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Sökning: WFRF:(Crona Joakim)

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  • Akerström, Tobias, et al. (författare)
  • Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter.
  • 2012
  • Ingår i: PloS one. - 1932-6203. ; 7:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.
  • Backman, Samuel, et al. (författare)
  • Detection of Somatic Mutations in Gastroenteropancreatic Neuroendocrine Tumors Using Targeted Deep Sequencing
  • 2017
  • Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 37:2, s. 705-712
  • Tidskriftsartikel (refereegranskat)abstract
    • Mutations affecting the mechanistic target of rapamycin (MTOR) signalling pathway are frequent in human cancer and have been identified in up to 15% of pancreatic neuroendocrine tumours (NETs). Grade A evidence supports the efficacy of MTOR inhibition with everolimus in pancreatic NETs. Although a significant proportion of patients experience disease stabilization, only a minority will show objective tumour responses. It has been proposed that genomic mutations resulting in activation of MTOR signalling could be used to predict sensitivity to everolimus.PATIENTS AND METHODS: Patients with NETs that underwent treatment with everolimus at our Institution were identified and those with available tumour tissue were selected for further analysis. Targeted next-generation sequencing (NGS) was used to re-sequence 22 genes that were selected on the basis of documented involvement in the MTOR signalling pathway or in the tumourigenesis of gastroenterpancreatic NETs. Radiological responses were documented using Response Evaluation Criteria in Solid Tumours.RESULTS: Six patients were identified, one had a partial response and four had stable disease. Sequencing of tumour tissue resulted in a median sequence depth of 667.1 (range=404-1301) with 1-fold coverage of 95.9-96.5% and 10-fold coverage of 87.6-92.2%. A total of 494 genetic variants were discovered, four of which were identified as pathogenic. All pathogenic variants were validated using Sanger sequencing and were found exclusively in menin 1 (MEN1) and death domain associated protein (DAXX) genes. No mutations in the MTOR pathway-related genes were observed.CONCLUSION: Targeted NGS is a feasible method with high diagnostic yield for genetic characterization of pancreatic NETs. A potential association between mutations in NETs and response to everolimus should be investigated by future studies.
  • Backman, Samuel, et al. (författare)
  • Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
  • 2017
  • Ingår i: Scientific Reports. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.
  • Backman, Samuel, et al. (författare)
  • Whole genome sequencing of apparently mutation-negative MEN1 patients
  • 2020
  • Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 182:1, s. 35-45
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.
  • Barbolosi, Dominique, et al. (författare)
  • Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma : Further step in understanding hereditary tumor differences and future therapeutic strategies.
  • 2018
  • Ingår i: PLOS ONE. - 1932-6203. ; 13:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Succinate dehydrogenase subunit B and D (SDHB and SDHD) mutations represent the most frequent cause of hereditary pheochromocytoma and paraganglioma (PPGL). Although truncation of the succinate dehydrogenase complex is thought to be the disease causing mechanism in both disorders, SDHB and SDHD patients exihibit different phenotypes. These phenotypic differences are currently unexplained by molecular genetics. The aim of this study is to compare disease dynamics in these two conditions via a Markov chain model based on 4 clinically-defined steady states. Our model corroborates at the population level phenotypic observations in SDHB and SDHD carriers and suggests potential explanations associated with the probabilities of disease maintenance and regression. In SDHB-related syndrome, PPGL maintenance seems to be reduced compared to SDHD (p = 0.04 vs 0.95) due to higher probability of tumor cell regression in SDHB vs SDHD (p = 0.87 vs 0.00). However, when SDHB-tumors give rise to metastases, metastatic cells are able to thrive with decreased probability of regression compared with SDHD counterparts (p = 0.17 vs 0.89). By constrast, almost all SDHD patients develop PGL (mainly head and neck) that persist throughout their lifetime. However, compared to SDHB, maintenance of metastatic lesions seems to be less effective for SDHD (p = 0.83 vs 0.11). These findings align with data suggesting that SDHD-related PPGL require less genetic events for tumor initiation and maintenance compared to those related to SDHB, but fail to initiate biology that promotes metastatic spread and metastatic cell survival in host tissues. By contrast, the higher number of genetic abnormalities required for tumor initiation and maintenance in SDHB PPGL result in a lower penetrance of PGL, but when cells give rise to metastases they are assumed to be better adapted to sustain survival. These proposed differences in disease progression dynamics between SDHB and SDHD diseases provide new cues for future exploration of SDHx PPGL behavior, offering considerations for future specific therapeutic and prevention strategies.
