based model is a novel tool for studying liver steatosis in mouse models on paraffin sections and, thus, can facilitate reliable quantification of the amount of steatosis in large preclinical study cohorts. (Am J Pathol 2023, 193: 1072-1080; https://doi.org/ 10.1016/j.ajpath.2023.04.014)
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
- Sjoblom, A., et al.
(author)
-
The influence of humic substances on the speciation and bioavailability of dissolved mercury and methylmercury, measured as uptake by Chaoborus larvae and loss by volatilization
- 2000
-
In: Science of the Total Environment. - 0048-9697 .- 1879-1026. ; 261:1-3, s. 115-124
-
Journal article (peer-reviewed)abstract
- The influence of dissolved humic substances (HS) on the bioavailability of dissolved inorganic and methyl mercury (Hg) was quantified by measuring the direct uptake of 203Hg in Chaoborus larvae using laboratory microcosms containing artificial freshwater. The animals were exposed individually in triplicate aquaria at 10 different concentrations of HS covering the whole range found in natural freshwaters (0-110 mg C l-1). Mercury-203 concentrations were monitored repeatedly in the same individuals and in their ambient water during up to 10 days. Near-steady state Hg concentrations in Chaoborus were usually reached within 5 days. The bioconcentration factor (BCF, direct uptake only) for the larvae in the absence of HS was 0.55 ± 0.09 (S.E.) ml individual-1 for inorganic Hg and 5.3 ± 0.7 ml individual-1 for methyl Hg, thus showing a 10-fold difference. Normalizing to the organic carbon content of the larvae yields a BCF(OC) in the absence of HS of 2.8 ± 0.4 x 103 ml (gC)-1 for inorganic Hg and 2.7 ± 0.3 x 104 ml (gC)-1 for methyl Hg. The uptake of both inorganic and methyl Hg decreased markedly with increasing concentration of HS. For inorganic Hg, the decrease in uptake was most pronounced at HS concentrations below 0.2 mg C l-1. For methyl Hg, the relationship between uptake and log([HS]) was sigmoid, showing a reduction by >90% when increasing HS concentrations from 1 to 50 mg C l-1. Similar patterns were observed for losses of Hg from the water phase, mainly through volatilization. These results have implications for both the biouptake and the abiotic cycling of Hg in natural ecosystems and suggest that most dissolved inorganic Hg is bound to dissolved organic matter in most natural freshwaters, whereas dissolved methyl Hg is bound only in humic waters. Assuming that only free aqueous Hg is taken up by the organisms, the rather simple methodology employed here can be used for estimating distribution coefficients (K(OC)) for Hg between HS and water. In this study, the K(OC) values were 2.5 ± 0.7 (S.E.) x 107 ml (gC)-1 for inorganic Hg and 1.5 ± 0.6 x 105 ml (gC)-1 for methyl Hg. Values of similar magnitude were derived from observed losses of Hg from the water phase, supporting the assumption of an immobilization of both inorganic and methyl Hg by HS. The strong negative influence of dissolved HS on the bioavailability of both inorganic and methyl Hg in freshwater suggests that the high Hg levels often found in fish from humic lakes in the boreal forest zone cannot be explained alone by direct uptake of methyl Hg from the water phase into biota at low trophic levels. (C) 2000 Elsevier Science B.V.
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
