Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Positron emission tomography (PET), together with suitable biomarkers, can aid in the clin-ical evaluation as well as in research investigations of these diseases. Straightforward and quantitative assessments of the parameters of inter-est estimated on a voxel-level, as parametric images, are possible when PET data is acquired over time. Prerequisites to facilitate clinical use of dynamic PET are simplified analysis methods and scan protocols suita-ble for clinical routine. The aim of this thesis was to validate simplified analysis methods, suitable for clinical use, for quantification of dopamine transporter (DAT) availability in patients with parkinsonism using [11C]PE2I PET and tau accumulation in AD patients with [18F]THK5317 PET. The included subjects comprised of both healthy controls and pa-tients with parkinsonism, AD or mild cognitive impairment and each subject underwent a dynamic PET scan with either [11C]PE2I or [18F]THK5317. Models for quantitative voxel-based analysis, resulting in parametric images of tracer binding and overall brain function, were validated in both patients and controls. These parametric methods were compared to region-based values acquired using both plasma- and refer-ence-input models. Clinically feasible scan durations were evaluated for both [11C]PE2I and [18F]THK5317, and a clustering method to obtain a reference time activity curve directly from the dynamic PET data was validated. Furthermore, images of DAT availability and overall brain functional activity, generated from one single dynamic [11C]PE2I PET scan, were compared to a dual-scan approach using [123I]FP-CIT single photon emission computed tomography (SPECT) and [18F]FDG PET, for differential diagnosis of patient with parkinsonism. Study I-III supply valuable information on the feasibility of dynamic [11C]PE2I in a clinical setting for differential diagnosis of parkinsonian disorders, by having easily accessible images of DAT availability and overall brain functional activity. The work in study IV-V showed that reference methods can be used for quantification of tau accumulation, and suggests that simplified analysis methods and shorter scan durations can be applied to further facilitate applications of dynamic [18F]THK5317 PET

Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Positron emission tomography (PET), together with suitable biomarkers, can aid in the clin-ical evaluation as well as in research investigations of these diseases. Straightforward and quantitative assessments of the parameters of inter-est estimated on a voxel-level, as parametric images, are possible when PET data is acquired over time. Prerequisites to facilitate clinical use of dynamic PET are simplified analysis methods and scan protocols suita-ble for clinical routine. The aim of this thesis was to validate simplified analysis methods, suitable for clinical use, for quantification of dopamine transporter (DAT) availability in patients with parkinsonism using [11C]PE2I PET and tau accumulation in AD patients with [18F]THK5317 PET. The included subjects comprised of both healthy controls and pa-tients with parkinsonism, AD or mild cognitive impairment and each subject underwent a dynamic PET scan with either [11C]PE2I or [18F]THK5317. Models for quantitative voxel-based analysis, resulting in parametric images of tracer binding and overall brain function, were validated in both patients and controls. These parametric methods were compared to region-based values acquired using both plasma- and refer-ence-input models. Clinically feasible scan durations were evaluated for both [11C]PE2I and [18F]THK5317, and a clustering method to obtain a reference time activity curve directly from the dynamic PET data was validated. Furthermore, images of DAT availability and overall brain functional activity, generated from one single dynamic [11C]PE2I PET scan, were compared to a dual-scan approach using [123I]FP-CIT single photon emission computed tomography (SPECT) and [18F]FDG PET, for differential diagnosis of patient with parkinsonism. Study I-III supply valuable information on the feasibility of dynamic [11C]PE2I in a clinical setting for differential diagnosis of parkinsonian disorders, by having easily accessible images of DAT availability and overall brain functional activity. The work in study IV-V showed that reference methods can be used for quantification of tau accumulation, and suggests that simplified analysis methods and shorter scan durations can be applied to further facilitate applications of dynamic [18F]THK5317 PET

