MEK inhibition is a promising therapeutic strategy for MLL-rearranged infant acute lymphoblastic leukemia patients carrying RAS mutations

Acute lymphoblastic leukemia (ALL) in infants is an aggressive malignancy with a poor clinical outcome, and is characterized by translocations of the Mixed Lineage Leukemia (MLL) gene. Previously, we identified RAS mutations in 14-24% of infant ALL patients, and showed that the presence of a RAS mutation decreased the survival chances even further. We hypothesized that targeting the RAS signaling pathway could be a therapeutic strategy for RAS-mutant infant ALL patients. Here we show that the MEK inhibitors Trametinib, Selumetinib and MEK162 severely impair primary RAS-mutant MLL-rearranged infant ALL cells in vitro. While all RAS-mutant samples were sensitive to MEK inhibitors, we found both sensitive and resistant samples among RAS-wildtype cases. We confirmed enhanced RAS pathway signaling in RASmutant samples, but found no apparent downstream over-activation in the wildtype samples. However, we did confirm that MEK inhibitors reduced p-ERK levels, and induced apoptosis in the RAS-mutant MLL-rearranged ALL cells. Finally, we show that MEK inhibition synergistically enhances prednisolone sensitivity,

Identification of genes transcriptionally responsive to the loss of MLL fusions in MLL-rearranged acute lymphoblastic leukemia

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is characterized by high relapse rates and a dismal prognosis. To facilitate the discovery of novel therapeutic targets, we here searched for genes directly influenced by the repression of various MLL fusions. Methods For this, we performed gene expression profiling after siRNA-mediated repression of MLLAF4, MLL-ENL, and AF4-MLL in MLL -rearranged ALL cell line models. The obtained results were compared with various already established gene signatures including those consisting of known MLL-AF4 target genes, or those associated with primary MLL-rearranged infant ALL samples. Results Genes that were down-regulated in response to the repression of MLL-AF4 and MLL-ENL appeared characteristically expressed in primary MLL-rearranged infant ALL samples, and often represented known MLL-AF4 targets genes. Genes that were up-regulated in response to the repression of MLL-AF4 and MLL-ENL often represented genes typically silenced by promoter hypermethylation in MLL-rearranged infant ALL. Genes that were aff

The use of the SF-36 questionnaire in adult survivors of childhood cancer: evaluation of data quality, score reliability, and scaling assumptions

BACKGROUND: The SF-36 has been used in a number of previous studies that have investigated the health status of childhood cancer survivors, but it never has been evaluated regarding data quality, scaling assumptions, and reliability in this population. As health status among childhood cancer survivors is being increasingly investigated, it is important that the measurement instruments are reliable, validated and appropriate for use in this population. The aim of this paper was to determine whether the SF-36 questionnaire is a valid and reliable instrument in assessing self-perceived health status of adult survivors of childhood cancer. METHODS: We examined the SF-36 to see how it performed with respect to (1) data completeness, (2) distribution of the scale scores, (3) item-internal consistency, (4) item-discriminant validity, (5) internal consistency, and (6) scaling assumptions. For this investigation we used SF-36 data from a population-based study of 10,189 adult survivors of childhood cancer. RESULTS: Overall, missing values ranged per item from 0.5 to 2.9 percent. Ceiling effects were found to be highest in the role limitation-physical (76.7%) and role limitation-emotional (76.5%) scales. All correlations between items and their hypothesised scales exceeded the suggested standard of 0.40 for satisfactory item-consistency. Across all scales, the Cronbach's alpha coefficient of reliability was found to be higher than the suggested value of 0.70. Consistent across all cancer groups, the physical health related scale scores correlated strongly with the Physical Component Summary (PCS) scale scores and weakly with the Mental Component Summary (MCS) scale scores. Also, the mental health and role limitation-emotional scales correlated strongly with the MCS scale score and weakly with the PCS scale score. Moderate to strong correlations with both summary scores were found for the general health perception, energy/vitality, and social functioning scales. CONCLUSION: The findings presented in this paper provide support for the validity and reliability of the SF-36 when used in long-term survivors of childhood cancer. These findings should encourage other researchers and health care practitioners to use the SF-36 when assessing health status in this population, although it should be recognised that ceiling effects can occur

