| 1. |
- Bossart, Martin, et al.
(författare)
-
Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist
- 2022
-
Ingår i: Cell Metabolism. - : CELL PRESS. - 1550-4131 .- 1932-7420. ; 34:1, s. 59-
-
Tidskriftsartikel (refereegranskat)abstract
- Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose -dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.
|
|
| 2. |
- Brauckhoff, Michael, et al.
(författare)
-
Long-term results and functional outcome after cervical evisceration in patients with thyroid cancer.
- 2006
-
Ingår i: Surgery. - : Elsevier BV. - 0039-6060 .- 1532-7361. ; 140:6, s. 953-9
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Surgical strategy in patients with thyroid cancer (TC) infiltrating the aerodigestive system is controversial. This study was undertaken to examine the long-term results of cervical evisceration (CE).PATIENTS AND METHODS: Since 1995, 14 consecutive patients with advanced TC underwent total laryngectomy (LE, n = 6) or esophagolaryngectomy (ELR, n = 8). Patients with unusual thyroid neoplasms or metastases to the thyroid (n = 3) were excluded. For esophageal reconstruction, free jejunal grafts (n = 6) and gastric tubes (n = 2) were used.RESULTS: Procedure-related morbidity and mortality were 42% and 14%, respectively. ELR was associated with a significant higher frequency of complications and reoperations compared with LE. Twelve-month and 30-month survival rates were 73% and 55%, respectively; 85% of the patients were satisfied with the surgical results. There were no long-term problems concerning food intake in the ELR patients. Two ELR patients were able to learn a substitutive voice.CONCLUSIONS: Cervical evisceration in patients with TC is associated with significant perioperative morbidity and mortality requiring careful patient selection. Regarding long-term survival, local tumor control, and patient's satisfaction, however, CE should be taken into account in suitable patients with advanced TC.
|
|
| 3. |
- Brauckhoff, Michael, et al.
(författare)
-
Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B : An exploratory analysis
- 2008
-
Ingår i: SURGERY. - : Elsevier BV. - 0039-6060. ; 144:6, s. 1044-1050
-
Tidskriftsartikel (refereegranskat)abstract
- Background. More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene. DNA-based screening for RET germline mutations is rarely useful for early diagnosis, which thus is contingent on the clinical ascertainment of MEN 2B-specifitc symptoms as soon as they emerge. Little information exists about the presence of these symptoms in infancy.Methods. Detailed information was gathered regarding the development of MEN 2B-associated symptoms from the parents of 25 M918T RET carriers and 50 age- and sex-matched, controls with the use of a disease-specific questionnaire.Results. Until the end of the study, at a median age of 16 2 (range, 0.5-34.9 years), all 25 M918T RET carriers had developed medullary thyroid cancer. By that time, 96%, 91%, 71%, 75%, and 28% Of carriers displayed oral manifestations, ocular abnormalities, intestinal symptoms, musculoskeletal malformations, and pheochromocytoma, respectively. During the first year of life, fewer than 20% of carriers were found to express the typical MEN 2B phenotype, whereas 86% and 61% of these children, but none of the controls, were noted for their inability to cry tears and for constipation.Conclusion. Because the classic MEW 2B phenotype is rare during the first year of life, more emphasis should be placed on the more subtle features of the syndrome. Additional studies are needed to validate the usefulness of the symptoms "inability to cry" and "constipation" for earlier diagnosis of MEAT 2B.
|
|
| 4. |
- Eriksson, Olof, et al.
