Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively ...measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer 18FAGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. 18FAGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with IC50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo 18FAGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.
Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively ...measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer sup.18FAGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. sup.18FAGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with ICsub.50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo sup.18FAGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.
5-Enolpyruvylshikimate-3-phosphate synthase (EPSPS) catalyzes the transfer of a carboxyvinyl group from phosphoenolpyruvate (PEP) to shikimate-3-phosphate and in plants is the target of the herbicide ...glyphosate. EPSPSs with high catalytic efficiency and insensitivity to glyphosate are of microbial origin, including the enzyme from Agrobacterium strain CP4, in which insensitivity is conferred by an active site alanine. In the sequence context of plant EPSPSs, alanine in place of glycine at the equivalent position interferes with the binding of both glyphosate and PEP. We show here that iterative optimization of maize EPSPS containing the G101A substitution yielded variants on par with CP4 in terms of catalytic activity in the presence of glyphosate. The improvement relative to G101A alone was entirely due to reduction in Km for PEP from 333 to 18 μm, versus 9.5 μm for native maize EPSPS. A large portion of the reduction in Km was conferred by two down-sizing substitutions (L97C and V332A) within 8 Å of glyphosate, which together reduced Km for PEP to 43 μm. Although the original optimization was conducted with maize EPSPS, contextually homologous substitutions conferred similar properties to the EPSPSs of other crops. We also discovered a variant having the known glyphosate-desensitizing substitution P106L plus three additional ones that reduced the Km for PEP from 47 μm, observed with P106L alone, to 10.3 μm. The improvements obtained with both Ala101 and Leu106 have implications regarding glyphosate-tolerant crops and weeds.
Background
The use of intravascular lithotripsy (IVL) in chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has received limited study.
Methods
We analyzed the baseline clinical ...and angiographic characteristics and procedural outcomes of 82 CTO PCIs that required IVL at 14 centers between 2020 and 2022.
Results
During the study period, IVL was used in 82 of 3301 (2.5%) CTO PCI procedures (0.4% in 2020 and 7% in 2022; p for trend < 0.001). Mean patient age was 69 ± 11 years and 79% were men. The prevalence of hypertension (95%), diabetes mellitus (62%), and prior PCI (61%) was high. The most common target vessel was the right coronary artery (54%), followed by the left circumflex (23%). The mean J‐CTO and PROGRESS‐CTO scores were 2.8 ± 1.1 and 1.3 ± 1.0, respectively. Antegrade wiring was the final successful crossing strategy in 65% and the retrograde approach was used in 22%. IVL was used in 10% of all heavily calcified lesions and 11% of all balloon undilatable lesions. The 3.5 mm lithotripsy balloon was the most commonly used balloon (28%). The mean number of pulses per lithotripsy run was 33 ± 32 and the median duration of lithotripsy was 80 (interquartile range: 40−103) seconds. Technical and procedural success was achieved in 77 (94%) and 74 (90%) cases, respectively. Two (2.4%) Ellis Class 2 perforations occurred after IVL use and were managed conservatively.
Conclusion
IVL is increasingly being used in CTO PCI with encouraging outcomes.
There is limited data on equipment loss or entrapment during chronic total occlusion (CTO) percutaneous coronary intervention (PCI).
We analyzed the baseline clinical and angiographic characteristics ...and outcomes of equipment loss/entrapment at 43 US and non-US centers between 2017 and 2023.
Equipment loss/entrapment was reported in 40 (0.4%) of 10 719 cases during the study period. These included guidewire entrapment/fracture (n = 21), microcatheter entrapment/fracture (n = 11), stent loss (n = 8) and balloon entrapment/fracture/rupture (n = 5). The equipment loss/entrapment cases were more likely to have moderate to severe calcification, longer lesion length, higher J-CTO and PROGRESS-CTO complications scores, and use of the retrograde approach compared with the remaining cases. Retrieval was attempted in 71.4% of the guidewire, 90.9% of the microcatheter, 100% of the stent loss, and 100% of the balloon cases, and was successful in 26.7%, 30.0%, 50%, and 40% of the cases, respectively. Procedures complicated by equipment loss/entrapment had higher procedure and fluoroscopy time, contrast volume and patient air kerma radiation dose, lower procedural (60.0% vs 85.6%, P less than .001) and technical (75.0% vs 86.8%, P = .05) success, and higher incidence of major adverse cardiac events (MACE) (17.5% vs 1.8%, P less than .001), acute MI (7.5% vs 0.4%, P less than .001), emergency coronary artery bypass graft (CABG) (2.5% vs 0.1%, P = .03), perforation (20.0% vs 4.9%, P less than .001), and death (7.5% vs 0.4%, P less than .001).
