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| 2. |
- Tomic, Tajana Tesan, et al.
(författare)
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MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 16:6
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Tidskriftsartikel (refereegranskat)abstract
- Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors. © 2020 Tomic et al.
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| 4. |
- Dutta, Nikita, 1992, et al.
(författare)
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Combinatory analysis of immune cell subsets and tumor-specific genetic variants predict clinical response to PD-1 blockade in patients with non-small cell lung cancer
- 2023
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Immunotherapy by blocking programmed death protein-1 (PD-1) or programmed death protein-ligand1 (PD-L1) with antibodies (PD-1 blockade) has revolutionized treatment options for patients with non-small cell lung cancer (NSCLC). However, the benefit of immunotherapy is limited to a subset of patients. This study aimed to investigate the value of combining immune and genetic variables analyzed within 3-4 weeks after the start of PD-1 blockade therapy to predict long-term clinical response.Blood collected from patients with NSCLC were analyzed for changes in the frequency and concentration of immune cells using a clinical flow cytometry assay. Next-generation sequencing (NGS) was performed on DNA extracted from archival tumor biopsies of the same patients. Patients were categorized as clinical responders or non-responders based on the 9 months' assessment after the start of therapy.We report a significant increase in the post-treatment frequency of activated effector memory CD4+ and CD8+ T-cells compared with pre-treatment levels in the blood. Baseline frequencies of B cells but not NK cells, T cells, or regulatory T cells were associated with the clinical response to PD-1 blockade. NGS of tumor tissues identified pathogenic or likely pathogenic mutations in tumor protein P53, Kirsten rat sarcoma virus, Kelch-like ECH-associated protein 1, neurogenic locus notch homolog protein 1, and serine/threonine kinase 11, primarily in the responder group. Finally, multivariate analysis of combined immune and genetic factors but neither alone, could discriminate between responders and non-responders.Combined analyses of select immune cell subsets and genetic mutations could predict early clinical responses to immunotherapy in patients with NSCLC and after validation, can guide clinical precision medicine efforts.
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- Grossmann, Benjamin, et al.
(författare)
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Patient-controlled Sedation During Flexible Bronchoscopy : A Randomized Controlled Trial
- 2020
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Ingår i: Journal of Bronchology & Interventional Pulmonology. - : Lippincott Williams & Wilkins. - 1944-6586 .- 1948-8270. ; 27:2, s. 77-85
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patient-controlled sedation (PCS) is a documented method for endoscopic procedures considered to facilitate early recovery. Limited data have been reported, however, on its use during flexible bronchoscopy (FB).Materials and Methods: This study hypothesized that PCS with propofol during FB would facilitate early recovery, with similar bronchoscopist and patient satisfaction compared with nurse-controlled sedation (NCS) with midazolam. A total of 150 patients were randomized 1:1:1 into a control group (premedication with morphine-scopolamine and NCS with midazolam), PCS-MS group (premedication with morphine-scopolamine and PCS with propofol), and PCS-G group (premedication with glycopyrronium and PCS with propofol).Results: The procedures included transbronchial biopsy, transbronchial needle aspiration, cryotherapy/biopsy, and/or multistation endobronchial ultrasound. FB duration values in median (range) were 40 (10 to 80), 39 (12 to 68), and 44 (10 to 82) minutes for the groups NCS, PCS-MS, and PCS-G, respectively. An overall 81% of the patients in the combined PCS groups were ready for discharge (modified Post Anaesthetic Discharge Scoring System, score 10) 2 hours after bronchoscopy compared with 40% in the control group (P<0.0001). Between PCS groups, 96% of the PCS-G group patients were ready for discharge compared with 65% in the PCS-MS group (P=0.0002) at 2 hours. Bronchoscopists’ and patients’ satisfaction scores were high in all groups. Postdischarge quality scores showed no differences among the groups.Conclusion: PCS with propofol during FB is feasible, as it shortened recovery time without compromising procedure conditions for bronchoscopists or patients. A rapid postsedation stabilization of vital signs facilitates surveillance before the patient leaves the hospital.
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| 6. |
- Grossmann, Benjamin, et al.
