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Susan D Mathias - One of the best experts on this subject based on the ideXlab platform.
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an evaluation of the acromegaly treatment satisfaction questionnaire acro TSQ in adult patients with acromegaly including correlations with other patient reported outcome measures data from two large multicenter international studies
Pituitary, 2020Co-Authors: Maria Fleseriu, Leon Fogelfeld, Murray B Gordon, Jill Sisco, Ross D Crosby, William H Ludlam, Asi Haviv, Susan D MathiasAbstract:The Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) is a new patient-reported outcome (PRO) measure for patients with acromegaly receiving injectable somatostatin analogs (SSAs) to assess clinical symptoms and adverse drug reaction interference, treatment satisfaction, and convenience. We evaluated its scale structure, reliability, validity, responsiveness, and what constitutes clinically meaningful change. Data from two longitudinal studies (N = 79 and 82) of patients receiving a stable injectable SSA dose for ≥ 6 months who completed the Acro-TSQ and other collateral measures (e.g., AcroQoL, AIS, WPAI:SHP, EQ-5D-5L) were analyzed. The first study demonstrated internal consistency of the Acro-TSQ. However, several items had high ceiling effects, responsiveness could not be established, and the minimally important difference (MID) was not estimable. In the second study, factor analysis revealed six scales: Symptom Interference, Treatment Convenience, Injection Site Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Internal consistency and test–retest reliability were confirmed; most scales demonstrated significant differences in mean scores by disease severity. Correlations between Acro-TSQ scales and other collateral measures exceeded 0.30 in absolute value, confirming convergent validity. Responsiveness in Acro-TSQ scale scores reflected improved disease control. The MID was estimated for Symptom Interference (10–12 points), Treatment Convenience (9–11) and GI Interference (8–10). The Acro-TSQ is a brief, yet comprehensive tool to monitor important outcomes associated with injectable acromegaly SSA treatments. Its content reflects both disease and treatment burden as well as patient satisfaction, and its relevant for use in clinical studies.
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development of a novel patient reported measure for acromegaly the acro TSQ
Pituitary, 2019Co-Authors: Maria Fleseriu, Leon Fogelfeld, Murray B Gordon, Jill Sisco, William H Ludlam, Asi Haviv, Hilary H Colwell, Susan D MathiasAbstract:Somatostatin analogs (SSAs) represent a mainstay of medical treatment for acromegaly, currently available as either intramuscular or deep subcutaneous injections. Patient-reported outcomes (PROs) are increasingly common as relevant outcomes in studies of acromegaly and its treatment, but there are no validated PRO measures available that focus on the disease burden and the impact of treatment, specifically designed for use in patients with acromegaly. We sought to develop a new and unique PRO measure, the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ). Concept elicitation (CE) interviews were conducted with acromegaly patients in the United States receiving SSA injections at a stable dose for ≥ 6 months. A questionnaire was drafted based on these interviews; combined CE and cognitive debriefing (CE/CD) interviews were then conducted to confirm the content, clarity, and relevance of the questionnaire. Nineteen subjects completed interviews [n = 9 CE, n = 10 CE/CD; n = 15 Lanreotide Depot/Autogel (Somatuline), n = 4 Octreotide LAR (Sandostatin LAR)]. Most subjects responded positively when asked about the effectiveness of their current treatment; however, breakthrough symptoms, injection site reactions, and side effects were commonly reported and had negative impacts on social and emotional well-being and daily activities. All 10 subjects involved in debriefing interviews found the questionnaire to be relevant, easy to complete, and found the response options to be clear. The resulting 26-item Acro-TSQ covers symptoms and symptom control, gastrointestinal side effects and their impact on daily activities, the emotional impact of treatment, convenience and ease of use, and overall satisfaction. The Acro-TSQ is a novel PRO, focused on both disease burden and impact of treatment; it was found to be comprehensive, clear, and relevant for patients with acromegaly receiving injectable SSA treatment.
Steven E Cala - One of the best experts on this subject based on the ideXlab platform.
