HIV-1 establishes a life-long reservoir of virally infected cells which cannot be eliminated by antiretroviral therapy (ART). Here, we demonstrate a markedly altered viral reservoir profile of ...long-term ART-treated individuals, characterized by large clones of intact proviruses preferentially integrated in heterochromatin locations, most prominently in centromeric satellite/micro-satellite DNA. Longitudinal evaluations suggested that this specific reservoir configuration results from selection processes that promote the persistence of intact proviruses in repressive chromatin positions, while proviruses in permissive chromosomal locations are more likely to be eliminated. A bias toward chromosomal integration sites in heterochromatin locations was also observed for intact proviruses in study participants who maintained viral control after discontinuation of antiretroviral therapy. Together, these results raise the possibility that antiviral selection mechanisms during long-term ART may induce an HIV-1 reservoir structure with features of deep latency and, possibly, more limited abilities to drive rebound viremia upon treatment interruptions.
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•After LT-ART, intact HIV proviruses are predominantly integrated in heterochromatin•These distinct integration sites result from longitudinal selection mechanisms•No similar selection processes are observed for defective proviruses•Intact proviruses are mainly integrated in heterochromatin in post-treatment controllers
Lian et al. show that following two decades of continuous antiretroviral therapy, the integration site profile of intact HIV-1 proviruses is heavily biased toward heterochromatin locations, likely as a result of immune selection mechanisms; such proviruses are less transcriptionally active and, possibly, less rebound competent.
Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in ...two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis.
We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96.
The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis—including those given placebo—had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (−0.2%, 95% confidence interval CI −1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (−0.4%, 95% CI −1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI −1.2 to 1.5, P = .84 for 200 mg; 95% CI −1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups.
In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.govNCT01672866 and NCT01672879.
The present study describes the presence of pseudoenhancement during contrast-enhanced ultrasound (CEUS) imaging of human carotid arteries and the reproduction of this pseudoenhancement in vitro. ...Seventy patients underwent bilateral CEUS examination of the carotid arteries using a Philips iU22 ultrasound system equipped with a L9-3 ultrasound probe and SonoVue microbubble contrast. During CEUS of the carotid arteries, we identified enhancement in close proximity to the far wall, parallel to the main lumen. The location of this enhancement does not correlate to the anatomical location of a parallel vessel. To corroborate the hypothesis that this is a pseudoenhancement artifact, the enhancement was recreated in a tissue-mimicking material phantom, using the same ultrasound system, settings and contrast agent as the patient study. The phantom study showed that pseudoenhancement may be present during vascular CEUS and that the degree of pseudoenhancement is influenced by the size and concentration of the microbubbles. During vascular CEUS, identification of the artifact is important to prevent misinterpretation of enhancement in and near the far wall.
B-mode and Doppler ultrasound are commonly used for the evaluation of atherosclerosis in the carotid arteries. Recently, contrast-enhanced ultrasound (CEUS) has been introduced as a technique to ...improve the detection of carotid atherosclerosis and evaluate the presence of intraplaque neovascularization, which is considered a marker of plaque vulnerability. The present review focuses on the role of CEUS for the assessment of atherosclerosis and plaque instability. Currently available literature and future developments with CEUS are discussed.
Background and Purpose
Cotadutide is a dual GLP‐1 and glucagon receptor agonist with balanced agonistic activity at each receptor designed to harness the advantages on promoting liver health, weight ...loss and glycaemic control. We characterised the effects of cotadutide on glucose, insulin, GLP‐1, GIP, and glucagon over time in a quantitative manner using our glucose dynamics systems model (4GI systems model), in combination with clinical data from a multiple ascending dose/Phase 2a (MAD/Ph2a) study in overweight and obese subjects with a history of Type 2 diabetes mellitus (NCT02548585).
Experimental Approach
The cotadutide PK‐4GI systems model was calibrated to clinical data by re‐estimating only food related parameters. In vivo cotadutide efficacy was scaled based on in vitro potency. The model was used to explore the effect of weight loss on insulin sensitivity and predict the relative contribution of the GLP‐1 and glucagon receptor agonistic effects on glucose.
Key Results
Cotadutide MAD/Ph2a clinical endpoints were successfully predicted. The 4GI model captured a positive effect of weight loss on insulin sensitivity and showed that the stimulating effect of glucagon on glucose production counteracts the GLP‐1 receptor‐mediated decrease in glucose, resulting in a plateau for glucose decrease around a 200‐μg cotadutide dose.
Conclusion and Implications
The 4GI quantitative systems pharmacology model was able to predict the clinical effects of cotadutide on glucose, insulin, GLP‐1, glucagon and GIP given known in vitro potency. The analyses demonstrated that the quantitative systems pharmacology model, and its successive refinements, will be a valuable tool to support the clinical development of cotadutide and related compounds.
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We examine soil drying rates by comparing surface soil moisture observations from the NASA Soil Moisture Active Passive (SMAP) mission to those from networks of in situ probes upscaled to SMAP's ...sensing footprint. SMAP and upscaled in situ probes record different soil drying dynamics after rainfall. We modeled this process by fitting an exponential curve to 63 drydown events: the median SMAP drying timescale is 44% shorter and the magnitude of drying is 35% greater than in situ measurements. We also calculated drying rates between consecutive observations from 193 events. For 6 days after rainfall, soil moisture from SMAP dries at twice the rate of in situ measurements. Restricting in situ observations to times of SMAP observations does not change the drying timescale, magnitude, or rate. Therefore, observed differences are likely due to differences in sensing depths: SMAP measures shallower soil moisture than in situ probes, especially after rainfall.
Key Points
SMAP and networks of in situ probes observe soil drying after rainfall
SMAP observes soil drying to occur over a 44% shorter timescale than in situ
SMAP observes soil drying to occur at twice the rate as in situ
FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used ...conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.
Introduction
P‐glycoprotein (P‐gp) is an efflux transporter responsible for the transport of various drugs across the blood‐brain barrier (BBB). Loss of P‐gp function with age may be one factor in ...the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P‐gp function. Furthermore, the relationship between BBB P‐gp activity and peripheral P‐gp activity in CD3‐positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11–labeled (R)‐verapamil was evaluated.
Methods
(R)‐11Cverapamil and positron emission tomography were used to assess gray matter P‐gp function. Because (R)‐11Cverapamil is a substrate for P‐gp, the volume of distribution of (R)‐11Cverapamil in the brain inversely reflects P‐gp function in the BBB.
Results
Mean volume of distribution values for 5 young healthy volunteers (age range, 21–27 years) and 5 elderly healthy volunteers (age range, 59–68 years) were 0.62 ± 0.10 and 0.73 ± 0.07, respectively (P=.03). The activity index of P‐gp activity in CD3‐positive leukocytes was 2.88 ± 0.77 in young volunteers and 1.76 ± 0.58 in elderly volunteers (P=.02).
Conclusion
This study showed decreased P‐gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.
Clinical Pharmacology & Therapeutics (2006) 79, 540–548; doi: 10.1016/j.clpt.2006.02.004
Objectives To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital ...warts (condyloma acuminata).Design Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months’ follow-up.Setting Primary care centres and university or hospital associated health centres in 24 countries and territories around the world.Participants 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy.Intervention Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6.Main outcome measures Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied.Results In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma.Conclusions Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up.Trial registrations NCT00092521 and NCT00092534.
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