Equipment loss is a rare complication of CTO PCI; it is more common in complex CTOs and is associated with lower technical success and higher MACE.
Ranolazine is an anti-anginal medication given to patients with chronic angina and persistent symptoms despite medical therapy. We examined 11 491 chronic total occlusion (CTO) percutaneous coronary ...interventions (PCI) that were performed at 41 US and non-US centers between 2012 and 2023 in the PROGRESS-CTO Registry. Patients on ranolazine at baseline had more comorbidities, more complex lesions, lower procedural and technical success (based on univariable but not multivariable analysis), and higher incidence of major adverse cardiac events (MACE) (on both univariable and multivariable analysis).
Antegrade wiring is the most commonly used chronic total occlusion (CTO) crossing technique.
Using data from the PROGRESS CTO registry (Prospective Global Registry for the Study of Chronic Total ...Occlusion Intervention; Clinicaltrials.gov identifier: NCT02061436), we examined the clinical and angiographic characteristics and procedural outcomes of CTO percutaneous coronary interventions (PCIs) performed using a primary antegrade wiring strategy.
Of the 13 563 CTO PCIs performed at 46 centers between 2012 and 2023, a primary antegrade wiring strategy was used in 11 332 (83.6%). Upon multivariable logistic regression analysis, proximal cap ambiguity (odds ratio OR: 0.52; 95% CI, 0.46-0.59), side branch at the proximal cap (OR: 0.85; 95% CI, 0.77-0.95), blunt/no stump (OR: 0.52; 95% CI: 0.47-0.59), increasing lesion length (OR per 10 mm increase: 0.79; 95% CI, 0.76-0.81), moderate to severe calcification (OR: 0.73; 95% CI, 0.66-0.81), moderate to severe proximal tortuosity (OR: 0.67; 95% CI, 0.59-0.75), bifurcation at the distal cap (OR: 0.66; 95% CI, 0.59-0.73), left anterior descending artery CTO (OR vs right coronary artery: 1.44; 95% CI, 1.28-1.62) and left circumflex CTO (OR vs right coronary artery: 1.22; 95% CI, 1.07-1.40), non-in-stent restenosis lesion (OR: 0.56; 95% CI, 0.49-0.65), and good distal landing zone (OR: 1.18; 95% CI, 1.06-1.32) were independently associated with primary antegrade wiring crossing success.
The use of antegrade wiring as the initial strategy was high (83.6%) in our registry. We identified several parameters associated with primary antegrade wiring success.
The Experiment for Space Radiation Analysis (ESRA) is the next in the series of Demonstration and Validation (DemVal) projects the Los Alamos National Laboratory (LANL) program will fly. The ESRA ...program will mature technologies such as the novel Wide-field-of-view Plasma Spectrometer (WPS) and the Energetic Charged Particle (ECP) telescope, along with high voltage power supply, a 3U Eurocard single board computers, flight software architecture, and analog-to-digital electronics. The WPS and ECP sensors are intended to actively monitor the local space environment, thus allowing for the attribution and rapid anomaly resolution of unanticipated instrument or spacecraft behavior as a result of space weather effects.
Displacing Whiteness makes a unique contribution to the study of race dominance. Its theoretical innovations in the analysis of whiteness are integrated with careful, substantive explorations of ...whiteness on an international, multiracial, cross-class, and gendered terrain. Contributors localize whiteness, as well as explore its sociological, anthropological, literary, and political dimensions. Approaching whiteness as a plural rather than singular concept, the essays describe, for instance, African American, Chicana/o, European American, and British experiences of whiteness. The contributors offer critical readings of theory, literature, film and popular culture; ethnographic analyses; explorations of identity formation; and examinations of racism and political process. Essays examine the alarming epidemic of angry white men on both sides of the Atlantic; far-right electoral politics in the UK; underclass white people in Detroit; whiteness in "brownface" in the film Gandhi; the engendering of whiteness in Chicana/o movement discourses; "whiteface" literature; Roland Barthes as a critic of white consciousness; whiteness in the black imagination; the inclusion and exclusion of suburban "brown-skinned white girls"; and the slippery relationships between culture, race, and nation in the history of whiteness. Displacing Whiteness breaks new ground by specifying how whiteness is lived, engaged, appropriated, and theorized in a range of geographical locations and historical moments, representing a necessary advance in analytical thinking surrounding the burgeoning study of race and culture. Contributors. Rebecca Aanerud, Angie Chabram-Dernersesian, Phil Cohen, Ruth Frankenberg, John Hartigan Jr., bell hooks, T. Muraleedharan, Chéla Sandoval, France Winddance Twine, Vron Ware, David Wellman
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