  • Björklund, Peyman, et al. (författare)
  • Precision medicine in pheochromocytoma and paraganglioma : current and future concepts
  • 2016
  • Ingår i: Journal of Internal Medicine. - 0954-6820 .- 1365-2796. ; 286:6, s. 559-573
  • Tidskriftsartikel (refereegranskat)abstract
    • Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.
  • Botling, Johan, et al. (författare)
  • High-grade progression confers poor survival in pancreatic neuroendocrine tumors
  • 2020
  • Ingår i: Neuroendocrinology. - 0028-3835 .- 1423-0194. ; 110:11-12, s. 891-898
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: Little is known about how Pancreatic Neuroendocrine Tumors (PanNETs) evolve over time and if changes towards a more aggressive biology correlates with prognosis. The purpose of this study was to characterize changes PanNET differentiation and proliferation over time, and to correlate findings to overall survival (OS).PATIENTS AND METHODS: In this retrospective cohort study we screened 475 PanNET patients treated at Uppsala University Hospital, Sweden. Sporadic patients with baseline and follow-up tumor samples were included. Pathology reports and available tissue sections were re-evaluated with regard to tumor histopathology and Ki-67 index.RESULTS: Forty-six patients with 106 tumor samples (56 available for pathology re-evaluation) were included. Median Ki-67 index at diagnosis was 7% (range 1-38%), grade 1 n=8, grade 2 n=36, and grade 3 n=2. The median change in Ki-67 index (absolute value; follow-up - baseline) was +14% (range -11 to +80%). Increase in tumor grade occurred in 28 patients (63.6%), the majority from grade 1/2 to grade 3 (n=24, 54.5%). The patients with a high-grade progression had a median OS of 50.2 months compared to 115.1 months in patients without such progression (HR 3.89, 95% CI 1.91-7.94, P<0.001).CONCLUSIONS: A longitudinal increase in Ki-67 index and increase in tumor grade were observed in a majority of PanNETs included in this study. We propose that increase in Ki-67 index and high-grade progression should be investigated further as important biomarkers in PanNET.
  • Crona, Joakim, et al. (författare)
  • Adrenocortical carcinoma : towards genomics guided clinical care
  • 2019
  • Ingår i: Nature Reviews Endocrinology. - 1759-5029 .- 1759-5037. ; 15:9, s. 548-560
  • Forskningsöversikt (refereegranskat)abstract
    • Adrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates in the cortex of the adrenal gland. The disease is associated with heterogeneous but mostly poor outcomes and lacks effective pharmaceutical treatment options. Multi-omics studies have defined the landscape of molecular alterations in ACC. Specific molecular signatures can be detected in body fluids, potentially enabling improved diagnostic applications for patients with adrenal tumours. Importantly, pan-molecular data sets further reveal a spectrum within ACC, with three major subgroups that have different disease outcomes. These new subgroups have value as prognostic biomarkers. Research has revealed that the p53-RB and the WNT-beta-catenin pathways are common disease drivers in ACC. However, these pathways remain difficult to target by therapeutic interventions. Instead, a unique characteristic of ACC is steroidogenic differentiation, which has emerged as a potential treatment target, with several agents undergoing preclinical or clinical investigations. Finally, a large proportion of ACC tumours have genetic profiles that are associated with promising therapeutic responsiveness in other cancers. All these opportunities now await translation from the laboratory into the clinical setting, thereby offering a real potential of improved survival outcomes and increased quality of life for patients with this serious condition.
  • Crona, Joakim, et al. (författare)
  • Advances in adrenal tumors 2018
  • 2018
  • Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 25:7, s. R405-R420
  • Forskningsöversikt (refereegranskat)abstract
    • This review aims to provide clinicians and researchers with a condensed update on the most important studies in the field during 2017. We present the academic output measured by active clinical trials and peer-reviewed published manuscripts. The most important and contributory manuscripts were summarized for each diagnostic entity, with a particular focus on manuscripts that describe translational research that have the potential to improve clinical care. Finally, we highlight the importance of collaborations in adrenal tumor research, which allowed for these recent advances and provide structures for future success in this scientific field.
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