Introduction: Forensic Fail

Background: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results. Aim: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours. Methods: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray. Results: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/ EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases. Conclusion: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients

Restaurering av kransalgsängar - test av metodik med borststräfse (Chara aspera) och rödsträfse (C. tomentosa)

Trenden med ökat behov av muddring (och även dumpning av muddermassor) kommer sannolikt att fortsätta, eftersom fritidsbåtstrafiken ökar och landhöjningen fortsätter i den nordliga delen av Sverige. De negativa effekterna av muddring och dumpning av muddermassor är speciellt tydliga i grunda skärgårdsmiljöer. Kransalger är särskilt känsliga mot muddring och dumpning eftersom de är känsliga för fysisk påverkan och förändringar i ljustillgänglighet. I dessa grunda skärgårdsmiljöer utför kransalger flera viktiga ekosystemtjänster, såsom stabilisering av sediment, förhindring av grumling, förbättrad vattenkvalitet och upptag och lagring av näring i sedimentet. De har också en viktig funktion som fiskuppväxtområden, habitat samt föda för evertebrater och som födosöksområden för fågel och fisk. De är även lämpliga indikatorarter då de är känsliga mot övergödning, fysisk störning och förändringar i vågexponeringsgrad. I denna rapport utvärderar vi två återplanteringsförsök av kransalger, arterna borststräfse (Chara aspera) och rödsträfse (C. tomentosa), i områden som utsatts för muddring och dumpning i Siviksfjärden i Gävleborgs län. Detta är det första dokumenterade försöket med återplantering av kransalger i Östersjön. Tre olika metoder för återplantering av C. aspera har testats: flytt av plantor med spade, att fästa skott med juteband och att använda en struktur gjord av nedbrytningsbara polymerer av potatisstärkelse (BESEelements©) för att förankra plantorna. Plantering med spade var den billigaste och snabbaste metoden, medan plantering med BESEelements© var dubbelt så tidskrävande och därmed relativ dyrt per kvadratmeter. Ingen metod lyckades bättre än den naturliga återkoloniseringen av dumpningsvallen, som återkoloniserades till ungefär hälften av den befintliga C. aspera äng täckningsgraden på tre år. För C. tomentosa testade vi endast plantering med BESEelements©, som ej var lyckat. Det skulle i framtida försök vara värdefullt att försöka plantera C. tomentosa med andra metodiker, till exempel med spade. Med beaktande av de positiva ekosystemtjänsterna och habitatbildande egenskaperna som är kopplade till friska kransalgsängar samt det faktum att det är både svårt och dyrt att återetablera dem bör vi iaktta ett stort ansvar att skydda dessa miljöer i Östersjön för att säkerställa framtida ekosystemfunktioner i grunda vågskyddade områden

Surface modification of pig endothelial cells with a branched heparin conjugate improves their compatibility with human blood

Corline Heparin Conjugate (CHC), a compound of multiple unfractionated heparin chains, coats cells with a glycocalyx-like layer and may inhibit (xeno) transplant-associated activation of the plasma cascade systems. Here, we investigated the use of CHC to protect WT and genetically modified (GTKO. hCD46. hTBM) pig aortic endothelial cells (PAEC) in two pig-to-human in vitro xenotransplantation settings. Model 1: incubation of untreated or hTNFa-treated PAEC with 10% human plasma induced complement C3b/c and C5b-9 deposition, cellular activation and coagulation activation in WT and GTKO. hCD46. hTBM PAEC. Coating of untreated or hTNFa-treated PAEC with CHC (100 mu g/ml) protected against human plasma-induced endothelial activation and damage. Model 2: PAEC were grown on microcarrier beads, coated with CHC, and incubated with non-anticoagulated whole human blood. Genetically modified PAEC significantly prolonged clotting time of human blood (115.0 +/- 16.1 min, p < 0.001) compared to WT PAEC (34.0 +/- 8.2 min). Surface CHC significantly improved the human blood compatibility of PAEC, as shown by increased clotting time (WT: 84.3 +/- 11.3 min, p < 0.001;GTKO. hCD46. hTBM: 146.2 +/- 20.4 min, p < 0.05) and reduced platelet adhesion, complement activation, coagulation activation and inhibition of fibrinolysis. The combination of CHC coating and genetic modification provided the greatest compatibility with human blood, suggesting that pre-transplant perfusion of genetically modified porcine organs with CHC may benefit post-transplant xenograft function

