| 1. |
- Borenäs, Marcus, et al.
(författare)
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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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| 2. |
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| 3. |
- Karidar, Hakima, et al.
(författare)
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Närståendestöd och efterlevandestöd – under och efter vårdtid inom specialiserad Palliativ vård och ASIH i Skåne
- 2022
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Ingår i: ; , s. 41-41
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Bakgrund: En av hörnstenarna i palliativ vård handlar om att ge stöd till alla närstående. Enligt lagstiftning har sjukvården även en skyldighet att speciellt beakta barns behov av information, råd och stöd om barnets föräldrar eller någon annan vuxen som barnet varaktigt bor tillsammans med har en livshotande sjukdom eller avlidit.Syfte: Alla närstående inom Palliativ vård och ASIH i Skåne ska erbjudas personcentrerad och jämlikt stöd under och efter vårdtiden.Metod: Uppdraget startades 2019 och beräknas vara klar under hösten 2022. All personal inom palliativ vård och ASIH i Skåne involverades genom att de fick göra nulägesanalys gällande närståendestöd. I nästa steg utfördes gapanalys för att identifiera likhet och olikhet kring närståendestöd. Vidare fick all personal ge förslag till att forma framtidens närståendestöd. Efter nulägesanalys och gapanalys bildades en multiprofessionell arbetsgrupp med representanter från alla verksamheterna i Skåne. Arbetsgruppens uppdrag var att framställa beslutsunderlag gällande närståendestöd under vårdtid och efterlevandestöd till närstående efter vårdtiden. Resultat: Nulägesanalys som utfördes 2019 visade att närstående med liknande behov har erbjudits olika professionella stöd. Gapanalys utfördes under 2020 för kartläggning av vilka former av stöd saknades/önskades samt var relevanta i nu tiden. Under 2021 arbetet har fortsatt med att definiera vad närståendestöd innefattar och under 2022 har arbete pågått med att ta fram beslutsunderlag för hur och vilka former av närståendestöd som ska erbjudas.Betydelse: Genom strukturerad arbetssätt identifiera närståendes förutsättningar, behov och önskemål ökar sannolikheten för att närstående erbjuds rätt stöd, i rätt tid och av rätt profession.
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| 4. |
- Martinsson, Bengt G., et al.
(författare)
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Elemental composition of fog interstitial particle size fractions and hydrophobic fractions related to fog droplet nucleation scavenging
- 1992
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Ingår i: Tellus. Series B: Chemical and Physical Meteorology. - : Stockholm University Press. - 0280-6509. ; 44:5, s. 593-603
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Tidskriftsartikel (refereegranskat)abstract
- The cloud nucleation scavenging process was studied during a joint campaign of the EUROTRAC sub‐project Ground‐based Cloud Experiment. It was found that the particle size has a strong influence on the partitioning of particles between the cloud droplet and the interstitial aerosol reservoirs. A new aerosol sampling unit, the relative humidity processing system, was employed for the extraction of particles with a low growth‐ability with respect to increased relative humidity. The system supplied tracer elements on the particle growth‐ability. These elements could be used to identify a factor related to particle hygroscopic properties, which was in effect as a selector of cloud condensation nuclei.
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| 5. |
- Nordqvist, Anneli, 1978-
(författare)
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Hit Identification and Hit Expansion in Antituberculosis Drug Discovery : Design and Synthesis of Glutamine Synthetase and 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase Inhibitors
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Since the discovery of Mycobacterium tuberculosis (Mtb) as the bacterial agent causing tuberculosis, the permanent eradication of this disease has proven challenging. Although a number of drugs exist for the treatment of tuberculosis, 1.7 million people still die every year from this infection. The current treatment regimen involves lengthy combination therapy with four different drugs in an effort to combat the development of resistance. However, multidrug-resistant and extensively drug-resistant strains are emerging in all parts of the world. Therefore, new drugs effective in the treatment of tuberculosis are much-needed. The work presented in this thesis was focused on the early stages of drug discovery by applying different hit identification and hit expansion strategies in the exploration of two new potential drug targets, glutamine synthetase (GS) and 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR). A literature survey was first carried out to identify new Mtb GS inhibitors from compounds known to inhibit GS in other species. Three compounds, structurally unrelated to the typical amino acid derivatives of previously known GS inhibitors, were then discovered by virtual screening and found to be Mtb GS inhibitors, exhibiting activities in the millimolar range. Imidazo[1,2-a]pyridine analogues were also investigated as Mtb GS inhibitors. The chemical functionality, size requirements and position of the substituents in the imidazo[1,2-a]pyridine hit were investigated, and a chemical library was designed based on a focused hierarchical design of experiments approach. The X-ray structure of one of the inhibitors in complex with Mtb GS provided additional insight into the structure–activity relationships of this class of compounds. Finally, new α-arylated fosmidomycin analogues were synthesized as inhibitors of Mtb DXR, exhibiting IC50 values down to 0.8 µM. This work shows that a wide variety of aryl groups are tolerated by the enzyme. Cinnamaldehydes are important synthetic intermediates in the synthesis of fosmidomycin analogues. These were prepared by an oxidative Heck reaction from acrolein and various arylboronic acids. Electron-rich, electron-poor, heterocyclic and sterically hindered boronic acids could be employed, furnishing cinnamaldehydes in 43–92% yield.