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rough endoplasmic reticulum to junctional sarcoplasmic reticulum trafficking of calsequestrin in adult cardiomyocytes
Journal of Molecular and Cellular Cardiology, 2010Co-Authors: Timothy P Mcfarland, Michelle L Milstein, Steven E CalaAbstract:Cardiac calsequestrin (CSQ) is synthesized on rough endoplasmic reticulum (ER), but concentrates within the junctional sarcoplasmic reticulum (SR) lumen where it becomes part of the Ca2+-release protein complex. To investigate CSQ trafficking through biosynthetic/secretory compartments of adult cardiomyocytes, CSQ-DsRed was overexpressed in cultured cells and examined using confocal fluorescence microscopy. By 48 h of adenovirus treatment, CSQ-DsRed fluorescence had specifically accumulated in perinuclear cisternae, where it co-localized with markers of rough ER. From rough ER, CSQ-DsRed appeared to traffic directly to junctional SR along a transverse (Z-line) pathway along which sec 23-positive (ER-exit) sites were enriched. In contrast to DsRed direct fluorescence that presumably reflected DsRed tetramer formation, both anti-DsRed and anti-CSQ immunofluorescence did not detect the perinuclear CSQ-DsRed protein, but labeled only junctional SR puncta. These putative CSQ-DsRed monomers, but not the fluorescent tetramers, were observed to traffic anterogradely over the course of a 48 h overexpression from rough ER towards the cell periphery. We propose a new model of CSQ and junctional SR protein traffic in the adult cardiomyocyte, wherein CSQ traffics from perinuclear cisternae, along contiguous ER/SR lumens in cardiomyocytes as a mobile monomer, but is retained in junctional SR as a polymer.
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inhibition of calsequestrin phosphorylation leads to its trafficking from rough endoplasmic reticulum
Biophysical Journal, 2010Co-Authors: Timothy P Mcfarland, Steven E CalaAbstract:Calsequestrin 2 (CSQ) is a protein in heart cells that concentrates within the sarcoplasmic reticulum (SR), where it incorporates into Ca2+-release complexes. CSQ has a single N-linked glycan that can be used to determine the extent of its trafficking through the secretory system, and multiple C-terminal protein kinase CK2 sensitive phosphorylation sites. Recent data suggests that polymerization of CSQ defines its localization, and leads to its retention within discrete secretory compartments. In these studies, we show that phosphorylation may be responsible for localization of cardiac CSQ within the rough ER of nonmuscle cells and cardiomyocytes. Triple point mutations were made to wild-type canine CSQ (CSQ-WT) phosphorylation sites, either mimicking (CSQ-aPP, S378,382,386E) or inhibiting phosphorylation (CSQ-nPP, S378,382,386A). Overexpression into COS cells showed that, compared to CSQ-WT, mannose trimming of the CSQ glycan increased for CSQ-nPP, reflecting movement out of rough ER; whereas no change was seen for CSQ-aPP. This apparent phosphorylation-dependent change in subcellular localization in COS cells could be observed by confocal immunofluorescence microscopy. The CK2 specific inhibitor tetrabromocinnamic acid (TBCA) blocks phosphorylation of CSQ in vitro by CK2 or by endogenous CSQ kinases with an identical dose response, supporting the identity of CK2 as the CSQ kinase. TBCA (100μM) also inhibited phosphorylation in cultured cells by roughly 80%. Analysis of CSQ overexpressed in these cells showed an effect on CSQ trafficking that was highly similar to the effects of the phosphorylation-site mutant CSQ-nPP. These data support a hypothesis that CSQ phosphorylation by protein kinase CK2 acts to retain cardiac CSQ in rough ER. In cardiomyocytes, growth-dependent phosphorylation of CSQ produces rough ER retention resulting in redistribution of CSQ from junctional SR to the nuclear envelope, the site of IP3-dependent ER Ca2+ storage.
