| 1. |
- Eliasson, Ann-Christin, 1950-, et al.
(författare)
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The effectiveness of Baby-CIMT in infants younger than 12 months with clinical signs of unilateral-cerebral palsy : an explorative study with randomized design
- 2018
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Ingår i: Research in Developmental Disabilities. - : Elsevier. - 0891-4222 .- 1873-3379. ; 72, s. 191-201
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To explore the effectiveness of baby-CIMT (constraint-induced movement therapy) and baby-massage for improving the manual ability of infants younger than 12 months with unilateral cerebral palsy (CP).METHOD: Infants eligible for inclusion were 3-8 months old with asymmetric hand function and at high risk of developing unilateral CP. Thirty-seven infants were assigned randomly to receive baby-CIMT or baby-massage. At one year of age 31 children were diagnosed with unilateral CP, 18 (8 boys, 6.1±1.7months) of these had received baby-CIMT and 13 (8 boys, 5.0±1.6months) baby-massage. There were two 6-week training periods separated by a 6-week pause. The Hand Assessment for Infants (HAI), Assisting Hand Assessment (AHA), the Parenting Sense of Competence Scale (PSCS) and a questionnaire concerning feasibility were applied.RESULTS: There was improvement in the "Affected hand score" of HAI from median 10 (6;13 IQR) to 13 (7;17 IQR) raw score in the baby-CIMT group and from 5 (4;11 IQR) to 6 (3;12 IQR) for baby-massage with a significant between group difference (p=0.041). At 18-month of age, the median AHA score were 51 (38;72 IQR) after baby-CIMT (n=18) compared to 24 (19;43 IQR) baby-massage (n=9). The PSCS revealed an enhanced sense of competence of being a parent among fathers in the baby-CIMT group compared to fathers in the baby-massage (p=0.002). Parents considered both interventions to be feasible.CONCLUSION: Baby-CIMT appears to improve the unimanual ability of young children with unilateral CP more than massage.
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| 2. |
- Colombo, Diego, et al.
(författare)
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Caffeic acid phenethyl ester targets ubiquitin-specific protease 8 and synergizes with cisplatin in endometrioid ovarian carcinoma cells
- 2022
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Ingår i: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 197
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Tidskriftsartikel (refereegranskat)abstract
- Deubiquitinases (DUBs) mediate the removal of ubiquitin from diverse proteins that participate in the regulation of cell survival, DNA damage repair, apoptosis and drug resistance. Previous studies have shown an association between activation of cell survival pathways and platinum-drug resistance in ovarian carcinoma cell lines. Among the strategies available to inhibit DUBs, curcumin derivatives appear promising, thus we hypothesized their use to enhance the efficacy of cisplatin in ovarian carcinoma preclinical models. The caffeic acid phenethyl ester (CAPE), inhibited ubiquitin-specific protease 8 (USP8), but not proteasomal DUBs in cell-free assays. When CAPE was combined with cisplatin in nine cell lines representative of various histotypes a synergistic effect was observed in TOV112D cells and in the cisplatin-resistant IGROV-1/Pt1 variant, both of endometrioid type and carrying mutant TP53. In the latter cells, persistent G1 accumulation upon combined treatment associated with p27(kip1) protein levels was observed. The synergy was not dependent on apoptosis induction, and appeared to occur in cells with higher USP8 levels. In vivo antitumor activity studies supported the advantage of the combination of CAPE and cisplatin in the subcutaneous model of cisplatin-resistant IGROV-1/Pt1 ovarian carcinoma as well as CAPE activity on intraperitoneal disease. This study reveals the therapeutic potential of CAPE in cisplatin-resistant ovarian tumors as well as in tumors expressing USP8.
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| 3. |
- Ek, Linda, et al.
