| 1. |
|
|
| 2. |
- Almqvist, Linnea, 1987-
(author)
-
Asthma epidemiology : prognosis of asthma with onset in childhood and in adulthood
- 2024
-
Doctoral thesis (other academic/artistic)abstract
- Aim: to update the knowledge on the epidemiology of asthma with onset in childhood and adulthood as well as examine the importance of risk factors in early childhood and clinical characteristics on the incidence and prognosis of asthma.Methods: The thesis is based on the epidemiological research program Obstructive Lung Disease in Northern Sweden (OLIN) studies. Pediatric cohort: recruited in 1996 (age 8y, n=3430, 97% of invited) and followed annually by questionnaire about asthma, allergy and risk factors until 19y and a postal questionnaire at 28y. Clinical examinations included skin prick tests (SPT at 8, 12 and 19y) and spirometry (19y). Adult cohort: 309 adults (age 20–60y) with asthma onset in the last 12 months were recruited 1995-99 and re-examined in 2012-14 (n=205). Structured interviews, spirometry and SPT were performed at recruitment and follow-up and bronchial hyperreactivity (BHR) at recruitment.Results: The asthma incidence rate was 10-13/1000/year in childhood and adolescence and 6/1000/year in young adulthood. Several risk factors in early life were associated with asthma onset in childhood, adolescence and young adulthood, e.g. family history of asthma, <3 months breastfeeding, rhinoconjunctivitis and positive SPT at 8y, while low birthweight, maternal smoking during pregnancy, severe respiratory infections and eczema were associated with onset in childhood and adolescence. Among those with asthma at 8y, 62% still had asthma at 28y and this was associated with positive SPT, rhinoconjunctivitis, severe respiratory infection in childhood, and bronchial hyperreactivity (BHR) in adolescence. Coexistence of asthma, rhinitis and eczema increased by age, especially among those with a positive SPT. However, having all three conditions was uncommon. In the 15y follow-up adult onset asthma, 89% had persistent asthma. Better lung function at recruitment and less severe BHR was associated with remission. Remission rate of adult onset asthma was <1% per year.Conclusion: The incidence of asthma was high during childhood and adolescence and then decreased in young adulthood. Factors in early life that were associated with incident asthma during childhood were still associated with the incidence in adult age. Among those with asthma onset by 8 years, 62%, still had asthma as young adults. The coexistence of asthma, rhinitis and eczema varied from 8 to 28y without following a specific pattern, only a small proportion reported having all three conditions. Remission of adult onset asthma was rare.
|
|
| 3. |
|
|
| 4. |
- Almqvist, Helena, et al.
(author)
-
CETSA screening identifies known and novel thymidylate synthase inhibitors and slow intracellular activation of 5-fluorouracil
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Target engagement is a critical factor for therapeutic efficacy. Assessment of compound binding to native target proteins in live cells is therefore highly desirable in all stages of drug discovery. We report here the first compound library screen based on biophysical measurements of intracellular target binding, exemplified by human thymidylate synthase (TS). The screen selected accurately for all the tested known drugs acting on TS. We also identified TS inhibitors with novel chemistry and marketed drugs that were not previously known to target TS, including the DNA methyltransferase inhibitor decitabine. By following the cellular uptake and enzymatic conversion of known drugs we correlated the appearance of active metabolites over time with intracellular target engagement. These data distinguished a much slower activation of 5-fluorouracil when compared with nucleoside-based drugs. The approach establishes efficient means to associate drug uptake and activation with target binding during drug discovery.
|
|
| 5. |
- Almqvist, Helena, et al.