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cardiac hypertrophy causes newly synthesized calsequestrin to remain around the nucleus in rough endoplasmic reticulum
Biophysical Journal, 2010Co-Authors: Steven E Cala, Sony Jacob, Naama H Sleiman, Hani N SabbahAbstract:Hypertrophy (LVH) leads to use of perinuclear Ca2+ distinct from junctional sarcoplasmic reticulum (jSR). Little is known about Ca2+-handling proteins associated with regulation of perinuclear Ca pools. Calsequestrin (CSQ), the Ca2+-binding protein of jSR, exists as a polymorphic collection of mass isoforms that results from actions of phosphatases and mannosidases following its biosynthesis in rough ER. To test the hypothesis that LVH triggers changes in CSQ structure by regulating its biosynthesis, we induced heart failure (LVEF <35%) in dogs by intracoronary microembolizations, resulting in increased cardiomyocyte cross-sectional area (60 ± 10%). Detergent-solubilized CSQ was purified from LV, and electrospray mass spectrometric analysis resolved individual CSQ protein structures in 3 failed and 3 normal hearts. In hypertrophic hearts, only higher mass CSQ structures were present, characteristic of perinuclear rough ER of cardiomyocytes (Figure). CSQ glycoforms and phosphoforms in LVH showed underprocessed structures characteristic of newly formed CSQ in rough ER that were more highly phosphorylated by CK2, a growth-activated kinase. These changes in CSQ processing in LVH may be part of a transformation from jSR Ca stores to perinuclear IP3-sensitive stores needed to maintain an altered phenotype.View Large Image | View Hi-Res Image | Download PowerPoint Slide
Giancarlo Orofino - One of the best experts on this subject based on the ideXlab platform.
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patient reported outcomes in an observational cohort of hiv 1 infected adults on darunavir cobicistat based regimens beyond viral suppression
The Patient: Patient-Centered Outcomes Research, 2020Co-Authors: Andrea Antinori, Maria Vittoria Cossu, Barbara Menzaghi, Gaetana Sterrantino, Nicola Squillace, Valentina Di Cristo, Annamaria Cattelan, Emanuele Foca, Antonella Castagna, Giancarlo OrofinoAbstract:OBJECTIVE: This prospective, multicenter, non-interventional cohort study enrolling human immunodeficiency virus (HIV)-1-infected, virally suppressed adult outpatients in Italy aimed to describe results obtained from patient-reported outcome questionnaires regarding treatment satisfaction and symptom perceptions in HIV-1-positive patients who switched to cobicistat-boosted darunavir antiretroviral regimens, coming from ritonavir-boosted protease inhibitors. METHODS: Patients entered this study between June 2016 and February 2017, once their treating physician had considered them eligible for cobicistat-boosted darunavir-based treatment as per clinical practice. Patients' satisfaction regarding regimen and current symptom burdens were assessed using two previously validated, patient-reported outcome questionnaires: HIV Treatment Satisfaction Questionnaire (HIV-TSQ) and HIV Symptoms Distress Module (HIV-SDM). These questionnaires were administered at prespecified time-points: enrollment (Visit 1), 4-8 weeks later (Visit 2), and 48 +/- 6 weeks after study enrollment (Visit 4). Data of patient-reported outcome total scores for both questionnaires are presented as median with 25th-75th percentiles. Questionnaires scores were analyzed overall and stratified by gender when applicable. A p value of less than 0.05 was considered statistically significant. A sensitivity analysis was conducted to evaluate the role of lost to follow-up, using the "last observation carried forward" method. RESULTS: A total of 348 patients were enrolled in this study; 296 patients (208 male and 88 female) provided both evaluable HIV-TSQ and HIV-SDM at enrollment and at 4-8 weeks, while 250 patients (174 male and 76 female) provided questionnaire data at enrollment and at 48 +/- 6 weeks. The total scores of HIV-TSQ showed improvements in patient satisfaction in the overall population both at Visit 2 and Visit 4 (p < 0.001, sign test) and also when stratified by gender throughout the study period. In addition, the overall burden of symptoms, as shown by the HIV-SDM scores, decreased. CONCLUSIONS: Switching to a cobicistat-boosted darunavir-based therapy led to overall increased patient satisfaction and reduced symptom burden when compared with previous regimens. The use of patient-reported outcomes in clinical daily practice could provide a useful tool towards achieving guideline goals to achieve "fourth 90", having 90% of virally suppressed patients with a good health-related quality of life.