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| 6. |
- Synnes, Kåre, 1969-, et al.
(författare)
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H2Al : The Human Health and Activity Laboratory
- 2018
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Ingår i: <em>Proceedings</em>, 2018, UCAmI 2018. - Basel Switzerland : MDPI.
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Konferensbidrag (refereegranskat)abstract
- The Human Health and Activity Laboratory (H2Al) is a new research facility at Luleå University of Technology implemented during 2018 as a smart home environment in an educational training apartment for nurses and therapists at the Luleå campus. This paper presents the design and implementation of the lab together with a discussion on potential impact. The aim is to identify and overcome economical, technical and social barriers to achieve an envisioned good and equal health and welfare within and from home environments. The lab is equipped with multiple sensor and actuator systems in the environment, worn by persons and based on digital information. The systems will allow for advanced capture, filtering, analysis and visualization of research data such as A/V, EEG, ECG, EMG, GSR, respiration and location while being able to detect falls, sleep apnea and other critical health and wellbeing issues. The resulting studies will be aimed towards supporting and equipping future home environments and care facilities, spanning from temporary care to primary care at hospitals, with technologies for activity and critical health and wellness issue detection. The work will be conducted at an International level and within a European context, based on a collaboration with other smart labs, such that experiments can be replicated at multiple sites. This paper presents some initial lessons learnt including design, setup and configuration for comparison of sensor placements and configurations as well as analytical methods.
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| 7. |
- Wang, Gang, et al.
(författare)
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Spirometric phenotypes from early childhood to young adulthood : a Chronic Airway Disease Early Stratification study
- 2021
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Ingår i: ERJ Open Research. - : ERS Publications. - 2312-0541. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: The prevalences of obstructive and restrictive spirometric phenotypes, and their relation to early-life risk factors from childhood to young adulthood remain poorly understood. The aim was to explore these phenotypes and associations with well-known respiratory risk factors across ages and populations in European cohorts.Methods: We studied 49334 participants from 14 population-based cohorts in different age groups (⩽10, >10–15, >15–20, >20–25 years, and overall, 5–25 years). The obstructive phenotype was defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) z-score less than the lower limit of normal (LLN), whereas the restrictive phenotype was defined as FEV1/FVC z-score ⩾LLN, and FVC z-score Results: The prevalence of obstructive and restrictive phenotypes varied from 3.2–10.9% and 1.8–7.7%, respectively, without clear age trends. A diagnosis of asthma (adjusted odds ratio (aOR=2.55, 95% CI 2.14–3.04), preterm birth (aOR=1.84, 1.27–2.66), maternal smoking during pregnancy (aOR=1.16, 95% CI 1.01–1.35) and family history of asthma (aOR=1.44, 95% CI 1.25–1.66) were associated with a higher prevalence of obstructive, but not restrictive, phenotype across ages (5–25 years). A higher current body mass index (BMI was more often observed in those with the obstructive phenotype but less in those with the restrictive phenotype (aOR=1.05, 95% CI 1.03–1.06 and aOR=0.81, 95% CI 0.78–0.85, per kg·m−2 increase in BMI, respectively). Current smoking was associated with the obstructive phenotype in participants older than 10 years (aOR=1.24, 95% CI 1.05–1.46).Conclusion: Obstructive and restrictive phenotypes were found to be relatively prevalent during childhood, which supports the early origins concept. Several well-known respiratory risk factors were associated with the obstructive phenotype, whereas only low BMI was associated with the restrictive phenotype, suggesting different underlying pathobiology of these two phenotypes.
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