| 1. |
- Berglund, Erik, et al.
(författare)
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Clinical Significance of Alloantibodies in Hand Transplantation : A Multicenter Study
- 2019
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 103:10, s. 2173-2182
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Tidskriftsartikel (refereegranskat)abstract
- Background. Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. Methods. We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. Results. Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. Conclusions. While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.
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| 2. |
- Berglund, Erik, et al.
(författare)
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Evidence for Ca2+-regulated ATP release in gastrointestinal stromal tumors
- 2013
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 319:8, s. 1229-1238
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca2+ concentration ([Ca(2+)1](i)), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca2+-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca2+ influx since exclusion of extracellular Ca2+ diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape.
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| 3. |
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| 4. |
- Berglund, Erik, et al.
(författare)
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Functional role of the Ca2+-activated Cl- channel DOG1/TMEM16A in gastrointestinal stromal tumor cells
- 2014
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 326:2, s. 315-325
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Tidskriftsartikel (refereegranskat)abstract
- DOG1, a Ca2+-activated Cl- channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl- currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.
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| 5. |
- Berglund, Erik, et al.
(författare)
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Intracellular concentration of the tyrosine kinase inhibitor imatinib in gastrointestinal stromal tumor cells.
- 2014
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Ingår i: Anti-Cancer Drugs. - 0959-4973 .- 1473-5741. ; 25:4, s. 415-22
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Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm in the gastrointestinal tract. In most GISTs, the underlying mechanism is a gain-of-function mutation in the KIT or the PDGFRA gene. Imatinib is a tyrosine kinase inhibitor that specifically blocks the intracellular ATP-binding sites of these receptors. A correlation exists between plasma levels of imatinib and progression-free survival, but it is not known whether the plasma concentration correlates with the intracellular drug concentration. We determined intracellular imatinib levels in two GIST cell lines: the imatinib-sensitive GIST882 and the imatinib-resistant GIST48. After exposing the GIST cells to imatinib, the intracellular concentrations were evaluated using LC-MS (TOF). The concentration of imatinib in clinical samples from three patients was also determined to assess the validity and reliability of the method in the clinical setting. Determination of imatinib uptake fits within detection levels and values are highly reproducible. The GIST48 cells showed significantly lower imatinib uptake compared with GIST882 in therapeutic doses, indicating a possible difference in uptake mechanisms. Furthermore, imatinib accumulated in the tumor tissues and showed intratumoral regional differences. These data show, for the first time, a feasible and reproducible technique to measure intracellular imatinib levels in experimental and clinical settings. The difference in the intracellular imatinib concentration between the cell lines and clinical samples indicates that drug transporters may contribute toward resistance mechanisms in GIST cells. This highlights the importance of further clinical studies to quantify drug transporter expression and measure intracellular imatinib levels in GIST patients.
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| 6. |
- Bratt, Ola, et al.
(författare)
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Prostate cancer diagnosed after prostate-specific antigen testing of men without clinical signs of the disease : a population-based study from the National Prostate Cancer Register of Sweden
- 2010
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa Healthcare. - 0036-5599 .- 1651-2065. ; 44:6, s. 384-390
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To investigate the effects of prostate-specific antigen (PSA) testing of men without clinical signs of prostate cancer on the incidence of prostate cancer in Sweden. Material and methods. Information on the cause of diagnosis, tumour characteristics and primary treatment for patients diagnosed with prostate cancer between January 1999 and December 2007 was extracted from the National Prostate Cancer Register of Sweden. This register includes data for 95% of Swedish prostate cancer cases. Results. The total age-standardized annual incidence of prostate cancer per 100 000 men increased from 187 in 1999 to 233 in 2004, but decreased thereafter to 196 in 2007. The incidence of asymptomatic cases also peaked in 2004 (at 62 per 100 000 men), but varied six-fold between different counties in that year (16–98 per 100 000 men). Asymptomatic cases (n = 17 143) constituted 15% of all new cases in 2000 and 30% in 2007. Almost as many cases were diagnosed in stage T1c in men with symptoms, usually from the lower urinary tract. Together these two groups constituted 29% of all new cases in 2000 and 52% in 2007. It was estimated that at least one-third of all Swedish men aged 50–75 years had a PSA test between 2000 and 2007. Conclusions. Even though screening for prostate cancer is not recommended in Sweden, PSA testing of men without clinical signs of prostate cancer is common. The effects on the Swedish incidence of prostate cancer were similar to those reported from the USA.