(author)
-
Organic hazardous substances in graywater from Swedish households
- 2006
-
In: Journal of environmental engineering. - 0733-9372 .- 1943-7870. ; 132:8, s. 901-908
-
Journal article (peer-reviewed)abstract
- The concentrations of several selected organic hazardous substances were investigated in domestic graywater. In total, 41 of 81 organic hazardous substances were found in concentrations above the detection limits (nonylphenol and octylphenol ethoxylates, brominated flame-retardants, organotin compounds, polyaromatic hydrocarbons, polychlorinated biphenyls, phthalates, linear-alkyl benzene sulfonate, and triclosan). Moreover, total solids, biochemical oxygen demand (BOD7), chemical oxygen demand (COD), total nitrogen, total phosphorus, potassium, and sulphur were investigated and presented for graywater. Another objective was to suggest potential household sources for a selected number of organic hazardous substances. The present and past investigations reveal households to be obvious contributors of organic hazardous substances to municipal wastewater, and that graywater is an important media in this transport. The spreading derives from diffuse household sources like everyday activities (laundry, cleaning, etc.), the wearing down of things such as pipe material and interior fittings, and from airborne deposition.
|
|
| 6. |
- Almqvist, Kjerstin, 1953-, et al.
(author)
-
Project Support : En genomförbarhetsstudie av ett individuellt föräldrastöd i socialtjänsten för våldsutsatta föräldrar
- 2016
-
Reports (other academic/artistic)abstract
- Genomförbarheten av Project Support (PS), ett individuellt föräldrastöd för våldsutsatta mammor utvecklat i USA, utvärderas inom ramen för svensk socialtjänst i denna studie. Sammanlagt trettio behandlare har utbildats i metoden, som anpassats till svenska förhållanden i samarbete med upphovsmännen. Tjugonio familjer hade inkluderats i behandling vid sttudiens avslut. Såväl behandlare som mammor uppskattade metoden och bedömde att den var en lämplig insats som förbättrade föräldrarnas samspel med sina barn. Mammornas självskattade föräldraförmåga förbättrades signifikant, och barnens symtomnivåer sänktes. Vissa svårigheter för implementering identifierades, dels metodspecifika, dels relaterade till omständigheter i socialtjänsten.
|
|
| 7. |
- Almqvist, Linnéa, et al.
(author)
-
Clinical outcome of adult onset asthma in a 15 year follow-up
- 2020
-
In: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 56:Suppl 64
-
Journal article (other academic/artistic)abstract
- Background: Adult onset asthma is poorly studied and there are few long-term clinical follow-up studies.Aim: To study clinical characteristics of adult onset asthma in a 15-year follow-up.Method: Within the Obstructive Lung Disease in Northern Sweden (OLIN) studies, a cohort of n=309 subjects with adult onset asthma (aged 20-60 years) was recruited during 1995-99. The cohort was followed up in 2012-14 (n=205). Structured interviews and clinical examinations including spirometry were performed at both recruitment and follow-up. Skin prick tests were performed at recruitment and blood samples for cell counts and IgE at the follow-up. Asthma control was classified according to GINA 2006.Results: At follow-up n=182 (89%) still had asthma, while n=23 (11%) were in remission. Among individuals with persistent asthma, mean pre-bronchodilator FEV1 percent of predicted was 89.0 at follow-up, similar as recruitment 88.3. At recruitment 16.5% were smokers, and of these, 86.7% had quit smoking at follow-up. At follow-up, 39% had blood neutrophils ≥4.0x109/L, 23% had blood eosinophils ≥0.3x109/L, and 28% had specific IgE>0.35 IU/ml to any airborne allergen. Any respiratory symptoms were reported by 90% and 31% used medium or high dose inhaled corticosteroids (ICS), 20% low dose ICS whereas 20% had no treatment. 55% had controlled asthma, 32% partly controlled and 13% uncontrolled asthma.Conclusion: In this 15-year follow-up of adult onset asthma, the majority had persistent asthma. Smoking and high proportion using ICS may contribute to the stable lung function. Still, it should be noted that merely around every other had well controlled asthma.
|
|
| 8. |
- Almqvist, Linnea, et al.