(författare)
-
Drug Occupancy Assessment at the Glucose-Dependent Insulinotropic Polypeptide Receptor by Positron Emission Tomography
- 2021
-
Ingår i: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 70:4, s. 842-853
-
Tidskriftsartikel (refereegranskat)abstract
- Targeting of the glucose-dependent insulinotropic polypeptide receptor (GIPR) is an emerging strategy in antidiabetic drug development. The aim of this study was to develop a positron emission tomography (PET) radioligand for the GIPR to enable the assessment of target distribution and drug target engagement in vivo. The GIPR-selective peptide S02-GIP was radiolabeled with Ga-68. The resulting PET tracer [Ga-68]S02-GIP-T4 was evaluated for affinity and specificity to human GIPR (huGIPR). The in vivo GIPR binding of [Ga-68]S02-GIP-T4 as well as the occupancy of a drug candidate with GIPR activity were assessed in nonhuman primates (NHPs) by PET. [Ga-68]S02-GIP-T4 bound with nanomolar affinity and high selectivity to huGIPR in overexpressing cells. In vivo, pancreatic binding in NHPs could be dose-dependently inhibited by coinjection of unlabeled S02-GIP-T4. Finally, subcutaneous pretreatment with a high dose of a drug candidate with GIPR activity led to a decreased pancreatic binding of [Ga-68]S02-GIP-T4, corresponding to a GIPR drug occupancy of almost 90%. [Ga-68]S02-GIP-T4 demonstrated a safe dosimetric profile, allowing for repeated studies in humans. In conclusion, [Ga-68]S02-GIP-T4 is a novel PET biomarker for safe, noninvasive, and quantitative assessment of GIPR target distribution and drug occupancy.
|
|
| 5. |
|
|
| 6. |
- Gualandro, Danielle M. M., et al.
(författare)
-
Acute heart failure after non-cardiac surgery: incidence, phenotypes, determinants and outcomes
- 2023
-
Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 25:3, s. 347-357
-
Tidskriftsartikel (refereegranskat)abstract
- Aims Primary acute heart failure (AHF) is a common cause of hospitalization. AHF may also develop postoperatively (pAHF). The aim of this study was to assess the incidence, phenotypes, determinants and outcomes of pAHF following non-cardiac surgery.Methods and results A total of 9164 consecutive high-risk patients undergoing 11 262 non-cardiac inpatient surgeries were prospectively included. The incidence, phenotypes, determinants and outcome of pAHF, centrally adjudicated by independent cardiologists, were determined. The incidence of pAHF was 2.5% (95% confidence interval [CI] 2.2-2.8%); 51% of pAHF occurred in patients without known heart failure (de novo pAHF), and 49% in patients with chronic heart failure. Among patients with chronic heart failure, 10% developed pAHF, and among patients without a history of heart failure, 1.5% developed pAHF. Chronic heart failure, diabetes, urgent/emergent surgery, atrial fibrillation, cardiac troponin elevations above the 99th percentile, chronic obstructive pulmonary disease, anaemia, peripheral artery disease, coronary artery disease, and age, were independent predictors of pAHF in the logistic regression model. Patients with pAHF had significantly higher all-cause mortality (44% vs. 11%, p < 0.001) and AHF readmission (15% vs. 2%, p < 0.001) within 1 year than patients without pAHF. After Cox regression analysis, pAHF was an independent predictor of all-cause mortality (adjusted hazard ratio [aHR] 1.7 [95% CI 1.3-2.2]; p < 0.001) and AHF readmission (aHR 2.3 [95% CI 1.5-3.7]; p < 0.001). Findings were confirmed in an external validation cohort using a prospective multicentre cohort of 1250 patients (incidence of pAHF 2.4% [95% CI 1.6-3.3%]).Conclusions Postoperative AHF frequently developed following non-cardiac surgery, being de novo in half of cases, and associated with a very high mortality.
|
|
| 7. |
- Lorenz, Kerstin, et al.
(författare)
-
Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma
- 2005
-
Ingår i: Surgery. - : Elsevier. - 0039-6060 .- 1532-7361. ; 138:6, s. 986-993
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hepatic metastases from medullary thyroid carcinoma (MTC) may impair quality of life by hypercalcitonemia-associated diarrhea and pain. In this prospective study, the effect of selective arterial chemoembolization (SACE) was evaluated.METHODS: Eleven patients with hepatic metastases from MTC received 1 to 9 courses of SACE using epirubicine. Symptomatic, biochemical, and morphologic responses on SACE were recorded.RESULTS: Symptomatic response was observed in all symptomatic patients. However, biochemical and radiologic response occurred only in 6 patients. Liver function was not affected by SACE. One patient with unexpected concurrent pheochromocytoma metastases died after the first course. Development of side effects in the course was observed in 8 patients but were only World Health Organization grade 1. Patients' satisfaction with SACE was excellent. Long-term follow-up found 7 patients alive (1-72 months). Three patients died with tumor 6, 12, and 24 months after SACE, respectively.CONCLUSION: SACE provided good symptom palliation for the majority of patients with hepatic metastases from MTC. However, transient remission or stabilization of hepatic metastases resulted in only 60%. Further studies using a randomized protocol are required.
|
|
| 8. |
- Pingen, Katrin, et al.