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| 7. |
- Fröbom, Robin, et al.
(författare)
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Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors
- 2020
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 69:11, s. 2393-2401
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma.MethodsThe trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered.ResultsNo severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months.ConclusionIlixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation.
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| 8. |
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| 9. |
- Montagnese, Sara, et al.
(författare)
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A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:1, s. 98-107
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis.Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks’ dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days.Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well.Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone.Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug.Clinical trial registration number: EudraCT 2016-003651-30.
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| 10. |
- Uhlén, Mathias, et al.
(författare)
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A human protein atlas for normal and cancer tissues based on antibody proteomics
- 2005
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 4:12, s. 1920-1932
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Tidskriftsartikel (refereegranskat)abstract
- Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, similar to 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.
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| 11. |
- Ali, Imran, et al.
(författare)
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Exposure to polychlorinated biphenyls and prostate cancer : population-based prospective cohort and experimental studies
- 2016
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Ingår i: Carcinogenesis. - : Oxford University Press. - 0143-3334 .- 1460-2180. ; 37:12, s. 1144-1151
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Tidskriftsartikel (refereegranskat)abstract
- Polychlorinated biphenyls (PCBs) are highly persistent environmental pollutants and are undesirable components of our daily food. PCBs are classified as human carcinogens, but the evidence for prostate cancer is limited and available data are inconsistent. We explored the link between non-dioxin-like PCB and grade of prostate cancer in a prospective cohort as well as in cell experiments. A population-based cohort of 32496 Swedish men aged 45-79 years was followed prospectively through 1998-2011, to assess the association between validated estimates of dietary PCB exposure and incidence of prostate cancer by grade (2789 cases, whereof 1276 low grade, 756 intermediate grade, 450 high grade) and prostate cancer mortality (357 fatal cases). In addition, we investigated a non-dioxin-like PCB153-induced cell invasion and related markers in normal prostate stem cells (WPE-stem) and in three different prostate cancer cell lines (PC3, DU145 and 22RV1) at exposure levels relevant to humans. After multivariable-adjustment, dietary PCB exposure was positively associated with high-grade prostate cancer, relative risk (RR) 1.35 [95% confidence interval (CI): 1.03-1.76] and with fatal prostate cancer, RR 1.43 (95% CI: 1.05-1.95), comparing the highest tertile with the lowest. We observed no association with low or intermediate grade of prostate cancer. Cell invasion and related markers, including MMP9, MMP2, Slug and Snail, were significantly increased in human prostate cancer cells as well as in prostate stem cells after exposure to PCB153. Our findings both from the observational and experimental studies suggest a role of non-dioxin-like PCB153 in the development of high-grade and fatal prostate cancer.
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| 12. |
- Berggren, Ulf, 1948, et al.
(författare)
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Tobacco use is associated with more severe alcohol dependence, as assessed by the number of DSM-IV criteria, in Swedish male type 1 alcoholics.
