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Background: Targeted therapy with tyrosine kinases inhibitors (TKIs) against epidermal growth factor receptor (EGFR) is part of routine clinical practice for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. These patients eventually develop resistance, frequently accompanied by a gatekeeper mutation, T790M. Osimertinib is a third-generation EGFR TKI displaying potency to the T790M resistance mutation. Here we aimed to analyze if exosomal RNAs, isolated from longitudinally sampled plasma of osimertinib-treated EGFR T790M NSCLC patients, could provide biomarkers of acquired resistance to osimertinib. Methods: Plasma was collected at baseline and progression of disease from 20 patients treated with osimertinib in the multicenter phase II study TKI in Relapsed EGFR-mutated non-small cell lung cancer patients (TREM). Plasma was centrifuged at 16,000 g followed by exosomal RNA extraction using Qiagen exoRNeasy kit. RNA was subjected to transcriptomics analysis with Clariom D. Results: Transcriptome profiling revealed differential expression [log2(fold-change) >0.25, false discovery rate (FDR) P0.05] of 128 transcripts. We applied network enrichment analysis (NEA) at the pathway level in a large collection of functional gene sets. This overall enrichment analysis revealed alterations in pathways related to EGFR and PI3K as well as to syndecan and glypican pathways (NEA FDR 0.05 and NEA z-score exceeding 3 in at least one sample). Conclusions: Our study demonstrates a potential usability of plasma-derived exosomal RNAs to characterize molecular phenotypes of emerging osimertinib resistance. Furthermore, it highlights the involvement of multiple RNA species in shaping the transcriptome landscape of osimertinib-refractory NSCLC patients.

Recensionen tar fasta på utvecklingen inom det högmedeltida Lübecks högre strata som föregångare och förebild i formeringen av ett svenskt borgerskap under senmedeltid. Den recenserade avhandlingen är författad på tyska.

Denna artikel redovisar några digitala experiment inom ett ekonomisk-historiskt medeltidsprojekt. Detta är inriktat på metodutveckling via studier av den svenska medeltida staten (kronan), ett föga väl definierat begrepp vars karaktäristika vårt projekt avser att modifiera. I fokus här ställs värdet av omsorgsfullt utarbetade index. Mer precist handlar det om personregister som urskiljer exakt vilka individer som uppträder i källorna. I digitaliserad form antas att dylika kan effektivisera våra studier även när källmaterialet är såväl sparsamt till omfånget som fragmentariskt till karaktären. Det valda typfallet utgör de svenska breven 1356–1360. Dessa tillkom parallellt med såväl en demografiska kris i Digerdödens kölvatten som en djup politisk kris. En tudelning av regeringsmakten skedde i det svenska riket med inbördeskrig som följd 1356–1359. Lennart Sjöstedt (1954) har noga avhandlat dessa strider. En kvalificerad och strävsam forskarinsats av nordisten Per-Axel Wiktorsson har senare (1972) renderat oss ett synnerligen informationsrikt personindex över breven från perioden 1356–1360, vilket undertecknad digitaliserat och uppdaterat. I förgrunden står denna fråga: Hur kan detta personindex via test av hypoteser något vidga gränserna för vår kunskap om den svenska medeltida statens karaktäristika?