Dale C Poulter - One of the best experts on this subject based on the ideXlab platform.
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Absolute Configuration of Hydroxysqualene. An Intermediate in Bacterial Hopanoid Biosynthesis
2016Co-Authors: Jian-jung Pan, Gurusankar Ramamoorthy, Dale C PoulterAbstract:Squalene (SQ) is a key intermediate in hopanoid biosynthesis. Many bacteria synthesize SQ from farnesyl diphosphate (FPP) in three steps: FPP to (1R,2R,3R)-presqualene diphosphate (PSPP), (1R,2R,3R)-PSPP to hydroxysqualene (HSQ), and HSQ to SQ. Chemical, biochemical, and spectroscopic methods were used to establish that HSQ synthase synthesizes (S)-HSQ. In contrast, eukaryotic squalene synthase catalyzes solvolysis of (1R,2R,3R)-PSPP to give (R)-HSQ. The bacterial enzyme that reduces HSQ to SQ does not accept (R)-HSQ as a substrate
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recombinant squalene synthase synthesis of non head to tail isoprenoids in the absence of nadph
Journal of the American Chemical Society, 2002Co-Authors: Michael B Jarstfer, Dong Lu Zhang, Dale C PoulterAbstract:Squalene synthase (SQase) catalyzes two consecutive reactions in sterol biosynthesis. The first is the condensation of two molecules of farnesyl diphosphate (FPP) to form a cyclopropylcarbinyl intermediate, presqualene diphosphate (PSPP). The subsequent conversion of PSPP to squalene (SQ) involves an extensive rearrangement of the carbon skeleton and a NADPH-dependent reduction. Incubation of a truncated soluble form of recombinant yeast SQase with FPP in buffer lacking NADPH gave (1R,2R,3R)-PSPP. As the incubation continued, SQase catalyzed the subsequent conversion of PSPP to a mixture of triterpenes. Two of the major products, (Z)-dehydrosqualene (DSQ) and (R)-12-hydroxysqualene (HSQ), have the same 1‘−1 linkage between the farnesyl units from FPP that is found in squalene. The other major product, (10S,13S)-10-hydroxybotryococcene (HBO), has a 1‘−3 linkage between the farnesyl units. Small quantities of (S)-HSQ and (10R,13S)-HBO were also formed. Three additional triterpenes, the allylic isomers of HS...
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recombinant squalene synthase a mechanism for the rearrangement of presqualene diphosphate to squalene
Journal of the American Chemical Society, 2002Co-Authors: Brian S J Blagg, Michael B Jarstfer, Daniel H Rogers, Dale C PoulterAbstract:Squalene synthase (SQase) catalyzes the condensation of two molecules of farnesyl diphosphate (FPP) to form presqualene diphosphate (PSPP) and the subsequent rearrangement and NADPH-dependent reduction of PSPP to squalene (SQ). These reactions are the first committed steps in cholesterol biosynthesis. When recombinant SQase was incubated with FPP in the presence of dihydroNADPH (NADPH3, an unreactive analogue lacking the 5,6-double bond in the nicotinamide ring), three products were formed: dehydrosqualene (DSQ), a C30 analogue of phytoene; 10(S)-hydroxysqualene (HSQ), a hydroxy analogue of squalene; and rillingol (ROH), a cyclopropylcarbinyl alcohol formed by addition of water to the tertiary cyclopropylcarbinyl cation previously proposed as an intermediate in the rearrangement of PSPP to SQ (Poulter, C. D. Acc. Chem. Res. 1990, 23, 70−77). The structure and absolute stereochemistry of the tertiary cyclopropylcarbinyl alcohol were established by synthesis using two independent routes. Isolation of ROH f...
Maria Fleseriu - One of the best experts on this subject based on the ideXlab platform.