Measuring temporal, spectral and spatial changes in electrophysiological brain network connectivity

The topic of functional connectivity in neuroimaging is expanding rapidly and many studies now focus on coupling between spatially separate brain regions. These studies show that a relatively small number of large scale networks exist within the brain, and that healthy function of these networks is disrupted in many clinical populations. To date, the vast majority of studies probing connectivity employ techniques that compute time averaged correlation over several minutes, and between specific pre-defined brain locations. However, increasing evidence suggests that functional connectivity is non-stationary in time. Further, electrophysiological measurements show that connectivity is dependent on the frequency band of neural oscillations. It is also conceivable that networks exhibit a degree of spatial inhomogeneity, i.e. the large scale networks that we observe may result from the time average of multiple transiently synchronised sub-networks, each with their own spatial signature. This means that the next generation of neuroimaging tools to compute functional connectivity must account for spatial inhomogeneity, spectral non-uniformity and temporal non-stationarity. Here, we present a means to achieve this via application of windowed canonical correlation analysis (CCA) to source space projected MEG data. We describe the generation of time–frequency connectivity plots, showing the temporal and spectral distribution of coupling between brain regions. Moreover, CCA over voxels provides a means to assess spatial non-uniformity within short time–frequency windows. The feasibility of this technique is demonstrated in simulation and in a resting state MEG experiment where we elucidate multiple distinct spatio-temporal-spectral modes of covariation between the left and right sensorimotor areas

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Establishment of Technical Life Science Consulting Services in a Local Government Market

This master thesis evaluates the possibility for Semcon AB to establish a business within the public sector of Uppsala. The need and prerequisites for technical life science consultant services has been investigated by interviewing experts in their field. The study is explanatory and contributes with an understanding of the current situation and the outlook for consultants in in the public sector, with Region Uppsala as the targeted customer. The results show that the need for consultants lies within IT, logistics, medtech, and construction. A consultant should preferably have a combination of these competences. Another possibility is to aid the public sector with the difficulties in specifying the requirements of a procurement. There are different ways of establishing a business with Region Uppsala. Either by a framework agreement, as a subcontractor, or by innovation procurement. One aspect of successful collaboration between a consultant company and the public sector is the attitudes toward consultants. The result indicates generally positive attitudes. Despite this a concern of knowledge disappearing when the assignment is finished exists. Therefore, transparency as well as constant feedback and evaluation is highly important

Establishment of Technical Life Science Consulting Services in a Local Government Market

This master thesis evaluates the possibility for Semcon AB to establish a business within the public sector of Uppsala. The need and prerequisites for technical life science consultant services has been investigated by interviewing experts in their field. The study is explanatory and contributes with an understanding of the current situation and the outlook for consultants in in the public sector, with Region Uppsala as the targeted customer. The results show that the need for consultants lies within IT, logistics, medtech, and construction. A consultant should preferably have a combination of these competences. Another possibility is to aid the public sector with the difficulties in specifying the requirements of a procurement. There are different ways of establishing a business with Region Uppsala. Either by a framework agreement, as a subcontractor, or by innovation procurement. One aspect of successful collaboration between a consultant company and the public sector is the attitudes toward consultants. The result indicates generally positive attitudes. Despite this a concern of knowledge disappearing when the assignment is finished exists. Therefore, transparency as well as constant feedback and evaluation is highly important