I denna uppsats undersöks priserna på fastigheter i Stockholm och Arboga 1300–1600. Fast egendom var den viktigaste materiella resursen i det förindustriella samhället, har trots det prisutvecklingen på fastigheter tidigare inte studerats systematiskt för någon svensk stad. Stockholm och Arboga är de städer som lämpar sig bäst för en sådan undersökning, eftersom ett rikt källmaterial i form av jordeböcker och tänkeböcker har bevarats från dem. Dessa källor registrerar priser på och värderingar av olika slag av fastigheter som gjorts i samband med köp och försäljningar. Omkring 3 000 prisnoteringar ligger till grund för uppsatsen. Här visas bland annat att priserna i Stockholm sjönk svagt på lång sikt och att nedgången var kraftigare i samband med pestepidemier. Houses, yards and sheds: Real property prices in Stockholm and Arboga, 1300-1600 The article explores real property prices in Swedish trading towns 1297-1600 based on c. 2900 transactions in Stockholm and the smaller town of Arboga. A consumer price index has been used to deflate nominal prices into real values. The analysis shows that houses made of both stone and wood became cheaper over time. In Isoo prices, the median price of a stone house in Stockholm was 343 Swedish marks in the period 1297-1449 compared to 184 marks in the period 1550-1600. For wooden houses the same downward trend was evident: a drop from 84 marks in the first period to 52 marks in the second period. Part of the price decline is due to the fact that building plots became smaller, which suggests an increase in population in Stockholm. Declining real wages of labourers also exerted a downward pressure on the cost of building a house. The slightly negative long-term trend in real property prices in Stockholm and Arboga, amounting to -0.3 and -0.1 percent per year, respectively, diverges from the strong decline in land prices in Eastern Sweden. This is an indication that the towns were less affected by the late medieval crisis than rural areas were. Plague outbreaks are shown to have affected real property prices in Stockholm, where prices fell during plague years, but quickly recovered afterwards. This pattern can be taken as an indication that real property prices were market prices that reacted to external shocks. The analysis also reports tentative results of real property prices as an indicator of economic inequality. The Gini coefficient for Stockholm varied between 0.55 in the period 1297-1449 to o.58 in the period 1450-1499. This is about the same level of inequality that has been calculated for Amsterdam in the mid-sixteenth century. The Gini coefficient for Arboga was also very similar to that of the Dutch towns taken as a whole. There is no clear trend in inequality over time in either Stockholm or Arboga. Finally, the article discusses trends in female ownership of real property by investigating if the position of women in the real property market deteriorated during the period of study. Female sellers of property amounted to nearly zo percent in Stockholm and Arboga, with no discernable time trend. Female property buyers were fewer, amounting to between three and six percent out of the total before 1500 and a somewhat higher percentage share in the sixteenth century. Välfärdens förhistoria: levnadsstandard, kris och skattetryck 1300–1600

Snart 20 år efter införandet av euron står det klart att den gemensamma valutan medför ­uppenbara risker för välfärden i deltagarländerna. I sin nya bok varnar den amerikanske Nobelpristagaren Joseph Stiglitz för följderna om inte EU snart hittar en mer hållbar lösning på sin ekonomiska politik.

Föreliggande uppsats analyserar framväxten av ett formellt penningväsende i Sverige 995–1525. Ett av de tidigaste tecknen på monetarisering inträffade under andra halvan av 1200-talet och innebar att betalningar i bevarade källor huvudsakligen anges i mynt som räknats i stället för att vägas. Skillnaden mellan ett mynts nominella värde och dess värde som silver utgjordes av slagskatt. Myntförsämringen under 1300- och 1400-talen motverkades av att silvrets köpkraft ökade kraftigt. Välfärdens förhistoria

The article is inspired by an idea from Eli Heckscher that the Viking Age in Sweden was followed by a long period of economic decline. That sugestion looks plausible when studing monetary conditions 800-1200. Välfärdens förhistoria / Levnadsstandard, kris och skattetryck 1300-1600

This essay scrutinizes Swedish legislation 1220-1360 from an institutional economic point of view inspired inter alia by Douglass C. North. Several books of law for different counties (sw. landskapslagar), as well as other kind of legislation, were worked out during the period and it was claimed that they were drafted to meet a changing society. My conclusion is that the real purpose was the opposite, i.e. that the upper strata tried to change society through legislation. In general were economic institutions hostile to a free exchange in favour of several compulsory institutions as slavery and serfdom, with the remarkable exception of the Town Law (sw. Stadslagen) in the 1350's that points in a modernizing direction. I've also come to the conclusion that the famous Swedish mining sector (sw. bergsbruket) came into being in spite of the ruling aristocratic classes. Much more was it a creation of gentile men and women witch in the fifteenth century contributed to the formation of two new estates in the Swedish parliament, burghers and peasants. Järnet och riksbildningen

Denna recension av två illustrerade numismatiska arbeten är penningteoretiskt och ekonomisk-historiskt inriktad. De två vetenskapliga verken bygger i huvudsak på numismatisk forskning. Enkelt uttryckt fördjupar de den tidigare bilden av ett i Väst-Europas utkant arkaiskt Sverige i ekonomiskt bakvatten 995-1290. Det gäller även vid vid en jämförelse med det samtida Norge och Danmark - två riken vars monetära system dessa intressanta arbeten också uppehåller sig vid. Granskade arbeten är:Brita Malmers Den svenska mynthistorien / Vikingatiden ca 995–1030, Kungl Myntkabinettet & Svenska Numismatiska Föreningen, 2010, 348 sidor, ISBN 978-91-633571-6-9.Roger Svenssons Renovatio Monetae / Brakteater och myntningspolitik i högmedeltidens Europa, Svenska Numismatiska Föreningen, 2012, 320 sidor, ISBN 978-91- 979427-1-3. Järnet och riksbildningen Välfärdens förhistoria