- 2007
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Ingår i: Alcohol and alcoholism (Oxford, Oxfordshire). - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 42:3, s. 247-51
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A high smoking prevalence has been reported in treatment-seeking alcohol-dependent individuals. It has also been suggested that alcohol-dependent individuals who smoke may have a more severe course and greater severity of their alcoholism. METHODS: This study evaluated the impact of tobacco use in 108 Swedish male type 1 alcohol-dependent individuals, recruited by advertisement in a local daily newspaper. They were sub-grouped into smokers (N = 50), snuffers (N = 12) and tobacco nonusers (N = 46). The number of criteria for the diagnosis of alcohol dependence was used to assess the severity of alcohol dependence. RESULTS: The smokers were significantly younger compared to the tobacco non-using group, and also younger at their onset of excessive alcohol consumption. Both smokers and snuffers fulfilled significantly more DSM-IV criteria for alcohol dependence than tobacco nonusers. Furthermore, significantly higher proportions of smokers and snuffers fulfilled the criteria no 2 (experiencing withdrawal syndrome) and no 7 (continuing to use alcohol despite problems). CONCLUSIONS: These findings indicate that not only smoking, but also snuffing, is associated with greater severity of alcohol dependence, as reflected by the greater number of DSM-IV criteria.
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| 13. |
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| 14. |
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| 15. |
- Berglund, Åke, et al.
(författare)
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An explorative randomised phase II study of sequential chemotherapy in advanced upper gastrointestinal cancer
- 2010
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 27:1, s. 65-72
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Tidskriftsartikel (refereegranskat)abstract
- The feasibility, safety, and efficacy of planned sequential administration of docetaxel and irinotecan with 5-fluorouracil (5-FU)/leucovorin in advanced upper gastrointestinal adenocarcinoma (UGIA) are unknown. Seventy-three patients with gastric (GC; n = 22), pancreatic (PC; n = 28) or biliary cancer (BC; n = 23) were randomised to start with 45 mg/m2 docetaxel or 180 mg/m2 irinotecan combined with 5-FU/leucovorin every 2nd week. After every 2nd course, the patients were crossed over to the other combination. Treatment was given for a maximum of 12 courses. Quality-of-life (QoL) was evaluated during the first two months using the EORTC QLQ-C30. Eighteen patients (25%; GC 32%, PC 21%, BC 22%) demonstrated partial response (PR) and 21 (29%) had prolonged stable disease. Mean QoL scores were low at baseline. Twenty-three (32%) patients had improved QoL using a summary measure and 13 were stable. Median time to progression was 4.4 months and overall survival 8.2 months. The treatments were reasonably well tolerated. Grade 3–4 toxicities were slightly more common for the docetaxel combination. There were two treatment-related deaths. Planned sequential treatment with docetaxel or irinotecan with 5-FU/leucovorin is feasible, reasonably tolerable and appears active in advanced UGIA.
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| 16. |
- Blomquist, Jens, et al.
(författare)
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Structure liming reduces draught requirement on clay soil
- 2023
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Ingår i: Soil and Tillage Research. - 0167-1987 .- 1879-3444. ; 231
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Tidskriftsartikel (refereegranskat)abstract
- Liming with ‘structure lime’, comprising approximately 80–85% ground limestone and 15–20% slaked lime, has been promoted in subsidised environmental schemes in Sweden since 2010 to increase clay aggregate stability and mitigate particulate phosphorus losses to surface waters. To date, approximately 65,000 ha have been structure-limed. Apart from stabilising aggregates, liming may also improve other physical properties, such as soil strength. This study examined the effect of increasing application rate (0–16 t ha-1) of structure lime on soil strength, approximated by horizontal (draught requirement) and vertical (penetrometer resistance) measurements, in eight field soils (clay content 26–38%) to which structure lime had been applied two, three, four or six years previously. Draught requirement when cultivating with a multipurpose cultivator significantly decreased (by 11%) with the highest application rate of structure lime (16 t ha-1) compared with an unlimed control. This reduced the wheel power requirement by 7.1 kW and diesel consumption by 1.2–1.4 L ha-1, and lowered CO2 emissions by 3–4 kg ha-1. To clarify the general effect of structure liming, the mean value of all limed treatments was compared with that of the unlimed control. This showed that structure liming in general significantly reduced the draught requirement (by 7%). However, penetrometer resistance measurements revealed no significant effects of structure liming and no relation between draught requirement and penetrometer resistance measurements. Overall, the results indicate that structure liming can reduce fuel consumption, due to easier soil tillage, and thus lower CO2 emissions.