(author)
-
No remission in 60% of those with childhood-onset asthma : a population-based cohort followed from 8 to 28 years of age
- 2024
-
In: Respiratory Medicine. - : Saunders Elsevier. - 0954-6111 .- 1532-3064. ; 224
-
Journal article (peer-reviewed)abstract
- Background: Although remission occur, childhood-onset asthma may persist until adulthood. Since few longitudinal population-based studies have followed a cohort from childhood until adulthood, the knowledge on predictors of persistence of asthma is sparse.Aim: To estimate persistence of asthma from 8 to 28 years and its associated factors. Methods: Within the OLIN (Obstructive Lung Disease in Northern Sweden) studies, a cohort was recruited in 1996 (age 8y, n = 3430) and followed annually with questionnaires about asthma and risk factors until 19y. Clinical examinations included skin prick tests (at 8, 12 and 19y) and lung function tests (17 and 19y) whereof a subsample performed bronchial hyperreactivity test. We identified n = 248 with asthma at 8y whereof 170 (69%) participated in a follow-up at 28y (73% of possible to invite).Results: Of the 170 participants at 28y, 105 (61.8%) had persistent asthma (women: 49/76, 64.5%; men: 56/94, 59.6%, p = 0.513). Factors collected at recruitment: allergic sensitization (OR7.8, 95%CI 3.0–20.2), severe respiratory infection (OR2.6, 95%CI 1.1–6.3) and higher asthma severity score (OR1.6, 95%CI 1.1–2.4) were associated with asthma at 28y after adjustment for sex, family history of asthma, breastfeeding <3 months and eczema. Replacing allergic sensitization with rhinoconjunctivitis in the model yielded OR3.4 (95%CI 1.5–8.0). Bronchial hyperreactivity at age 17y associated with asthma at 28y (OR9.0, 95%CI 1.7–47.0).Conclusions: Among children with asthma onset by 8y, 62% still had asthma at age 28 years. Persistent asthma was associated with allergic sensitization, rhinoconjunctivitis, severe respiratory infection, a more severe asthma and bronchial hyperreactivity.
|
|
| 9. |
- Almqvist, Linnéa, et al.
(author)
-
Remission of adult-onset asthma is rare: a 15-year follow-up study
- 2020
-
In: Erj Open Research. - : European Respiratory Society (ERS). - 2312-0541. ; 6:4
-
Journal article (peer-reviewed)abstract
- Background: There are few long-term clinical follow-up studies of adult-onset asthma. The aim of this article was to study clinical characteristics of adult-onset asthma in relation to remission and persistence of the disease in a 15-year follow-up. Methods: A cohort of 309 adults aged 20-60 years with asthma onset during the last 12 months verified by bronchial variability, was recruited between 1995 and 1999 from the general population in northern Sweden. The cohort was followed-up in 2003 (n=250) and between 2012 and 2014 (n=205). Structured interviews and spirometry were performed at recruitment and the follow-ups. Bronchial hyperreactivity (BHR) and skin-prick tests were performed at recruitment and blood samples were collected at the last follow-up. Remission of asthma was defined as no asthma symptoms and no use of asthma medication during the last 12 months. Results: Of eight individuals in remission in 2003, five had relapsed between 2012 and 2014 and in total, 23 (11%) were in remission, while 182 had persistent asthma. Those in remission had higher mean forced expiratory volume in 1 s % predicted at recruitment than those with persistent asthma (94.6 versus 88.3, p=0.034), fewer had severe BHR (27.3% versus 50.9%, p=0.037) and they had less body mass index increase (+1.6 versus +3.0, p=0.054). Of those with persistent asthma, 13% had uncontrolled asthma and they had higher levels of blood neutrophils than those with partly controlled or controlled asthma. Conclusion: Higher forced expiratory volume in 1 s % predicted and less-severe BHR was associated with remission of adult-onset asthma, but still, the proportion in remission in this 15-year follow-up was low.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Danielsson, Henrik, et al.
(author)
-
A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities
- 2024
-
In: Journal of Developmental and Physical Disabilities. - : Springer. - 1056-263X .- 1573-3580. ; 36, s. 203-242
-
Research review (peer-reviewed)abstract
- To review the longitudinal trajectories - and the factors influencing their development - of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by < 10% between the first and last time point. Despite multiple studies reporting longitudinal trajectories of mental health problems, greater conceptual clarity and consideration of the measures included in research is needed, along with the inclusion of a more diverse range of populations of children with neurodevelopmental disabilities.
|
|
| 14. |
- Draxler, Helena, 1977-, et al.
(author)
-
Changes in Psychiatric Symptoms in Swedish Mothers Who Took Part in Project Support : An Intervention for Mothers Exposed to Intimate Partner Violence With Children Who Have Developed Conduct Problems
- 2023
-
In: Violence against Women. - : Sage Publications. - 1077-8012 .- 1552-8448.