(författare)
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Patient-controlled sedation with propofol for endoscopic procedures : A cost analysis
- 2020
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Ingår i: Acta Anaesthesiologica Scandinavica. - : John Wiley & Sons. - 0001-5172 .- 1399-6576. ; 64:1, s. 53-62
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundPatient‐controlled sedation (PCS) with propofol accompanied by a bedside nurse anaesthetist is an alternative sedation method for endoscopic procedures compared with midazolam administered by a nurse or endoscopist. Increasing costs in health care demands an economic perspective when introducing alternative methods. We applied a hospital perspective on a cost analysis comparing different methods of sedation and the resource use that were expected to affect cost differences related to the sedation.MethodsBased on two randomised previous studies, the direct costs were determined for different sedation methods during two advanced endoscopic procedures: endoscopic retrograde cholangiopancreatography (ERCP) and flexible bronchoscopy including endobronchial ultrasound. ERCP comparisons were made between midazolam sedation by the endoscopic team, PCS with a bedside nurse anaesthetist and propofol sedation administered by a nurse anaesthetist. Bronchoscopy comparisons were made between midazolam sedation by the endoscopic team and PCS with a bedside nurse anaesthetist, categorised by premedication morphine‐scopolamine or glycopyrronium.ResultsPropofol PCS with a bedside nurse anaesthetist resulted in lower costs per patient for sedation for both ERCP (233 USD) and bronchoscopy (premedication morphine‐scopolamine 267 USD, premedication glycopyrronium 269 USD) compared with midazolam (ERCP 425 USD, bronchoscopy 337 USD). Aborted procedures that needed to be repeated and prolonged hospital stays significantly increased the cost for the midazolam groups.ConclusionPropofol PCS with a bedside nurse anaesthetist reduces the direct sedation costs for ERCP and bronchoscopy procedures compared with midazolam sedation.
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| 7. |
- Grossmann, Benjamin
(författare)
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Procedural sedation : Aspects on methods, safety and effectiveness
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Safety and effectiveness are fundamental principles within the healthcare sector to provide quality of care and health improvement for patients. By ensuring that care is provided based on evidence-based knowledge, risks and complications can be minimised and the use of scarce resources optimised. An increasing demand for diagnostic and therapeutic procedures challenges the traditional methods for sedation regarding safety and effectiveness. It is desirable that the fundamental principles are improved when refining existing or developing new sedation methods. In this doctoral thesis, safety and effectiveness were evaluated for adult patient-controlled sedation (PCS) using propofol during two endoscopic procedures: endoscopic retrograde cholangiopancreaticography (ERCP) and flexible bronchoscopy (FB); and different doses of rectal racemic ketamine for paediatric (< 4 years) burn wound care.Methods: Data on vital functions, sedation level, safety interventions, procedure feasibility, patient-reported outcome and experience measures, and recovery, from three clinical randomised controlled trials were collected. Costs of sedation for the endoscopic procedures were compiled in a cost-analysis study.Results: PCS with propofol and bedside anaesthetic personnel was shown to be a safe and effective alternative method of sedation during ERCP and FB compared with intravenous sedation with midazolam. The PCS method gives stable cardiorespiratory conditions with few adverse events and interventions, with a low risk of oversedation. PCS offers similar (FB) or better (ERCP) procedure feasibility and patient satisfaction during the procedures than midazolam. Recovery after PCS is quick, minimises the risk for prolonged hospitalisation and is thereby a potential cost-saving sedation method. The optimal dose of rectal racemic ketamine, 6 mg/kg with the addition of 0.5 mg/kg midazolam during severely painful procedures, gives minimal risk for outbreaks of pain, offers stable vital signs conditions and allows rapid recovery without affecting procedure feasibility.Conclusions: The sedation method can be adjusted to type of procedure and patient population. PCS with propofol offers an alternative and reliable method for adult sedation during endoscopic procedures, whereas rectal racemic ketamine combined with midazolam provides good conditions for burn care dressing procedures in young children.
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| 8. |
- Grossmann, Benjamin, et al.