New prostate cancer grade grouping system predicts survival after radical prostatectomy

Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively. Patients' all-cause and prostate cancer specific mortality information was updated in November 2015 from the Finnish Cancer Registry. Secondary therapy information was also available from the patients' records at Helsinki. Univariate and multivariate statistical analyses were performed to assess predictive significance of the Grade Grouping system. Grade Grouping associated independently with increased risk of prostate cancer specific mortality within 15 years of follow-up in a multivariable model containing age at operation, diagnostic prostate-specific antigen, pathological stage and lymph node status at operation. Additionally, the all-cause mortality-free survival time and time to secondary therapies were different between the Grade Groups, emphasized in the subanalysis of Grade Groups 1-2 versus Grade Groups 3-5. We can conclude that the new Grade Grouping system is feasible in predicting prostate cancer specific survival after radical surgical treatment. Grade Grouping offers a simpler way to interpret the predicted course of the disease to individual patients and thus may help in justifying more conservative follow-up approaches, especially in the lower Grade Group patients. (C) 2018 The Authors. Published by Elsevier Inc.Peer reviewe

Network modeling of the transcriptional effects of copy number aberrations in glioblastoma

DNA copy number aberrations (CNAs) are a characteristic feature of cancer genomes. In this work, Rebecka Jörnsten, Sven Nelander and colleagues combine network modeling and experimental methods to analyze the systems-level effects of CNAs in glioblastoma

New prostate cancer grade grouping system predicts survival after radical prostatectomy

Histological Gleason grading of prostate cancer has been through modifications and conjoined into a Grade Grouping system recently. The aim of this study was to determine whether the new Grade Grouping system predicts disease-specific and all-cause mortality after radical prostatectomy. We constructed a clinical database consisting of all consecutively radical prostatectomy–treated men between 1983 and 1998 and between 2000 and 2005 at the Helsinki University Hospital and at the Turku University Hospital, respectively. Patients' all-cause and prostate cancer–specific mortality information was updated in November 2015 from the Finnish Cancer Registry. Secondary therapy information was also available from the patients' records at Helsinki. Univariate and multivariate statistical analyses were performed to assess predictive significance of the Grade Grouping system. Grade Grouping associated independently with increased risk of prostate cancer–specific mortality within 15 years of follow-up in a multivariable model containing age at operation, diagnostic prostate-specific antigen, pathological stage and lymph node status at operation. Additionally, the all-cause mortality-free survival time and time to secondary therapies were different between the Grade Groups, emphasized in the subanalysis of Grade Groups 1-2 versus Grade Groups 3-5. We can conclude that the new Grade Grouping system is feasible in predicting prostate cancer–specific survival after radical surgical treatment. Grade Grouping offers a simpler way to interpret the predicted course of the disease to individual patients and thus may help in justifying more conservative follow-up approaches, especially in the lower Grade Group patients.</p

A 150-Year Perspective on Swedish Capital Income Taxation

This paper describes the evolution of capital income taxation, including corporate, dividend, interest, capital gains and wealth taxation, in Sweden between 1862 and 2010. To illustrate the evolution, we present annual time-series data on the marginal effective tax rates on capital income (METR) for a marginal investment financed with new share issues, retained earnings or debt. Tax tables covering the period are presented. These data are unique in their consistency, thoroughness and time span covered. The METR is low, is stable and does not exceed five percent until World War I, when it starts to drift somewhat upward and vary depending on the source of finance. The outbreak of World War II starts a period when the magnitude and variation of the METR sharply increases. The METR peaks during the 1970s and 1980s and often exceeds 100 percent. The 1990-1991 tax reform and lower inflation reduce the magnitude and variation of the METR. The METR varies between 15 and 40 percent at the end of the examined period

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat