Intracellular signaling cascades are a series of regulated protein-protein interactions that may provide a number of targets for potential drug discovery. Here, the authors examine the interaction of regulators of G-protein signaling (RGS) proteins with the G-protein Gαo, using a flow cytometry protein interaction assay (FCPIA). FCPIA accurately measures nanomolar binding constants of this protein-protein interaction and has been used in high-throughput screening. This report focuses on 5 RGS proteins (4, 6, 7, 8, and 16). To increase the content of screens, the authors assessed high-throughput screening of these RGS proteins in multiplex, by establishing binding constants of each RGS with Gαo in isolation, and then in a multiplex format with 5 RGS proteins present. To use this methodology as a higher-content multiplex protein-protein interaction screen, they established Z-factor values for RGS proteins in multiplex of 0.73 to 0.92, indicating this method is suitable for screening using FCPIA. To increase throughput, they also compressed a set of 8000 compounds by combining 4 compounds in a single assay well. Subsequent deconvolution of the compounds mixtures verified the identification of active compounds at specific RGS targets in their mixtures using the polyplexed FCPIA method. (Journal of Biomolecular Screening 2009: 610-619)
This study's purpose was to provide qualitative evidence to support the development of two observer‐reported outcome measures assessing the physical symptoms/complications of achondroplasia in children and impacts on children's quality of life. Individual/focus group concept elicitation interviews were conducted with parents of children aged 2 to <12 years with achondroplasia and experts. Qualitative analysis of transcripts, based on an adapted grounded theory approach, informed item generation and measure development. Cognitive debriefing (CD) interviews were conducted with parents to confirm relevance and understanding. Thirty‐six parents participated in concept elicitation interviews. The analysis identified major physical symptoms/complications and impacts of achondroplasia, which informed the development of the Achondroplasia Child Experience Measures (ACEMs): ACEM—Symptom and ACEM—Impact. ACEM—Symptom was comprised of eight major symptoms/complications including pain (58%), ear infections/fluid in ear (56%), and low stamina/tiring easily (56%). ACEM—Impact consisted of 31 major impacts in the domains of daily functioning, emotional well‐being, social well‐being, and need for assistance/adaptive devices. Impacts on functioning included difficulty reaching objects/high places (89%) and toileting (67%). Emotional impacts included feeling different (53%) and feeling frustrated/annoyed (47%). Social impacts included difficulty participating in sports/physical play (86%) and being treated as younger than age (83%). Following CD interviews with 16 additional parents, validation‐ready ACEM measures were generated. The study improves our understanding of the experiences of children with achondroplasia and provides evidence supporting the content validity of the ACEMs. Validated ACEMs may be used to assess potential benefits of future treatments for comorbidities of achondroplasia.
Background: Regulators of G protein signaling (RGSs) accelerate GTP hydrolysis by Gα subunits and profoundly inhibit signaling by G protein-coupled receptors (GPCRs). The distinct expression patterns and pathophysiologic regulation of RGS proteins suggest that inhibitors may have therapeutic potential. We recently described a focused one-bead, one-compound (OBOC) library screen to identify peptide inhibitors of RGS4. Here we extend our observations to include another peptide with a different mechanism of action.
Purpose This study’s purpose was to develop a better understanding of the experiences of parents of children with achondroplasia and to provide qualitative evidence to support the development of a patient-reported outcome (PRO) measure of parent impacts. Methods Concept elicitation (CE) individual/focus group interviews were conducted with parents of children aged 2 to < 12 years with achondroplasia in the United States and Spain. The qualitative analysis informed the PRO measure development. Cognitive debriefing (CD) interviews were conducted to ensure parent understanding and item relevance. Results Thirty-six parents participated in individual/focus group CE interviews. The analysis identified parent impacts in four domains, including caretaking responsibilities, emotional well-being, family, and work, and results informed the development of the Achondroplasia Parent Experience Measure (APEM). Caretaking responsibilities included managing child’s medical care (92%), helping child with self-care (67%), advocating for child (64%), assisting child (56%), and observing/monitoring child (e.g., to ensure safety; 47%). Impacts on parents’ emotional well-being included worry about the future (75%), worry about child’s physical health (67%), safety concerns (50%), feeling stressed/overwhelmed (44%), and worry about child’s social relationships (42%). Impacts on family and work included family strain (56%), limiting/adapting family activities (42%), and missed work time (50%). CD interviews with an additional 16 parents of children with achondroplasia confirmed understanding and item relevance. Conclusion The results improve our understanding of the experiences of parents of children with achondroplasia and provide qualitative evidence to support the content validity of the APEM. A psychometric study is needed to validate the measure.
Background Currently, there is limited research on how having a child diagnosed with achondroplasia affects parents’ lives. The purpose of the study was to investigate the experiences of parents of infants and young children less than two years of age with achondroplasia. Methods Concept elicitation interviews were conducted with parents of children less than 2 years of age with achondroplasia in the United States and Spain. Using grounded theory methods modified for health outcomes research, a qualitative analysis of interview transcripts was conducted. Based on the qualitative analysis, a preliminary theoretical model of the experiences of parents of infants and young children with achondroplasia was developed. Results Fifteen parents, including 14 mothers and 1 father from 15 unique families, participated in individual or focus group concept elicitation interviews in the US (n = 9) and Spain (n = 6). The qualitative analysis identified four key parent impact domains, which included caretaking responsibilities, impacts on emotional well-being, having worries and concerns about their child, and impacts on daily well-being. Frequently discussed caretaking responsibilities among parents were managing child’s medical care/treatment (93%), obtaining adaptations/items for child (73%), and monitoring child to avoid complications of achondroplasia (67%). Emotional impacts included feeling stressed/overwhelmed (67%), depressed/sad (40%), and anxious/nervous (33%). Worries and concerns included worry/concern about the future (100%), concerns regarding child’s physical health (87%), worry about child’s social well-being (80%), concern for child’s emotional well-being (73%), and worry about child being able to function independently (67%). Daily well-being impacts included family strain (60%), missed work time (47%), and missed/limited social activities (33%). Based on the qualitative findings, a preliminary theoretical model depicting the experiences of parents of infants and young children with achondroplasia was created. Conclusions The study sheds light on the range of impacts that parents of infants and young children with achondroplasia may experience, including caretaking responsibilities, impacts on emotional well-being, worries/concerns regarding their child, and impacts on daily well-being. The theoretical model of parent experiences may provide a helpful framework for informing future research and clinical practice.
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