Blood Flow Modeling of H215O PET Studies in Liver Metastases

Positron Emission Tomography, PET, is a noninvasive medical imaging technique to get functional information of the kinetics of radioactive compound injected in the body. The data used in this thesis comes from a total of five H215O PET studies of one patient. This was done in order to study the blood flow in liver metastasis of the patient, before and after treatment. A one compartment model was used to do the ROI based analyses. With a least square method in Matlab the unknown parameters in the model, such as the kinetic rate constants, the dispersion and the fraction of blood in the tissue, was extracted. Also a brief analysis of different parts of the metastases, edge and center, was done to see the variations within the metastases. The results show some increase of the blood flow after the treatment, and two of the three studied metastases showed a distinct difference of the activity in the center versus the edge. Given in the thesis are also some basic PET and compartmental modeling theory.Positronemissionstomografi, PET, är en icke-invasiv medicinsk bildteknik för att få funktionell information om kinetiken av radioaktiva föreningar injicerade i kroppen. Det data som används i denna kandidatuppsats kommer från totalt fem H215O PET-studier av en patient. Detta gjordes för att studera blodflödet i levermetastaser hos patienten före och efter behandling. En 1-kompartmentmodell användes för att göra ROI-baserade analyser. Med en minsta kvadrat-metod i Matlab kunde de okända parametrarna i modellen, såsom den kinetiska hastighetskonstanten, spridningen och andelen blod i vävnaden, fås ut. En kort analys gjordes också av olika delar av metastaserna, kanten och mitten, för att se variationerna inuti metastaserna. Resultaten visar en viss ökning av blodflödet efter behandlingen, och två av de tre studerade metastaser visade en tydlig skillnad av aktiviteten i mitten jämfört med kanten. I rapporten ges också grundläggande teori om bland annat PET och kompartmentmodellering

Blood Flow Modeling of H215O PET Studies in Liver Metastases

Positron Emission Tomography, PET, is a noninvasive medical imaging technique to get functional information of the kinetics of radioactive compound injected in the body. The data used in this thesis comes from a total of five H215O PET studies of one patient. This was done in order to study the blood flow in liver metastasis of the patient, before and after treatment. A one compartment model was used to do the ROI based analyses. With a least square method in Matlab the unknown parameters in the model, such as the kinetic rate constants, the dispersion and the fraction of blood in the tissue, was extracted. Also a brief analysis of different parts of the metastases, edge and center, was done to see the variations within the metastases. The results show some increase of the blood flow after the treatment, and two of the three studied metastases showed a distinct difference of the activity in the center versus the edge. Given in the thesis are also some basic PET and compartmental modeling theory.Positronemissionstomografi, PET, är en icke-invasiv medicinsk bildteknik för att få funktionell information om kinetiken av radioaktiva föreningar injicerade i kroppen. Det data som används i denna kandidatuppsats kommer från totalt fem H215O PET-studier av en patient. Detta gjordes för att studera blodflödet i levermetastaser hos patienten före och efter behandling. En 1-kompartmentmodell användes för att göra ROI-baserade analyser. Med en minsta kvadrat-metod i Matlab kunde de okända parametrarna i modellen, såsom den kinetiska hastighetskonstanten, spridningen och andelen blod i vävnaden, fås ut. En kort analys gjordes också av olika delar av metastaserna, kanten och mitten, för att se variationerna inuti metastaserna. Resultaten visar en viss ökning av blodflödet efter behandlingen, och två av de tre studerade metastaser visade en tydlig skillnad av aktiviteten i mitten jämfört med kanten. I rapporten ges också grundläggande teori om bland annat PET och kompartmentmodellering

Towards Clinical Implementation of Dynamic Positron Emission Tomography in Neurodegenerative Diseases

