While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody–drug conjugate (ADC) ...could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
We report measurements of the parity-conserving beam-normal single-spin elastic scattering asymmetries \(B_n\) on \(^{12}\)C and \(^{27}\)Al, obtained with an electron beam polarized transverse to ...its momentum direction. These measurements add an additional kinematic point to a series of previous measurements of \(B_n\) on \(^{12}\)C and provide a first measurement on \(^{27}\)Al. The experiment utilized the Qweak apparatus at Jefferson Lab with a beam energy of 1.158 GeV. The average lab scattering angle for both targets was 7.7 degrees, and the average \(Q^2\) for both targets was 0.02437 GeV\(^2\) (Q=0.1561 GeV). The asymmetries are \(B_n\) = -10.68 \(\pm\) 0.90 stat) \(\pm\) 0.57 (syst) ppm for \(^{12}\)C and \(B_n\) = -12.16 \(\pm\) 0.58 (stat) \(\pm\) 0.62 (syst) ppm for \(^{27}\)Al. The results are consistent with theoretical predictions, and are compared to existing data. When scaled by Z/A, the Q-dependence of all the far-forward angle (theta < 10 degrees) data from \(^{1}\)H to \(^{27}\)Al can be described by the same slope out to \(Q \approx 0.35\) GeV. Larger-angle data from other experiments in the same Q range are consistent with a slope about twice as steep.
Background
Antitachycardia pacing (ATP) provides safe and painless termination of reentrant ventricular arrhythmias in patients with implantable cardioverter defibrillator (ICDs), improving their ...quality of life. Established predictors of ATP responsiveness are not well known; only longer ventricular tachycardia (VT) cycle length and higher ejection fraction have been found to predict ATP success.
Objective
To investigate clinical and ECG predictors of ATP response in ICD patients with monomorphic VT.
Methods
The ICD clinic database was searched for monomorphic VT events requiring ICD therapy in patients with ischemic or non‐ischemic cardiomyopathy. Each patient's first ICD encounter for VT was assessed. Patient demographics, clinical characteristics, VT rate, and ATP responsiveness (always, sometimes, and never successful) were recorded. An ECG was analyzed for QRS morphology and duration. Data was assessed for predictors of ATP responsiveness.
Results
In 527 patients, characteristics associated with always successful ATP included ACE‐I/ARB therapy and slower VT rate (never successful ATP 197 ± 28 bpm, sometimes successful ATP 190 ± 27 bpm, always successful ATP 183 ± 22 bpm, P < .0001). Secondary prevention indication, amiodarone therapy, and longer QRS duration were associated with ATP failure. After multivariate analysis, only faster VT rate and amiodarone therapy were predictive of ATP failure.
Conclusions
Neither QRS morphology nor duration was predictive of ATP success. Slower VT rate was predictive of repeated ATP responsiveness. Amiodarone therapy, which is known to increase VT cycle length, interestingly was associated with ATP failure for unclear reasons. More individualized and possibly more aggressive ATP programming may be warranted in patients on amiodarone.
Recent studies of the northeastern part of the Tibetan Plateau have called attention to two emerging views of how the Tibetan Plateau has grown. First, deformation in northern Tibet began essentially ...at the time of collision with India, not 10–20 Myr later as might be expected if the locus of activity migrated northward as India penetrated the rest of Eurasia. Thus, the north‐south dimensions of the Tibetan Plateau were set mainly by differences in lithospheric strength, with strong lithosphere beneath India and the Tarim and Qaidam basins steadily encroaching on one another as the region between them, the present‐day Tibetan Plateau, deformed, and its north‐south dimension became narrower. Second, abundant evidence calls for acceleration of deformation, including the formation of new faults, in northeastern Tibet since ~15 Ma and a less precisely dated change in orientation of crustal shortening since ~20 Ma. This reorientation of crustal shortening and roughly concurrent outward growth of high terrain, which swings from NNE‐SSW in northern Tibet to more NE‐SW and even ENE‐WSW in the easternmost part of northeastern Tibet, are likely to be, in part, a consequence of crustal thickening within the high Tibetan Plateau reaching a limit, and the locus of continued shortening then migrating to the northeastern and eastern flanks. These changes in rates and orientation also could result from removal of some or all mantle lithosphere and increased gravitational potential energy per unit area and from a weakening of crustal material so that it could flow in response to pressure gradients set by evolving differences in elevation.