-
Journal article (peer-reviewed)abstract
- Project Support (PS) is an evidence-based individual support and parenting program developed for mothers exposed to intimate partner violence (IPV) whose children have developed conduct disorders. This Swedish feasibility study focuses on changes in the mothers' psychiatric symptoms, in relation to social and emotional support received as part of PS. In a within-subject design in a naturalistic setting (i.e., 10 social service units), mothers (n = 35) reported a significant decrease in symptoms, but from an individual perspective, most mothers still suffered from clinical levels of psychiatric symptoms. The need for additional interventions for mothers exposed to IPV is discussed.
|
|
| 15. |
- Draxler, Helena, 1977-, et al.
(author)
-
From doubt to trust : Swedish mothers' and counsellors' experience testing a parenting programme for mothers exposed to intimate partner violence whose children have developed behavioural problems
- 2020
-
In: Clinical Child Psychology and Psychiatry. - : Sage Publications. - 1359-1045 .- 1461-7021.
-
Journal article (peer-reviewed)abstract
- Many countries seek evidence-based interventions for children who have been exposed to domestic violence, and they frequently turn to interventions developed in the US and disseminated to Europe as a solution. Societal and cultural differences may, however, pose barriers to successful implementation. Project Support (PS), piloted in this study through social services agencies in Sweden, has shown positive effects in the US for families with children who have been exposed to intimate partner violence (IPV). The aim of this study was to investigate counselors' and caregivers' experiences when giving/receiving PS in Sweden. The study was based on interviews conducted with 11 mothers and 13 counselors with experience in the programme. A thematic analysis showed three themes (Initial doubts, Confidence from positive change, and Flexibility- challenge for the organization) and the study adds information about obstacles for implementation of PS in Sweden. Cultural and organizational differences between Sweden and the US in practice and child-rearing attitudes are highlighted, as well as the importance of making adjustments while maintaining treatment fidelity, and promoting the dissemination of the approach.
|
|
| 16. |
- Draxler, Helena, 1977-
(author)
-
Initial transfer of Project Support from the US to Sweden : Feasibility and clinical aspects as viewed by counsellors and parents
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Project Support (PS) is a parenting programme developed and studied in the US for parents and children exposed to intimate partner violence (IPV) and for these children with subsequent behavioural problems. By examining feasibility aspects and using qualitative and quantitative methods, the study aimed to explore the transferability of PS to a new naturalistic context, i.e., Swedish social services. In the qualitative Study I, IPV-exposed mothers and counsellors who received/conducted PS were interviewed about their experiences. Study II explored whether the effects of PS in the US, i.e., reduced children’s psychological symptoms and improved parenting capacity among parents and children exposed to IPV, could be replicated in Sweden. Study III explored group and individual impacts of PS on parents regarding aspects of IPV, global psychiatric symptoms, and post-traumatic stress symptoms. Study IV is a qualitative follow-up study where counsellors were interviewed about how the PS work was or was not continued. The results indicate cultural differences between the US and Sweden in practising parenting skills though role-playing and in how to address and understand child misbehaviour, necessitating adaptation to Swedish values and norms. Results further indicate that PS is a promising intervention for Swedish IPV-exposed parents and their children with behavioural problems, leading to improved parental capacity and decreased child behavioural problems, supporting prior research in an American context. PS generally seems to improve parents’ psychiatric symptoms, but examining each individual revealed that most parents still had dysfunctional levels of symptoms post treatment. Maintenance and use of PS was inconsistent, due to lack of organisational support. The study indicates that PS can be further implemented and evaluated in Sweden, and stresses the importance of conducting feasibility studies when an intervention is to be transferred to a new context.