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative disorders worldwide. Positron emission tomography (PET), together with suitable biomarkers, can aid in the clin-ical evaluation as well as in research investigations of these diseases. Straightforward and quantitative assessments of the parameters of inter-est estimated on a voxel-level, as parametric images, are possible when PET data is acquired over time. Prerequisites to facilitate clinical use of dynamic PET are simplified analysis methods and scan protocols suita-ble for clinical routine. The aim of this thesis was to validate simplified analysis methods, suitable for clinical use, for quantification of dopamine transporter (DAT) availability in patients with parkinsonism using [11C]PE2I PET and tau accumulation in AD patients with [18F]THK5317 PET. The included subjects comprised of both healthy controls and pa-tients with parkinsonism, AD or mild cognitive impairment and each subject underwent a dynamic PET scan with either [11C]PE2I or [18F]THK5317. Models for quantitative voxel-based analysis, resulting in parametric images of tracer binding and overall brain function, were validated in both patients and controls. These parametric methods were compared to region-based values acquired using both plasma- and refer-ence-input models. Clinically feasible scan durations were evaluated for both [11C]PE2I and [18F]THK5317, and a clustering method to obtain a reference time activity curve directly from the dynamic PET data was validated. Furthermore, images of DAT availability and overall brain functional activity, generated from one single dynamic [11C]PE2I PET scan, were compared to a dual-scan approach using [123I]FP-CIT single photon emission computed tomography (SPECT) and [18F]FDG PET, for differential diagnosis of patient with parkinsonism. Study I-III supply valuable information on the feasibility of dynamic [11C]PE2I in a clinical setting for differential diagnosis of parkinsonian disorders, by having easily accessible images of DAT availability and overall brain functional activity. The work in study IV-V showed that reference methods can be used for quantification of tau accumulation, and suggests that simplified analysis methods and shorter scan durations can be applied to further facilitate applications of dynamic [18F]THK5317 PET

Blood Flow Modeling of H215O PET Studies in Liver Metastases

Positron Emission Tomography, PET, is a noninvasive medical imaging technique to get functional information of the kinetics of radioactive compound injected in the body. The data used in this thesis comes from a total of five H215O PET studies of one patient. This was done in order to study the blood flow in liver metastasis of the patient, before and after treatment. A one compartment model was used to do the ROI based analyses. With a least square method in Matlab the unknown parameters in the model, such as the kinetic rate constants, the dispersion and the fraction of blood in the tissue, was extracted. Also a brief analysis of different parts of the metastases, edge and center, was done to see the variations within the metastases. The results show some increase of the blood flow after the treatment, and two of the three studied metastases showed a distinct difference of the activity in the center versus the edge. Given in the thesis are also some basic PET and compartmental modeling theory.Positronemissionstomografi, PET, är en icke-invasiv medicinsk bildteknik för att få funktionell information om kinetiken av radioaktiva föreningar injicerade i kroppen. Det data som används i denna kandidatuppsats kommer från totalt fem H215O PET-studier av en patient. Detta gjordes för att studera blodflödet i levermetastaser hos patienten före och efter behandling. En 1-kompartmentmodell användes för att göra ROI-baserade analyser. Med en minsta kvadrat-metod i Matlab kunde de okända parametrarna i modellen, såsom den kinetiska hastighetskonstanten, spridningen och andelen blod i vävnaden, fås ut. En kort analys gjordes också av olika delar av metastaserna, kanten och mitten, för att se variationerna inuti metastaserna. Resultaten visar en viss ökning av blodflödet efter behandlingen, och två av de tre studerade metastaser visade en tydlig skillnad av aktiviteten i mitten jämfört med kanten. I rapporten ges också grundläggande teori om bland annat PET och kompartmentmodellering

Styrning i organisationer och dess samband med etiskt resonemang -En empirisk studie av bankpersonal