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| 17. |
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| 18. |
- Ebbinge, Maria, et al.
(författare)
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Clinical and prognostic significance of changes in haemoglobin concentration during 1 year of androgen-deprivation therapy for hormone-naive bone-metastatic prostate cancer
- 2018
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Ingår i: BJU International. - : WILEY. - 1464-4096 .- 1464-410X. ; 122:4, s. 583-591
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Tidskriftsartikel (refereegranskat)abstract
- Objective To estimate the strength of change in haemoglobin (Hb) concentrations during 1 year of androgen-deprivation therapy (ADT) as a predictor of survival in hormone-naive patients with bone-metastatic (Stage M1b) prostate cancer. Patients and Methods The patients included in this study were taken from the randomised trial (number 5) carried out by the Scandinavian Prostate Cancer Group (SPCG), comparing parenteral oestrogen with total androgen blockade (TAB) in hormone-naive M1b prostate cancer. We identified 597 men where Hb measurements were made at enrolment, as well as at 3, 6 and 12 months of ADT. The time-dependent impact of Hb concentration changes on overall survival (OS) was analysed using multivariate Cox proportional hazards analysis. The 10-year OS according to increase/decrease in Hb concentration for the three treatment periods was demonstrated using Kaplan-Meier curves. Results Multivariate analysis of changes in Hb concentration between baseline and 3 months showed better survival in patients with a decrease in Hb concentration (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.11-1.80) compared to those with an increase, whilst there was no difference in survival associated with a change in Hb concentration between 3 and 6 months (HR 0.93, 95% CI 0.76-1.12). Contrary to the first 3 months, poorer survival was seen in patients with a decrease in Hb concentration between 6 and 12 months (HR 0.76, 95% CI 0.62-0.92) compared to those with an increase. Conclusions In a large cohort of Scandinavian men with hormone-nave M1b prostate cancer, an increase in Hb concentration between baseline and 3 months of ADT was associated with significantly poorer survival, whereas an increase between 6 and 12 months was associated with better survival. These findings provide new information about patterns of change in Hb concentrations during 12 months of ADT for M1b prostate cancer, and survival. Clinicians should be aware of the prognostic value of Hb concentration changes during ADT in M1b prostate cancer.
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| 19. |
- Engström, Gunnar, et al.
(författare)
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The Swedish CArdioPulmonary BioImage Study : objectives and design
- 2015
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 278:6, s. 645-659
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Tidskriftsartikel (refereegranskat)abstract
- Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.
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| 20. |
- Eriksson, Olof, et al.
(författare)
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Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:5, s. 794-800
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Tidskriftsartikel (refereegranskat)abstract
- The glucagonlike peptide-1 receptor (GLP1R) is a gut hormone receptor, intricately linked to regulation of blood glucose homeostasis via several mechanisms. It is an established and emergent drug target in metabolic disease. The PET radioligand 68Ga-DO3A-VS-exendin4 (68Ga-exendin4) has the potential to enable longitudinal studies of GLP1R in the human pancreas.Methods: 68Ga-exendin4 PET/CT examinations were performed on overweight-to-obese individuals with type 2 diabetes (n = 13) as part of a larger target engagement study (NCT03350191). A scanning protocol was developed to optimize reproducibility (target amount of 0.5 MBq/kg [corresponding to peptide amount of <0.2 µg/kg], blood sampling, and tracer stability assessment). The pancreas and abdominal organs were segmented, and binding was correlated with clinical parameters.Results: Uptake of 68Ga-exendin4 in the pancreas, but not in other abdominal tissues, was high but variable between individuals. There was no evidence of self-blocking of GLP1R by the tracer in this protocol, despite the high potency of exendin4. The results showed that a full dynamic scan can be simplified to a short static scan, potentially increasing throughput and reducing patient discomfort. The 68Ga-exendin4 concentration in the pancreas (i.e., GLP1R density) correlated inversely with the age of the individual and tended to correlate positively with body mass index. However, the total GLP1R content in the pancreas did not.Conclusion: In summary, we present an optimized and simplified 68Ga-exendin4 scanning protocol to enable reproducible imaging of GLP1R in the pancreas. 68Ga-exendin4 PET may enable quantification of longitudinal changes in pancreatic GLP1R during the development of type 2 diabetes, as well as target engagement studies of novel glucagonlike peptide-1 agonists.