Structured time observation of human modelling tool users' activites

Most statements regarding human modeling tools efficiency are based on perceived time. No structured time observation of task activities performed by a simulation engineers working with the tools are previous performed. The aim of the study is to identify digital human modelling tool users’ activates and measure the time distribution of the activities. Furthermore, measured time distribution is compare with users perceived time distribution. Five simulation engineers at Volvo were observed for five days each. The simulation engineers’ activities can be categorised in twelve groups. The direct value added work and the indirect value added work important for a new introduced tool were of similar size as direct value added work for a vehicle disassembly worker. Waiting time, there simulation is out of control e.g. waiting for information from colleague and computer processor, was perceived much longer compared to measured time. The human modelling tool seems to have matured and most of the activities identified seems to be necessary to perform human modelling simulations of high quality; however the time distribution could to some extend be questioned. There are a lot of activities associated with communication, i.e. different kinds of contacts and meetings. Therefore it appears to be a potential to increase efficiency with respect to communication

Snabba mikrofluidiska test möjliggör specialanpassad sjukvård : Utveckling av två designförslag med fokus på material, struktur och pump

Två designförslag har utvecklats för ett snabbtest av antibiotikakänslighet baserat på ettmikrofluidiskt system av Gradientech AB. Antibiotikaresistens är ett stort och växande problem ivärlden. För att förbättra diagnostiken av bakteriella blodinfektioner krävs snabbarediagnostiska tester vilket möjliggör specialanpassad behandling. Linjära gradienter av antibiotikai det mikrofluidiska systemet möjliggör snabbare detektion av antibiotikakänslighet jämfört meddiagnostiska test som används idag. Projektet har syftat till att anpassa testet utvecklat avGradientech AB för en klinisk marknad. Fokus har varit på material, pumpsystem och strukturför snabbtestet. De två designförslagen baseras på krav på ett pålitligt och billigt test som äranvändarvänligt och som minimerar smittorisker. Det ena designförslaget använder sig av enchipbaserad peristaltisk pump och det andra förslaget är ett trelagersystem med endiafragmapump. De två förslagen består av både hårdplast och ett elastiskt material. När dettatest kommer ut på den kliniska marknaden så kommer det förbättra vården av patienter medbakteriella blodinfektioner och minska sjukvårdskostnader. Testet kommer även minskabehovet av behandling med bredspektrumantibiotika och därmed hjälpa till att stoppa spridningav antibiotikaresistens.Two designs were developed for a fast antibiotic susceptibility test (AST) based on a microfluidicsystem by Gradientech AB. Antibiotic resistance is a big and growing global problem. Fasterdiagnostic tests are needed to improve the diagnostics of bacterial infections and enablespecialized antibiotic therapy. Linear gradients of antibiotics in the microfluidic system in thisproject enables faster detection of antibiotic susceptibility compared to ASTs used today inhealth care. The aim of this project has been to adapt the test developed by Gradientech AB fora clinical market. The main focus has been on materials, pumping systems and structure of theAST. The two designs are based on requirements of a reliable and cheap test that is easy to useand minimizes the biohazard. The first design uses a chip-based peristaltic pump and the otherdesign is a three-layer structure with a diaphragm pump. The two designs consists of both arigid plastic material and an elastic material. When this test becomes available to the clinicalmarket it will improve the care of patients with bacterial blood infections and reduce healthcarecosts. It will also reduce the use of broad-spectrum treatment of antibiotics and help counteractincreased global antibiotic resistance

Structured time observation of human modelling tool users\u27 activites.

Most statements regarding human modeling tools efficiency are based on perceived time. No structured timeobservation of task activities performed by a simulation engineers working with the tools are previous performed.The aim of the study is to identify digital human modelling tool users’ activates and measure the time distributionof the activities. Furthermore, measured time distribution is compared with users perceived time distribution.Five simulation engineers at Volvo were observed for five days each. The simulation engineers’ activities can becategorised in twelve groups. The direct value added work and the indirect value added work important for a newintroduced tool were of similar size as direct value added work for a vehicle disassembly worker. Waiting time, theresimulation is out of control e.g. waiting for information from colleague and computer processor, was perceived muchlonger compared to measured time.The human modelling tool seems to have matured and most of the activities identified seems to be necessary to perform human modelling simulations of high quality; however the time distribution could to some extend be questioned. There are a lot of activities associated with communication, i.e. different kinds of contacts and meetings. Therefore it appears to be a potential to increase efficiency with respect to communication