Bakgrund och problem: Banker har en särställning i den finansiella ekonomin och konsekvenser av de anställdas handlande kan ge stora effekter. Då banker är tjänsteföretag ställs de inför problemet att deras personal kan välja att agera efter eget huvud vilket inte behöver vara förenligt med bankens etiska intentioner och strävan efter att upprätthålla ett högt förtroende. Det är således viktigt hur ledningen utformar sina styrsystem med avseende på det etiska resonemang som råder. Följande frågeställningar identifierades: Vilket styrsystem är mest lämpat utifrån det rådande etiska resonemanget hos bankpersonalen? Hur kan styrsystem anpassas för att påverka det etiska resonemanget hos bankpersonalen? Syfte: Att undersöka bankpersonals etiska resonemang och utröna vilket styrsystem det är mest samstämmigt med. Uppsatsen ämnade även undersöka huruvida det etiska resonemanget kan främjas beroende på vilket styrsystem som väljs. Metod: En kvantitativ metod har använts då primärdata samlats in från respondenter med hjälp av enkäter. Enkäterna bestod av tre dilemman från Defining Issues Test och svaren från dessa gav svar på vilken nivå av etiskt resonemang respondenterna befann sig. Vidare kompletterades enkäterna med frågor om respondenternas kön och utbildning. Förutom primärdata har sekundärdata samlats in i från böcker och artiklar som dels behandlar etiskt resonemang, dels ekonomistyrning. Resultat och slutsatser: Resultaten visade att majoriteten av respondenterna befann sig på den konventionella nivån av etiskt resonemang. Författarna drog slutsatsen att handlingsstyrning är den typ av styrning som bankerna bör använda om utgångspunkten ligger på den rådande etiska nivån hos respondenterna. Om bankerna önskar höja det etiska resonemanget kan dock inte handlingsstyrning tillämpas då denna typ av styrning kommer att hämma utvecklingen. I detta fall är i stället social styrning att föredra. Således råder det en diskrepans mellan det mest lämpade styrsystemet för det rådande etiska resonemanget och det mest lämpade för att öka det. Förslag till vidare forskning: För att kunna dra generella slutsatser kring svensk bankpersonals etiska resonemang krävs fler studier med större stickprov. Studier kan även utformas för att undersöka eventuella skillnader mellan olika banker . Dessutom skulle ytterligare forskning kunna lägga vikt vid hur styrningen inom bankerna ser ut, genom till exempel en kvalitativ studie. Ytterligare en aspekt som skulle vara intressant att undersöka är hur de etiska policydokument som bankerna upprättat efterlevs i förhållande till det etiska resonemanget. Även en longitudinell studie som undersöker det etiska resonemanget hos bankpersonal över tid anser författarna vore intressant

Optimal timing of tau pathology imaging and automatic extraction of a reference region using dynamic [18F]THK5317 PET

[F-18]THK5317 is a PET tracer for in-vivo imaging of tau associated with Alzheimer's disease (AD). This work aimed to evaluate optimal timing for standardized uptake value ratio (SUVR) measures with [F-18]THK5317 and automated generation of SUVR-1 and relative cerebral blood flow (R-1) parametric images. Nine AD patients and nine controls underwent 90 min [F-18]THK5317 scans. SUVR-1 was calculated at transient equilibrium (TE) and for seven different 20 min intervals and compared with distribution volume ratio (DVR; reference Logan). Cerebellar grey matter (MRI) was used as reference region. A supervised cluster analysis (SVCA) method was implemented to automatically generate a reference region, directly from the dynamic PET volume without the need of a structural MRI scan, for computation of SUVR-1 and R-1 images for a scan duration matching the optimal timing. TE was reached first in putamen, frontal- and parietal cortex at 22 +/- 4 min for AD patients and in putamen at 20 +/- 0 min in controls. Over all regions and subjects, SUVR20-40-1 correlated best with DVR-1, R-2 = 0.97. High correlation was found between values generated using MRI- and SVCA-based reference (R-2 = 0.93 for SUVR20-40-1; R-2 = 0.94 for R-1). SUVR20-40 allows for accurate semi-quantitative assessment of tau pathology and SVCA may be used to obtain a reference region for calculation of both SUVR-1 and R-1 with 40 min scan duration