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| 21. |
- Eriksson, Olof, et al.
(författare)
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Imaging of the Glucagon Receptor in Subjects with Type 2 Diabetes
- 2021
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Ingår i: Journal of Nuclear Medicine. - : SOC NUCLEAR MEDICINE INC. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:6, s. 833-838
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Tidskriftsartikel (refereegranskat)abstract
- Despite the importance of the glucagon receptor (GCGR) in disease and in pharmaceutical drug development, there is a lack of specific and sensitive biomarkers of its activation in humans. The PET radioligand Ga-68-DO3A-VS-Tuna-2 (Ga-68-Tuna-2) was developed to yield a noninvasive imaging marker for GCGR target distribution and drug target engagement in humans. Methods: The biodistribution and dosimetry of Ga-68-Tuna-2 was assessed by PET/CT in 13 individuals with type 2 diabetes as part of a clinical study assessing the occupancy of the dual GCGR/glucagon like peptide-1 receptor agonist SAR425899. Binding of Ga-68-Tuna-2 in liver and reference tissues was evaluated and correlated to biometrics (e.g., weight or body mass index) or other biomarkers (e.g., plasma glucagon levels). Results: Ga-68-Tuna-2 binding was seen primarily in the liver, which is in line with the strong expression of GCGR on hepatocytes. The kidneys demonstrated high excretion-related retention, whereas all other tissue demonstrated rapid washout. The SUV55 (min) (SUV during the last 10-min time frame, 50-60 min after administration) uptake endpoint was sensitive to endogenous levels of glucagon. Ga-68-Tuna-2 exhibited a safe dosimetry profile and no adverse events after intravenous administration. Conclusion: Ga-68-Tuna-2 can be used for safe and accurate assessment of the GCGR in human. It may serve as an important tool in understanding the in vivo pharmacology of novel drugs engaging the GCGR.
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| 22. |
- Eriksson, Olof, et al.
(författare)
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Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes
- 2020
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Ingår i: Scientific Reports. - : NATURE RESEARCH. - 2045-2322. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Unimolecular dual agonists for the glucagon-like peptide 1 receptor (GLP1R) and glucagon receptor (GCGR) are emerging as a potential new class of important therapeutics in type 2 diabetes (T2D). Reliable and quantitative assessments of in vivo occupancy on each receptor would improve the understanding of the efficacy of this class of drugs. In this study we investigated the target occupancy of the dual agonist SAR425899 at the GLP1R in pancreas and GCGR in liver by Positron Emission Tomography/Computed Tomography (PET/CT). Patients with T2D were examined by [Ga-68]Ga-DO3A-Tuna-2 and [Ga-68]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. Follow up PET examinations were performed after 17 (GCGR) and 20 (GLP-1R) days of treatment with SAR425899, to assess the occupancy at each receptor. Six out of 13 included patients prematurely discontinued the study due to adverse events. SAR425899 at a dose of 0.2 mg daily demonstrated an average GCGR occupancy of 11.2 +/- 14.4% (SD) in N=5 patients and a GLP1R occupancy of 49.9 +/- 13.3%. Fasting Plasma Glucose levels (-3.30 +/- 1.14 mmol/L) and body weight (-3.87 +/- 0.87%) were lowered under treatment with SAR425899. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET.
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| 23. |
- Fredén, Filip, et al.