(författare)
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Rectal ketamine during paediatric burn wound dressing procedures : a randomised dose-finding study
- 2019
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Ingår i: Burns. - : Pergamon Press. - 0305-4179 .- 1879-1409. ; 45:5, s. 1081-1088
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundWorldwide, ketamine is used during paediatric procedures, but no recommendations are available regarding a suitable dose for rectal administration during procedures involving high levels of pain and/or anxiety such as burn wound dressing change.MethodsWe evaluated three different single doses of rectally administered racemic ketamine mixed with a fixed dose of 0.5 mg/kg of midazolam. In total, 90 children – aged 6 months to 4 years – were randomised 1:1:1 to receive 4 mg/kg (K-4 group), 6 mg/kg (K-6 group) or 8 mg/kg (K-8 group) of racemic ketamine for a maximum of three consecutive procedures. Primary outcome measure was procedural pain evaluated by Face, Legs, Activity, Cry, Consolability (FLACC) behavioural scale. Secondary outcome included feasibility and recovery time. Patient safety was evaluated using surrogate outcomes.ResultsIn total, 201 procedures in 90 children aged 19 ± 8 months were completed. The median maximum pain was FLACC 0 in all groups (p = 0.141). The feasibility was better for groups K-6 (p = 0.049) and K-8 (p = 0.027) compared with K-4, and the mean recovery time was the longest for group K-8 (36 ± 22 min) compared with groups K-4 (25 ± 15 min; p = 0.003) and K-6 (27 ± 20 min; p = 0.025). Median maximum sedation measured by the University of Michigan Sedation Scale (UMSS) was higher in group K-8 compared with group K-4 (p < 0.0001) and K-6 (p = 0.023). One child in group K-8 had a study drug-related serious adverse event — laryngospasm/airway obstruction. No rescue analgosedative medication was administered for group K-6.ConclusionsA rectally administered mixture of racemic ketamine (6 mg/kg) and midazolam (0.5 mg/kg) during paediatric burn dressing procedures with a duration of approximately 30 min provides optimal conditions regarding pain relief, feasibility, recovery time and patient safety, with no need for rescue analgosedative medication.
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| 9. |
- Jagers, Sverker C., 1967, et al.
(författare)
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On the preconditions for large-scale collective action
- 2020
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Ingår i: Ambio. - : Springer Science and Business Media LLC. - 0044-7447 .- 1654-7209. ; 49:7, s. 1282-1296
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Tidskriftsartikel (refereegranskat)abstract
- The phenomenon of collective action and the origin of collective action problems have been extensively and systematically studied in the social sciences. Yet, while we have substantial knowledge about the factors promoting collective action at the local level, we know far less about how these insights travel to large-scale collective action problems. Such problems, however, are at the heart of humanity's most pressing challenges, including climate change, large-scale natural resource depletion, biodiversity loss, nuclear proliferation, antibiotic resistance due to overconsumption of antibiotics, and pollution. In this paper, we suggest an analytical framework that captures the theoretical understanding of preconditions for large-scale collective action. This analytical framework aims at supporting future empirical analyses of how to cope with and overcome larger-scale collective action problems. More specifically, we (i) define and describe the main characteristics of a large-scale collective action problem and (ii) explain why voluntary and, in particular, spontaneous large-scale collective action among individual actors becomes more improbable as the collective action problem becomes larger, thus demanding interventions by an external authority (a third party) for such action to be generated. Based on this, we (iii) outline an analytical framework that illustrates the connection between third-party interventions and large-scale collective action. We conclude by suggesting avenues for future research.
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| 10. |
- Karakaya, Sinan, et al.
(författare)
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Cytoplasmic HIF-2α as tissue biomarker to identify metastatic sympathetic paraganglioma
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors. PGLs can further be divided into sympathetic (sPGLs) and head-and-neck (HN-PGLs). There are virtually no treatment options, and no cure, for metastatic PCCs and PGLs (PPGLs). Here, we composed a tissue microarray (TMA) consisting of 149 PPGLs, reflecting clinical features, presenting as a useful resource. Mutations in the pseudohypoxic marker HIF-2 & alpha; correlate to an aggressive tumor phenotype. We show that HIF-2 & alpha; localized to the cytoplasm in PPGLs. This subcompartmentalized protein expression differed between tumor subtypes, and strongly correlated to proliferation. Half of all sPGLs were metastatic at time of diagnosis. Cytoplasmic HIF-2 & alpha; was strongly expressed in metastatic sPGLs and predicted poor outcome in this subgroup. We propose that higher cytoplasmic HIF-2 & alpha; expression could serve as a useful clinical marker to differentiate paragangliomas from pheochromocytomas, and may help predict outcome in sPGL patients.
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