|
|
| 17. |
- Draxler, Helena
(author)
-
Project Support i svensk socialtjänst : En genomförbarhetsstudie av ett föräldrastödsprogram för våldsutsatta föräldrar och deras barn som utvecklat beteendeproblematik
- 2017
-
Licentiate thesis (other academic/artistic)abstract
- Projekt Support (PS) är ett föräldrastödsprogram som har utvecklats i USA för mammor och barn som utsatts för våld i nära relationer där barnen också utvecklat känslomässiga och beteendemässiga problem. Syftet med denna licentiatuppsats är att undersöka hur interventionen mottogs av behandlare och föräldrar inom ramen för svensk socialtjänst med hänsyn till skillnaderna mellan länderna.Två studier genomfördes. I den första studien (studie I) intervjuades behandlare (n 11) och mammor (n 13) från tre kommuner och Sveriges största skyddade boende om sina erfarenheter av att ge och ta emot föräldraintervention. Intervjuerna analyserades separat med hjälp av tematisk analys, vilka sedan sammanslogs i en syntes. Resultaten grupperades i sex teman, vilket indikerade initiala tvivel på interventionene och på deltagarnas egen förmåga. Teman visade också att arbetet med PS ledde till en upplevd positiv förändring av barns beteende, liksom betonades behovet av kompetenta behandlare och anpassning utifrån kulturella skillnader. Den andra studien (studie II) utvärderade interventionens effekt avseende föräldrarnas föräldrakapacitet (n 35) och deras barns psykiska symtom (19 pojkar och 16 flickor, medelålder 6 år). Resultaten visade att effekten som erhållits av PS i Sverige kan i nästan samma omfattning likställas med den effekt som framgår av tidigare studier gjorda i USA. Även barnens känslomässiga symptom, problem och hyperaktivitet minskade, och föräldrarna bemötte sina barn på ett mer positivt sätt. Föräldrarna upplevde också minskad hjälplöshet och rädsla i relationen till sina barn. Det var också en kovarians mellan föräldrarnas känslor (hjälplöshet och rädsla) och barns uppförandeproblem och hyperaktivitet där båda minskade.Slutsatserna i denna licentiatuppsats är för det första att det är möjligt att genomföra PS med föräldrar utsatta för våld i nära relationer och deras barn som har utvecklat känslomässiga och beteendemässiga problem och för det andra att organisatoriska förhållanden behöver anpassas för att interventionen ska kunna implementeras i svensk socialtjänst.
|
|
| 18. |
- Draxler, Helena, 1977-, et al.
(author)
-
Replicability of effect when transferring a supportive programme for parents exposed to intimate partner violence and their children from the US to Sweden
- 2019
-
In: Child Care in Practice. - : Routledge. - 1357-5279 .- 1476-489X. ; 25:4, s. 367-382
-
Journal article (peer-reviewed)abstract
- Transferring an evidence-based parenting programme for parents exposed to intimate partner violence (IPV) and their children with emotional and behavioural problems reveals the extent to which cultural and social aspects can interfere with the programme’s effectiveness. Feasibility studies are of value in such circumstances, and the aim of the present feasibility study was to explore, on a small scale and in its natural context, whether the effects of the parenting programme, Project Support, were replicable when transferred to another country. In this study, the programme, which was originally designed for parents exposed to IPV and their children who had developed psychological symptoms in the United States, was evaluated in an equivalent population receiving Swedish social services. Parents (n = 35) self-assessed their parenting capacity and their children’s (n = 35) psychological symptoms. The results indicate that the parents improved their parenting capacity, and feelings of helplessness and fear regarding parenting their children decreased. Those feelings were also associated with the children’s psychological symptoms. The promising results are similar to the findings of previous research from the US, and further implementation and evaluation of Project Support in Sweden are indicated.
|
|
| 19. |
- Hedman, Linnea, 1979-, et al.