(författare)
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Inhalation of a nitric oxide synthase inhibitor to a hypoxic or collapsed lung lobe in anaesthetized pigs : effects on pulmonary blood flow distribution
- 1996
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Ingår i: British Journal of Anaesthesia. - : Elsevier BV. - 0007-0912 .- 1471-6771. ; 77:3, s. 413-418
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Tidskriftsartikel (refereegranskat)abstract
- I.v. administration of the nitric oxide synthase inhibitor, nitro-L-arginine methyl ester (L-NAME), not only reduces blood flow in a hypoxic lung region but also causes systemic vasoconstriction and a decrease in cardiac output. In this study, we delivered nebulized L-NAME 0.2-1 mg kg-1 to the left lower lobe of 10 anaesthetized pigs. The left lower lobe was made hypoxic by selective inhalation of 5% oxygen or collapsed by interrupted ventilation, or both. Inhalation of L-NAME reduced fractional blood flow to the left lower lobe from 5.3 (SD 3.1)% to 1.7 (1.4)% (P < 0.05) in lobar hypoxia and from 6.0 (3.3) to 2.7 (2.7)% (P < 0.05) in lobar collapse. These reductions were accompanied by a significant increase in PaO2. There were no significant changes in arterial pressure, cardiac output or heart rate. We have shown that selective inhalation of L-NAME reduced blood flow to a hypoxic or collapsed lung region without systemic effects. The possible role for nitric oxide synthase inhibition in reducing shunt during one-lung ventilation, however, requires further study.
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| 24. |
- Fridén, Michael, et al.
(författare)
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Effects of a low-carbohydrate high polyunsaturated fat diet or a healthy Nordic diet versus usual care on liver fat content and cardiometabolic risk factors in people with type 2 diabetes and prediabetes: a randomized controlled trial (NAFLDiet)
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Previous trials have shown that plant-derived polyunsaturated fatty acids (PUFA) in place of saturated fat reduces liver fat, a prerequisite for non-alcoholic fatty liver disease (NAFLD). The effect on liver fat from a novel “anti-lipogenic diet” replacing carbohydrates with PUFA or a healthy Nordic diet (HND) higher in whole-grains but lower in saturated fat has not yet been examined. Objectives: To investigate the effects on changes in liver fat (primary outcome) and other cardiometabolic risk factors after 12 months of follow-up in individuals with prediabetes or T2D from three different diet comparisons: a low carbohydrate high PUFA (LCPUFA) diet versus a HND, a LCPUFA diet versus usual care (UC) and a HND versus UC. Methods: A three-arm parallel ad libitum randomized trial was conducted. Adult men and women (n=148) were randomized to one of the three diet groups. Participants in all groups received key food items on a monthly/bimonthly basis. Liver fat and cardiometabolic risk factors were assessed at baseline and after 12 months. Dietary adherence was assessed using weighed food diaries and objective biomarkers. General linear models were employed to estimate the intention-to-treat (ITT) effect. Results: Dietary adherence was high for all diet groups. Liver fat was reduced to a similar extent in the LCPUFA and the HND group compared to UC (-1.46% (95% CI: -2.42, -0.51)) and -1.76 % (95% CI: -2.96, -0.57), respectively. No difference in liver fat between LCPUFA and HND was observed. Body weight and HbA1c decreased more in the HND compared to the other diet groups whereas no differences were observed between LCPUFA and UC. Similar reductions in LDL-cholesterol were observed for the HND and the LCPUFA group compared to UC, but only the HND reduced triglycerides and C-reactive protein (CRP) compared with UC. No differences were observed for any other secondary outcomes.Conclusions: A LCPUFA diet and a HND both reduced liver fat as compared with UC. Given the sustained weight loss after the HND compared to the other groups, together with improvements in other cardiometabolic markers, the HND in particular seems to be useful for the treatment of T2D and NAFLD.
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| 25. |
- Hennies, Franz, et al.
(författare)
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Resonant Inelastic Scattering Spectra of Free Molecules with Vibrational Resolution
- 2010
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 104:19, s. 193002-
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Tidskriftsartikel (refereegranskat)abstract
- Inelastic x-ray scattering spectra excited at the 1s(-1) pi* resonance of gas phase O-2 have been recorded with an overall energy resolution that allows for well-resolved vibrational progressions. The nuclear wave packet dynamics in the intermediate state is reflected in vibrational excitations of the electronic ground state, and by fine-tuning the excitation energy the dissociation dynamics in the predissociative B' (3) Pi(g) final state is controlled.