Key Points
The north‐south limits of Tibet were set by lateral variations in strength
Roughly 15 million years ago, deformation of NE Tibet accelerated
Since 20–15 million years ago, the orientation of shortening rotated eastward
Summary
Gut bacteria recognize accessible glycan substrates within a complex environment. Carbohydrate binding modules (CBMs) of cell surface glycoside hydrolases often drive binding to the target ...substrate. Eubacterium rectale, an important butyrate‐producing organism in the gut, consumes a limited range of substrates, including starch. Host consumption of resistant starch increases the abundance of E. rectale in the intestine, likely because it successfully captures the products of resistant starch degradation by other bacteria. Here, we demonstrate that the cell wall anchored starch‐degrading α‐amylase, Amy13K of E. rectale harbors five CBMs that all target starch with differing specificities. Intriguingly these CBMs efficiently bind to both regular and high amylose corn starch (a type of resistant starch), but have almost no affinity for potato starch (another type of resistant starch). Removal of these CBMs from Amy13K reduces the activity level of the enzyme toward corn starches by ∼40‐fold, down to the level of activity toward potato starch, suggesting that the CBMs facilitate activity on corn starch and allow its utilization in vivo. The specificity of the Amy13K CBMs provides a molecular rationale for why E. rectale is able to only use certain starch types without the aid of other organisms.
Gut bacteria attach to dietary fiber such as starch via carbohydrate binding modules (CBMs). Here, we demonstrate that a cell surface starch‐degrading enzyme Amy13K from the prominent gut bacterium Eurbacterium rectale harbors five CBMs that have different specificities and affinity for starch. The specificity of the Amy13K CBMs provides a molecular rationale for why E. rectale is only able to process certain types of dietary starch in the human large intestine.
While thousands of patients undergo stress testing annually, the risk of exercise and pharmacologic stress in patients with carotid artery disease has not been fully defined but is of concern as ...patients are at risk for cerebrovascular accidents and transient ischemic attacks.
All patients with either ultrasound or CTA evaluation of their carotid arteries from over a 10 year period who underwent stress testing within 180 days without intervening carotid intervention were reviewed for any adverse events within 24 hours of their stress test. The primary end point was any cerebrovascular event or syncope while the secondary endpoints included death, myocardial infarction, urgent angiography, urgent revascularization, or exaggerated hemodynamic response (systolic BP drop > 20 mmHg or systolic BP > 180 mmHg at peak stress). Patients were stratified into categories based on their level of carotid disease. Patients with severe carotid stenosis were propensity matched to those with mild or no stenosis.
A total of 4457 patients underwent carotid ultrasound, 10,644 CTA, and 16,011 had stress testing during this time period with 514 having both a carotid evaluation and a stress test within 6 months. After propensity matching, 62 patients with severe carotid stenosis were matched to 170 patients with mild or no carotid stenosis. Incidentally, all patients with severe carotid stenosis underwent pharmacologic stress. There were no primary endpoints and only three secondary endpoints in two patients in the mild or no carotid stenosis group. The proportion of exaggerated hemodynamic response to stress was similar in both groups—21.0% in the carotid stenosis group vs 31.2% without (P = .17) having a significant drop in systolic BP, and 3.2% vs 4.7% (P = 1.0) having a significantly elevated systolic BP.
In this study cohort there were few primary and secondary outcome events with no events occurring in patients with significant carotid stenosis. Additionally, there was no difference in exaggerated hemodynamic responses. While these results suggest that stress testing entails no demonstrable increased risk in patients with significant carotid stenosis, continued care should be taken given the limitations of the small size of this study.
Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic ...health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.
A two-tiered, nested molecular phylogenetic study of panicoid grasses to explore character state transitions between the C sub(3) and C sub(4) adaptive syndromes is presented. A broad survey of 92 ...panicoid species was sampled for the grass-specific insert sequence in the chloroplast RNA polymerase locus (rpoC2), combining published and unpublished sequences. This portion of the study also included an intensive phylogenetic investigation of one clade of seven species that included Steinchisma hians, which is notable for exhibiting intermediacy between the C sub(3) and C sub(4) photosynthetic types. Both rpoC2 data and previously published sequences of the F subunit of an NADH-dependent dehydrogenase were analyzed together for this small group. A rigorous phylogenetic investigation of S. hians and 13 other species of Panicoideae included in the broad survey was then performed with sequences of both rpoC2 and the externally transcribed spacer region of the nuclear ribosomal repeat. These 14 species were selected to maximize representation among photosynthetic subtypes. Combined analysis resolved single origins of two photosynthetic subtypes. A reversion of C sub(4) to C sub(3) photosynthesis during the evolution of the lineage that includes S. hians is identified. These and other recent results indicate that repeated reversions from C sub(4) to C sub(3) have occurred. The C sub(3) species Panicum laxum has a strongly supported sister group relationship to S. hians (C sub(3)-C sub(4)). The most parsimonious interpretation is that S. hians represents an incipient reversal from C sub(3) to C sub(4) photosynthesis, beginning with the capacity to compartmentalize photorespiratory metabolism in the bundle sheath tissue.
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