(författare)
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Hand Assessment for Infants : normative reference values
- 2019
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Ingår i: Developmental Medicine & Child Neurology. - : Mac Keith Press. - 0012-1622 .- 1469-8749. ; 61:9, s. 1087-1092
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To create normative reference values for unilateral and bilateral use of the hands, using the Hand Assessment for Infants (HAI), a newly developed criterion-referenced assessment measuring hand use in infants aged 3 months to 12 months at risk of cerebral palsy (CP).METHOD: In total, 489 HAI assessments of typically developing infants (243 females, 246 males), aged 3 months to 10 months (mean 6mo 14d [SD 2mo 5d]), were collected in Italy and Sweden. Normative growth curves based on mean and SDs were created, as well as skill acquisition curves for each test item. Correlation to age and differences between groups based on sex and nationality, as well as differences between the right and the left hand, were investigated.RESULTS: The growth curves showed a steady increase in mean value and a decrease in SD over age. There were no differences between groups based on sex or nationality. There was a negligible mean difference (0.1 raw score) between the right and left hands.INTERPRETATION: HAI normative reference values are now available, which can assist in identifying deviating hand use for each month of age, as well as a side difference between hands in infants at risk of CP.WHAT THIS PAPER ADDS: A Hand Assessment for Infants (HAI) result greater than 2SD below the mean indicates atypical hand use. Skill acquisition curves describe the age at which typically developing infants master the HAI items. Most typically developing infants do not demonstrate asymmetry in hand use.
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| 4. |
- Eliasson, Ann-Christin, 1950-, et al.
(författare)
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Efficacy of baby-CIMT : study protocol for a randomised controlled trial on infants below age 12 months, with clinical signs of unilateral CP
- 2014
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Ingår i: BMC Pediatrics. - : BioMed Central. - 1471-2431. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Infants with unilateral brain lesions are at high risk of developing unilateral cerebral palsy (CP). Given the great plasticity of the young brain, possible interventions for infants at risk of unilateral CP deserve exploration. Constraint-induced movement therapy (CIMT) is known to be effective for older children with unilateral CP but is not systematically used for infants. The development of CIMT for infants (baby-CIMT) is described here, as is the methodology of an RCT comparing the effects on manual ability development of baby-CIMT versus baby-massage. The main hypothesis is that infants receiving baby-CIMT will develop manual ability in the involved hand faster than will infants receiving baby-massage in the first year of life.METHOD AND DESIGN: The study will be a randomised, controlled, prospective parallel-group trial. Invited infants will be to be randomised to either the baby-CIMT or the baby-massage group if they: 1) are at risk of developing unilateral CP due to a known neonatal event affecting the brain or 2) have been referred to Astrid Lindgren Children's Hospital due to asymmetric hand function. The inclusion criteria are age 3-8 months and established asymmetric hand use. Infants in both groups will receive two 6-weeks training periods separated by a 6-week pause, for 12 weeks in total of treatment. The primary outcome measure will be the new Hand Assessment for Infants (HAI) for evaluating manual ability. In addition, the Parenting Sense of Competence scale and Alberta Infant Motor Scale will be used. Clinical neuroimaging will be utilized to characterise the brain lesion type. To compare outcomes between treatment groups generalised linear models will be used.DISCUSSION: The model of early intensive intervention for hand function, baby-CIMT evaluated by the Hand Assessment for Infants (HAI) will have the potential to significantly increase our understanding of how early intervention of upper limb function in infants at risk of developing unilateral CP can be performed and measured.TRIAL REGISTRATION: SFO-V4072/2012, 05/22/2013.
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| 5. |
- Eliasson, Ann-Christin, et al.
(författare)
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Efficacy of the small step program in a randomised controlled trial for infants below age 12 months with clinical signs of CP; a study protocol
- 2016
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Ingår i: BMC Pediatrics. - London : Springer Science and Business Media LLC. - 1471-2431. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Children with cerebral palsy (CP) have life-long motor disorders, and they are typically subjected to extensive treatment throughout their childhood. Despite this, there is a lack of evidence supporting the effectiveness of early interventions aiming at improving motor function, activity, and participation in daily life. The study will evaluate the effectiveness of the newly developed Small Step Program, which is introduced to children at risk of developing CP during their first year of life. The intervention is based upon theories of early learning-induced brain plasticity and comprises important components of evidence-based intervention approaches used with older children with CP.Method and design: A two-group randomised control trial will be conducted. Invited infants at risk of developing CP due to a neonatal event affecting the brain will be randomised to either the Small Step Program or to usual care. They will be recruited from Astrid Lindgren Children's Hospital at regular check-up and included at age 3-8 months. The Small Step Program was designed to provide individualized, goal directed, and intensive intervention focusing on hand use, mobility, and communication in the child's own home environment and carried out by their parents who have been trained and coached by therapists. The primary endpoint will be approximately 35 weeks after the start of the intervention, and the secondary endpoint will be at 2 years of age. The primary outcome measure will be the Peabody Developmental Motor Scale (second edition). Secondary assessments will measure and describe the children's general and specific development and brain pathology. In addition, the parents' perspective of the program will be evaluated. General linear models will be used to compare outcomes between groups.Discussion: This paper presents the background and rationale for developing the Small-Step Program and the design and protocol of a randomized controlled trial. The aim of the Small Step Program is to influence development by enabling children to function on a higher level than if not treated by the program and to evaluate whether the program will affect parent's ability to cope with stress and anxiety related to having a child at risk of developing CP.