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an evaluation of the acromegaly treatment satisfaction questionnaire acro TSQ in adult patients with acromegaly including correlations with other patient reported outcome measures data from two large multicenter international studies
Pituitary, 2020Co-Authors: Maria Fleseriu, Leon Fogelfeld, Murray B Gordon, Jill Sisco, Ross D Crosby, William H Ludlam, Asi Haviv, Susan D MathiasAbstract:The Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ) is a new patient-reported outcome (PRO) measure for patients with acromegaly receiving injectable somatostatin analogs (SSAs) to assess clinical symptoms and adverse drug reaction interference, treatment satisfaction, and convenience. We evaluated its scale structure, reliability, validity, responsiveness, and what constitutes clinically meaningful change. Data from two longitudinal studies (N = 79 and 82) of patients receiving a stable injectable SSA dose for ≥ 6 months who completed the Acro-TSQ and other collateral measures (e.g., AcroQoL, AIS, WPAI:SHP, EQ-5D-5L) were analyzed. The first study demonstrated internal consistency of the Acro-TSQ. However, several items had high ceiling effects, responsiveness could not be established, and the minimally important difference (MID) was not estimable. In the second study, factor analysis revealed six scales: Symptom Interference, Treatment Convenience, Injection Site Interference, GI Interference, Treatment Satisfaction, and Emotional Reaction. Internal consistency and test–retest reliability were confirmed; most scales demonstrated significant differences in mean scores by disease severity. Correlations between Acro-TSQ scales and other collateral measures exceeded 0.30 in absolute value, confirming convergent validity. Responsiveness in Acro-TSQ scale scores reflected improved disease control. The MID was estimated for Symptom Interference (10–12 points), Treatment Convenience (9–11) and GI Interference (8–10). The Acro-TSQ is a brief, yet comprehensive tool to monitor important outcomes associated with injectable acromegaly SSA treatments. Its content reflects both disease and treatment burden as well as patient satisfaction, and its relevant for use in clinical studies.
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development of a novel patient reported measure for acromegaly the acro TSQ
Pituitary, 2019Co-Authors: Maria Fleseriu, Leon Fogelfeld, Murray B Gordon, Jill Sisco, William H Ludlam, Asi Haviv, Hilary H Colwell, Susan D MathiasAbstract:Somatostatin analogs (SSAs) represent a mainstay of medical treatment for acromegaly, currently available as either intramuscular or deep subcutaneous injections. Patient-reported outcomes (PROs) are increasingly common as relevant outcomes in studies of acromegaly and its treatment, but there are no validated PRO measures available that focus on the disease burden and the impact of treatment, specifically designed for use in patients with acromegaly. We sought to develop a new and unique PRO measure, the Acromegaly Treatment Satisfaction Questionnaire (Acro-TSQ). Concept elicitation (CE) interviews were conducted with acromegaly patients in the United States receiving SSA injections at a stable dose for ≥ 6 months. A questionnaire was drafted based on these interviews; combined CE and cognitive debriefing (CE/CD) interviews were then conducted to confirm the content, clarity, and relevance of the questionnaire. Nineteen subjects completed interviews [n = 9 CE, n = 10 CE/CD; n = 15 Lanreotide Depot/Autogel (Somatuline), n = 4 Octreotide LAR (Sandostatin LAR)]. Most subjects responded positively when asked about the effectiveness of their current treatment; however, breakthrough symptoms, injection site reactions, and side effects were commonly reported and had negative impacts on social and emotional well-being and daily activities. All 10 subjects involved in debriefing interviews found the questionnaire to be relevant, easy to complete, and found the response options to be clear. The resulting 26-item Acro-TSQ covers symptoms and symptom control, gastrointestinal side effects and their impact on daily activities, the emotional impact of treatment, convenience and ease of use, and overall satisfaction. The Acro-TSQ is a novel PRO, focused on both disease burden and impact of treatment; it was found to be comprehensive, clear, and relevant for patients with acromegaly receiving injectable SSA treatment.