(författare)
-
High growth rate magnetron sputter epitaxy of GaN using a solid Ga target
- 2024
-
Ingår i: Vacuum. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0042-207X .- 1879-2715. ; 220
-
Tidskriftsartikel (refereegranskat)abstract
- Magnetron sputter epitaxy (MSE) is a promising processing route for group-III nitride semiconductors, with the potential to enable high-quality and low cost GaN growth for widespread use. However, fundamental techno-logical hurdles must be overcome to enable the adoption of MSE in industrial production. Here, we present a new UHV-compatible magnetron design with high-performance cooling, enabling high GaN growth rates at high growth temperatures using a solid Ga target. The magnetron is tested with a wide range of process parameters and a stable process is feasible while maintaining the solid state of the Ga target. High GaN growth rates of up to 5 mu m/h are achieved at room temperature and a growth rate of 4 mu m/h at high temperature, which is one order of magnitude higher compared to MSE with a liquid target. We grow GaN on c-plane sapphire substrates and show the impact of partial pressure ratio and target-to-substrate distance (TSD) on growth rate, film morphology and crystal quality of GaN films with scanning electron microscopy and X-ray diffraction. While the growth rate and film morphology are strongly impacted by the process parameter variation, the crystal quality is further impacted by the overall film thickness. For a 2 mu m thick GaN film a full width at half maximum of X-ray rocking curve (omega-FWHM) of GaN 10 1 1 reflection of 0.32 degrees is achieved. We demonstrate a process window for growth of dense and smooth GaN films with high crystal quality using low N2 flow rates and high TSD. By introducing a 20 nm AlN nucleation layer prior to the growth of 390 nm GaN, the omega-FWHM of GaN 0002 reflection of 0.19 degrees is achieved. The epitaxially grown crystalline structure is precisely examined by transmission electron microscopy.
|
|
| 9. |
- Rodriguez, Sébastien, et al.
(författare)
-
Science goals and new mission concepts for future exploration of Titan's atmosphere, geology and habitability : titan POlar scout/orbitEr and in situ lake lander and DrONe explorer (POSEIDON)
- 2022
-
Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 54:2-3, s. 911-973
-
Tidskriftsartikel (refereegranskat)abstract
- In response to ESA’s “Voyage 2050” announcement of opportunity, we propose an ambitious L-class mission to explore one of the most exciting bodies in the Solar System, Saturn’s largest moon Titan. Titan, a “world with two oceans”, is an organic-rich body with interior-surface-atmosphere interactions that are comparable in complexity to the Earth. Titan is also one of the few places in the Solar System with habitability potential. Titan’s remarkable nature was only partly revealed by the Cassini-Huygens mission and still holds mysteries requiring a complete exploration using a variety of vehicles and instruments. The proposed mission concept POSEIDON (Titan POlar Scout/orbitEr and In situ lake lander DrONe explorer) would perform joint orbital and in situ investigations of Titan. It is designed to build on and exceed the scope and scientific/technological accomplishments of Cassini-Huygens, exploring Titan in ways that were not previously possible, in particular through full close-up and in situ coverage over long periods of time. In the proposed mission architecture, POSEIDON consists of two major elements: a spacecraft with a large set of instruments that would orbit Titan, preferably in a low-eccentricity polar orbit, and a suite of in situ investigation components, i.e. a lake lander, a “heavy” drone (possibly amphibious) and/or a fleet of mini-drones, dedicated to the exploration of the polar regions. The ideal arrival time at Titan would be slightly before the next northern Spring equinox (2039), as equinoxes are the most active periods to monitor still largely unknown atmospheric and surface seasonal changes. The exploration of Titan’s northern latitudes with an orbiter and in situ element(s) would be highly complementary in terms of timing (with possible mission timing overlap), locations, and science goals with the upcoming NASA New Frontiers Dragonfly mission that will provide in situ exploration of Titan’s equatorial regions, in the mid-2030s.
|
|
| 10. |
|
|