(author)
-
Early-life risk factors for development of asthma from 8 to 28 years of age : a prospective cohort study
- 2022
-
In: ERJ Open Research. - : European Respiratory Society. - 2312-0541. ; 8:4
-
Journal article (peer-reviewed)abstract
- Background: The objective was to estimate the incidence rate of asthma from age 8 to 28 years and evaluate early-life risk factors for asthma onset at different ages.Methods: In 1996, within the Obstructive Lung Disease in Northern Sweden (OLIN) studies, a cohort of 3430 schoolchildren (97% of invited) was recruited at age 8 years to a prospective study about asthma. The cohort was followed annually from age 8 to 19 years and at 28 years by questionnaire surveys (67% of the original cohort participated). Asthma was categorised as never-asthma, onset age ⩽8 years, onset age 9–13 years, onset age 14–19 years or onset age >19 years.Results: Of the 3430 individuals in the cohort, 690 (20.1%) reported asthma in any survey. The average incidence rate was 10.0/1000 per year at ⩽8 years, 11.9/1000 per year at 9–13 years, 13.3/1000 per year at 14–19 years and 6.1/1000 per year at >19 years. The incidence was higher among boys until age 10 years, but from age 15 years, it became higher among girls. Family history of asthma, allergic sensitisation and breastfeeding <3 months were associated with asthma onset throughout the study. Low birthweight, maternal smoking during pregnancy, severe respiratory infection, rhinoconjunctivitis and eczema were associated with asthma onset ⩽8 and 9–13 years.Conclusions: The incidence of asthma was high during childhood and the teenage period, and decreased substantially during young adulthood. Early-life factors were associated with asthma onset throughout childhood but had also a lasting effect on asthma incidence until adulthood.
|
|
| 20. |
- Lidström, Helene, et al.
(author)
-
Computer-based assistive technology device for use by children with physical disabilities : a cross sectional study
- 2012
-
In: Disability and Rehabilitation. - : Informa UK Limited. - 1748-3107 .- 1748-3115. ; 7:4, s. 287-293
-
Journal article (peer-reviewed)abstract
- OBJECTIVE:To investigate the prevalence of children with physical disabilities who used a computer-based ATD, and to examine characteristics differences in children and youths who do or do not use computer-based ATDs, as well as, investigate differences that might influence the satisfaction of those two groups of children and youths when computers are being used for in-school and outside school activities.METHOD:A cross-sectional survey about computer-based activities in and outside school (n = 287) and group comparisons.Results: The prevalence of using computer-based ATDs was about 44 % (n = 127) of the children in this sample. These children were less satisfied with their computer use in education and outside school activities than the children who did not use an ATD.CONCLUSION:Improved coordination of the usage of computer-based ATDs in school and in the home, including service and support, could increase the opportunities for children with physical disabilities who use computer-based ATDs to perform the computer activities they want, need and are expected to do in school and outside school.
|
|
| 21. |
|
|
| 22. |
- Mateus, André, 1986-, et al.
(author)
-
Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery
- 2017
-
In: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 114:30, s. E6231-E6239
-
Journal article (peer-reviewed)abstract
- Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Nordlund, Michael, et al.
(author)
-
Side-selective self-assembly of graphene and FLG on piezoelectric PVDF from suspension
- 2016
-
In: Journal of Physics D. - 0022-3727 .- 1361-6463. ; 49:7
-
Journal article (peer-reviewed)abstract
- The deposition of few-layer graphene by self-assembly from suspension onto a piezoelectric polymer substrate is presented. The graphene self-assembles with negligible overlap between flakes, and with high selectivity for one of the faces of the substrate, an observation which is discussed and rationalized. A computational study on a model system further confirms the theory and supports the experimental results. The highest obtained degree of surface coverage was estimated to 77%.
|
|
| 26. |
- Page, Brent D. G., et al.
(author)
-
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
- 2018
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADPribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
|
|
| 27. |
- Seashore-Ludlow, Brinton, et al.
(author)
-
Quantitative Interpretation of Intracellular Drug Binding and Kinetics Using the Cellular Thermal Shift Assay
- 2018
-
In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 57:48, s. 6715-6725
-
Journal article (peer-reviewed)abstract
- Evidence of physical interaction with the target protein is essential in the development of chemical probes and drugs. The cellular thermal shift assay (CETSA) allows evaluation of drug binding in live cells but lacks a framework to support quantitative interpretations and comparisons with functional data. We outline an experimental platform for such analysis using human kinase p38 alpha. Systematic variations to the assay's characteristic heat challenge demonstrate an apparent loss of compound potency with an increase in duration or temperature, in line with expectations from the literature for thermal shift assays. Importantly, data for five structurally diverse inhibitors can be quantitatively explained using a simple model of linked equilibria and published binding parameters. The platform further distinguishes between ligand mechanisms and allows for quantitative comparisons of drug binding affinities and kinetics in live cells and lysates. We believe this work has broad implications in the appropriate use of the CETSA for target and compound validation.
|
|