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| 26. |
- Huang, Jing, 1987-, et al.
(författare)
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Large-Area Transparent “Quantum Dot Glass” for Building-Integrated Photovoltaics
- 2022
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Ingår i: ACS Photonics. - : American Chemical Society (ACS). - 2330-4022. ; 9:7, s. 2499-2509
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Tidskriftsartikel (refereegranskat)abstract
- A concept of transparent “quantum dot glass”(TQDG) is proposed for a combination of a quantum dot(QD)-based glass luminescent solar concentrator (LSC) and itsedge-attached solar cells, as a type of transparent photovoltaics(TPVs) for building-integrated photovoltaics (BIPVs). Differentfrom conventional LSCs, which typically serve as pure opticaldevices, TQDGs have to fulfill requirements as both powergeneratingcomponents and building construction materials. In thiswork, we demonstrate large-area (400 cm2) TQDGs based onsilicon QDs in a triplex glass configuration. An overall powerconversion efficiency (PCE) of 1.57% was obtained with back-reflection for a transparent TQDG (average visible transmittance of84% with a color rendering index of 88 and a low haze ≤3%), contributing to a light utilization efficiency (LUE) of 1.3%, which isamong the top reported TPVs based on the LSC technology with similar size. Most importantly, these TQDGs are shown to havebetter thermal and sound insulation properties compared to normal float glass, as well as improved mechanical performance andsafety, which significantly pushes the TPV technology toward practical building integration. TQDGs simultaneously exhibit favorablephotovoltaic, aesthetic, and building envelope characteristics and can serve as a multifunctional material for the realization of nearlyzero-energy building concepts.
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| 27. |
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| 28. |
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| 29. |
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| 30. |
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| 31. |
- Sun, Yuping, et al.
(författare)
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Intramolecular soft modes and intermolecular interactions in liquid acetone
- 2011
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Ingår i: Physical Review B Condensed Matter. - 0163-1829 .- 1095-3795. ; 84:13
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Tidskriftsartikel (refereegranskat)abstract
- Resonant inelastic x-ray scattering spectra excited at the O1s−1π* resonance of liquid acetone are presented. Scattering to the electronic ground state shows a resolved vibrational progression where the dominant contribution is due to the C-O stretching mode, thus demonstrating a unique sensitivity of the method to the local potential energy surface in complex molecular systems. For scattering to electronically excited states, soft vibrational modes and, to a smaller extent, intermolecular interactions give a broadening, which blurs the vibrational fine structure. It is predicted that environmental broadening is dominant in aqueous acetone.
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| 32. |
- Vesikari, Timo, et al.
(författare)
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Immunogenicity and Safety of a Trivalent Inactivated Influenza Vaccine in Children 6 Months to 17 Years of Age, Previously Vaccinated with an AS03-Adjuvanted A(H1N1)Pdm09 Vaccine Two Open-label, Randomized Trials
- 2015
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Ingår i: The Pediatric Infectious Disease Journal. - 0891-3668 .- 1532-0987. ; 34:7, s. 774-782
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Tidskriftsartikel (refereegranskat)abstract
- Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1) pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1) pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1) pdm09 vaccine. Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1) pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1) pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months. Results: At day 0, >93.9% of all children had HI titers >= 1:40 for the A(H1N1) pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1) pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively. Conclusion: AS03-adjuvanted A(H1N1) pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1) pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03adjuvanted A(H1N1) pdm09 vaccine.
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| 33. |
- Willander, Hanna, et al.
(författare)
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High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C
- 2012
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:7, s. 2325-2329
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Tidskriftsartikel (refereegranskat)abstract
- BRICHOS domains are encoded in >30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 angstrom crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.
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