In Medieval Sweden, we find that archaic compulsory institutions, such as slavery and serfdom, were not abolished until the middle of the fourteenth century. They, as well as other customs and rules, were a detriment to the development of more numerous and extensive markets. In spite of these signs of economic backwardness, we have good reason to believe that the trends, in the loose federation of provinces that preceded the Swedish nation-state, were in the direction of a greater degree of freedom and increased exchange of free will (i.e. labour and real property markets). The purpose of this study is to examine the Swedish charters by quantitative means, to see how these trends are mirrored by the representation of trading towns versus rural areas, and the percentage of the names of women that appear as first issuer of these charters. Other variables are also applied, e.g. geographical and prosopographic variables. A database (SDhk) published by the National Archives of Sweden contains summaries of more than 39,000 charters from, or attached to, Medieval Sweden, which have been converted into a so called relational database. The above mentioned trends generally point upwards. More and more charters were being drawn up in towns until the middle of the fourteenth century, ending with an average urban representation of more than 50%. Generally, the urbanization of early Swedish society seems to have been at its highest point in the last quarter of the thirteenth century. This period appears to parallel the most intense period of emancipation of Swedish slaves, reminding us that the many new towns in Western Europe were characterized by the use of free labour. In the Late Middle Ages, however, the rising urban trend is broken, which here is seen, as an indication that the densely populated towns were more severely hit by the Black Death in the years 1350-1450. The slight relative decrease in urban charters in the fifteenth century can be interpreted as a sign of a higher economic interest in agriculture among the upper strata of Swedish society. There are also interesting geographical differences, showing that Sweden in many ways was a typical feudal (i.e. decentralized) realm. The southern part of Sweden – Götaland – appears to have had an edge in development compared to the northern part of Sweden – Svealand – but the latter part seems to have diminished that gap from the late thirteenth century, up to the Swedish Reformation in the year 1527. Across the Middle Ages we find an increasing number of women among the first issuers of Swedish charters. The fact that there were some reversals in this rising trend, particularly in times of civil war, does not change the overall impression of a continually greater acceptance of Medieval Swedish women as active participants in public life. If the new protestant faith meant a step backwards in the process of emancipation, as some scholars have argued was the case in Western Europe, this study does not support the notion of a Medieval patriarchal forerunner. Regioner och marknader i medeltidens Sverige

Jordpris och jordränta i Sverige under medeltid och tidigmodern tid

Swedish Medieval Grain Prices in a European Perspective This article compares Swedish grain prices for the period 1291–1530 with European prices. All prices are expressed in grams of silver per hectolitre of grain. The analysis focuses on two aspects of the price series: the average price level and the volatility of prices. A low price level, expressed in terms of silver, is characteristic of a low-wage economy that is little monetized. High prices are typical of the advanced economies of the period. Price volatility can be seen as a welfare indicator, since great swings from year to year imply difficulties in provisioning the population. In a comparative perspective we should therefore expect a negative association between price level and volatility. This hypothesis is supported by the data: in Figure 5, based on 24 European price series, the correlation between price level and volatility is as strong as –.70. The advanced, high-price economies thus enjoyed greater price stability. Price volatility in Sweden was higher than in any other area studied here, which suggests a comparatively low level of welfare for those parts of the population who were not self-sufficient in grain. In a correlation analysis, north-west Europe stands out as a comparatively price-integrated area during medieval times. Several of the towns and regions exhibiting the strongest level of price integration are found in the Low Countries, but England and parts of Germany were also included in this area (Figure 6). In contrast, Sweden was only weakly price-integrated with north-west Europe and the North German town of Rostock. Finally, the article discusses the possible impact of short-run climatological variations on prices. Estimates of medieval temperature and precipitation in England correlate rather weakly with wheat yields and wheat prices, whereas correlations with grain prices are much stronger. This suggests that the observed price integration in north-west Europe may be seen mainly as the result of economic integration and not as an effect of shared variations in climate. This is a preliminary conclusion, however, since estimates of medieval temperature and precipitation are as yet uncertain.