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| 6. |
- Gubat, Johannes, 1986-, et al.
(författare)
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Comprehensive Target Screening and Cellular Profiling of the Cancer-Active Compound b-AP15 Indicate Abrogation of Protein Homeostasis and Organelle Dysfunction as the Primary Mechanism of Action
- 2022
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Dienone compounds have been demonstrated to display tumor-selective anti-cancer activity independently of the mutational status of TP53. Previous studies have shown that cell death elicited by this class of compounds is associated with inhibition of the ubiquitin-proteasome system (UPS). Here we extend previous findings by showing that the dienone compound b-AP15 inhibits proteasomal degradation of long-lived proteins. We show that exposure to b-AP15 results in increased association of the chaperones VCP/p97/Cdc48 and BAG6 with proteasomes. Comparisons between the gene expression profile generated by b-AP15 to those elicited by siRNA showed that knock-down of the proteasome-associated deubiquitinase (DUB) USP14 is the closest related to drug response. USP14 is a validated target for b-AP15 and we show that b-AP15 binds covalently to two cysteines, Cys203 and Cys257, in the ubiquitin-binding pocket of the enzyme. Consistent with this, deletion of USP14 resulted in decreased sensitivity to b-AP15. Targeting of USP14 was, however, found to not fully account for the observed proteasome inhibition. In search for additional targets, we utilized genome-wide CRISPR/Cas9 library screening and Proteome Integral Solubility Alteration (PISA) to identify mechanistically essential genes and b-AP15 interacting proteins respectively. Deletion of genes encoding mitochondrial proteins decreased the sensitivity to b-AP15, suggesting that mitochondrial dysfunction is coupled to cell death induced by b-AP15. Enzymes known to be involved in Phase II detoxification such as aldo-ketoreductases and glutathione-S-transferases were identified as b-AP15-targets using PISA. The finding that different exploratory approaches yielded different results may be explained in terms of a “target” not necessarily connected to the “mechanism of action” thus highlighting the importance of a holistic approach in the identification of drug targets. We conclude that b-AP15, and likely also other dienone compounds of the same class, affect protein degradation and proteasome function at more than one level.
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| 7. |
- Gubat, Johannes, 1986-, et al.
(författare)
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Loss of the proteasomal deubiquitinase USP14 induces growth defects and a senescence phenotype in colorectal cancer cells
- 2024
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Ingår i: Scientific Reports. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- The proteasome-associated deubiquitinase USP14 is a potential drug target. Using an inducible USP14 knockout system in colon cancer cells, we found that USP14 depletion impedes cellular proliferation, induces cell cycle arrest, and leads to a senescence-like phenotype. Transcriptomic analysis revealed altered gene expression related to cell division and cellular differentiation. USP14 knockout cells also exhibited changes in morphology, actin distribution, and expression of actin cytoskeletal components. Increased ubiquitin turnover was observed, offset by upregulation of polyubiquitin genes UBB and UBC. Pharmacological inhibition of USP14 with IU1 increased ubiquitin turnover but did not affect cellular growth or morphology. BioGRID data identified USP14 interactors linked to actin cytoskeleton remodeling, DNA damage repair, mRNA splicing, and translation. In conclusion, USP14 loss in colon cancer cells induces a transient quiescent cancer phenotype not replicated by pharmacologic inhibition of its deubiquitinating activity.
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| 8. |
- Krumlinde-Sundholm, Lena, et al.
(författare)
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Development of the Hand Assessment for Infants : evidence of internal scale validity
- 2017
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Ingår i: Developmental Medicine & Child Neurology. - : Mac Keith Press. - 0012-1622 .- 1469-8749. ; 59:12, s. 1276-1283
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this study was to develop a descriptive and evaluative assessment of upper limb function for infants aged 3 to 12 months and to investigate its internal scale validity for use with infants at risk of unilateral cerebral palsy.METHOD: The concepts of the test items and scoring criteria were developed. Internal scale validity and aspects of reliability were investigated on the basis of 156 assessments of infants at 3 to 12 months corrected age (mean 7.2mo, SD 2.5) with signs of asymmetric hand use. Rasch measurement model analysis and non-parametric statistics were used.RESULTS: The new test, the Hand Assessment for Infants (HAI), consists of 12 unimanual and five bimanual items, each scored on a 3-point rating scale. It demonstrated a unidimensional construct and good fit to the Rasch model requirements. The excellent person reliability enabled person separation to six significant ability strata. The HAI produced an interval-level measure of bilateral hand use as well as unimanual scores of each hand, allowing a quantification of possible asymmetry expressed as an asymmetry index.INTERPRETATION: The HAI can be considered a valid assessment tool for measuring bilateral hand use and quantifying side difference between hands among infants at risk of developing unilateral cerebral palsy.WHAT THIS PAPER ADDS: The Hand Assessment for Infants (HAI) measures the use of both hands and quantifies a possible asymmetry of hand use. HAI is valid for infants at 3 to 12 months corrected age at risk of unilateral cerebral palsy.
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| 9. |
- Lässer, Cecilia, 1981, et al.
(författare)
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RNA-containing exosomes in human nasal secretions.
- 2011
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Ingår i: American journal of rhinology & allergy. - : SAGE Publications. - 1945-8932 .- 1945-8924. ; 25:2, s. 89-93
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exosomes are nanovesicles of endocytic origin released by cells and present in human body fluids such as plasma, breast milk, andbronchoalveolar lavage fluid. These vesicles take part in communication between cells. Recently, it was shown that exosomes contain both mRNA andmicroRNA. This RNA can be shuttled between cells (exosomal shuttle RNA), which is a new route of communication between cells. The aim of this study wasto determine whether nasal secretions harbor exosomes and furthermore, whether these exosomes contain RNA.METHODS: Human nasal lavage fluid (NLF) underwent centrifugation and filtration to discard cells and debris, followed by a final ultracentrifugation at 120,000 X g to pellet the exosomes. Exosomes were detected using electron microscopy (EM), flow cytometry, and Western blot. RNA was extracted and analyzed using a Bioanalyzer.RESULTS: Exosomes were visualized as 40-80 nm, CD63+ vesicles using EM. Flow cytometry of exosomes using anti-major histocompatibility complex classII beads revealed exosomes positive for the tetraspanins CD9, CD63, and CD81. Western blot confirmed the presence of exosomal protein and absence ofproteins from the endoplasmic reticulum (ER), because the exosomes were positive for Tsg101, but negative for the ER marker, calnexin. Bioanalyzer analysis revealed that, these exosomes contain RNA.CONCLUSION: This study shows for the first time that NLF contains exosomes and that these exosomes contain RNA. Further characterization of the exosomalRNA and proteins may provide important information about communication in the nose and potentially provide a source of biomarkers for upper airwaydiseases.
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| 10. |
- Salomonsson, Johannes, et al.
(författare)
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Transient interdomain interactions in free USP14 shape its conformational ensemble
- 2024
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Ingår i: Protein Science. - : WILEY. - 0961-8368 .- 1469-896X. ; 33:5
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Tidskriftsartikel (refereegranskat)abstract
- The deubiquitinase (DUB) ubiquitin-specific protease 14 (USP14) is a dual domain protein that plays a regulatory role in proteasomal degradation and has been identified as a promising therapeutic target. USP14 comprises a conserved USP domain and a ubiquitin-like (Ubl) domain separated by a 25-residue linker. The enzyme activity of USP14 is autoinhibited in solution, but is enhanced when bound to the proteasome, where the Ubl and USP domains of USP14 bind to the Rpn1 and Rpt1/Rpt2 units, respectively. No structure of full-length USP14 in the absence of proteasome has yet been presented, however, earlier work has described how transient interactions between Ubl and USP domains in USP4 and USP7 regulate DUB activity. To better understand the roles of the Ubl and USP domains in USP14, we studied the Ubl domain alone and in full-length USP14 by nuclear magnetic resonance spectroscopy and used small angle x-ray scattering and molecular modeling to visualize the entire USP14 protein ensemble. Jointly, our results show how transient interdomain interactions between the Ubl and USP domains of USP14 predispose its conformational ensemble for proteasome binding, which may have functional implications for proteasome regulation and may be exploited in the design of future USP14 inhibitors.
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