Mycobacterium tuberculosis infection in humans triggers formation of granulomas, which are tightly organized immune cell aggregates that are the central structure of tuberculosis. Infected and ...uninfected macrophages interdigitate, assuming an altered, flattened appearance. Although pathologists have described these changes for over a century, the molecular and cellular programs underlying this transition are unclear. Here, using the zebrafish-Mycobacterium marinum model, we found that mycobacterial granuloma formation is accompanied by macrophage induction of canonical epithelial molecules and structures. We identified fundamental macrophage reprogramming events that parallel E-cadherin-dependent mesenchymal-epithelial transitions. Macrophage-specific disruption of E-cadherin function resulted in disordered granuloma formation, enhanced immune cell access, decreased bacterial burden, and increased host survival, suggesting that the granuloma can also serve a bacteria-protective role. Granuloma macrophages in humans with tuberculosis were similarly transformed. Thus, during mycobacterial infection, granuloma macrophages are broadly reprogrammed by epithelial modules, and this reprogramming alters the trajectory of infection and the associated immune response.
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•Macrophages mobilize classical epithelial modules during granuloma formation•Macrophage reprogramming shares features of mesenchymal-epithelial transitions•Inhibition of macrophage epithelialization leads to disordered granulomas•Granuloma disruption increases immune access and promotes host survival
A hallmark of tuberculosis is aggregation of macrophages into a structure termed the granuloma. Cronan et al. show that macrophages deploy classical epithelialization pathways to construct mycobacterial granulomas. This reprogramming is host detrimental, as macrophage-specific inhibition of the process enhances host survival and immune cell access and reduces bacterial burden.
The efficacy of closure of a patent foramen ovale (PFO) in the prevention of recurrent stroke after cryptogenic stroke is uncertain. We investigated the effect of PFO closure combined with ...antiplatelet therapy versus antiplatelet therapy alone on the risks of recurrent stroke and new brain infarctions.
In this multinational trial involving patients with a PFO who had had a cryptogenic stroke, we randomly assigned patients, in a 2:1 ratio, to undergo PFO closure plus antiplatelet therapy (PFO closure group) or to receive antiplatelet therapy alone (antiplatelet-only group). Imaging of the brain was performed at the baseline screening and at 24 months. The coprimary end points were freedom from clinical evidence of ischemic stroke (reported here as the percentage of patients who had a recurrence of stroke) through at least 24 months after randomization and the 24-month incidence of new brain infarction, which was a composite of clinical ischemic stroke or silent brain infarction detected on imaging.
We enrolled 664 patients (mean age, 45.2 years), of whom 81% had moderate or large interatrial shunts. During a median follow-up of 3.2 years, clinical ischemic stroke occurred in 6 of 441 patients (1.4%) in the PFO closure group and in 12 of 223 patients (5.4%) in the antiplatelet-only group (hazard ratio, 0.23; 95% confidence interval CI, 0.09 to 0.62; P=0.002). The incidence of new brain infarctions was significantly lower in the PFO closure group than in the antiplatelet-only group (22 patients 5.7% vs. 20 patients 11.3%; relative risk, 0.51; 95% CI, 0.29 to 0.91; P=0.04), but the incidence of silent brain infarction did not differ significantly between the study groups (P=0.97). Serious adverse events occurred in 23.1% of the patients in the PFO closure group and in 27.8% of the patients in the antiplatelet-only group (P=0.22). Serious device-related adverse events occurred in 6 patients (1.4%) in the PFO closure group, and atrial fibrillation occurred in 29 patients (6.6%) after PFO closure.
Among patients with a PFO who had had a cryptogenic stroke, the risk of subsequent ischemic stroke was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone; however, PFO closure was associated with higher rates of device complications and atrial fibrillation. (Funded by W.L. Gore and Associates; Gore REDUCE ClinicalTrials.gov number, NCT00738894 .).
Zeta potential is often used to approximate a nanoparticle’s surface charge, i.e., cationic, anionic, or neutral character, and has become a standard characterization technique to evaluate ...nanoparticle surfaces. While useful, zeta potential values provide only very general conclusions about surface charge character. Without a thorough understanding of the measurement parameters and limitations of the technique, these values can become meaningless. This case study attempts to explore the sensitivity of zeta potential measurement using specifically formulated cationic, anionic, and neutral liposomes. This study examines zeta potential dependence on pH and ionic strength, resolving power, and highlights the sensitivity of zeta potential to charged liposomes. Liposomes were prepared with cholesterol, 1,2-distearoyl-
sn
-glycero-3-phosphocholine (DSPC), and varying amounts of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 1,2-dioleoyl-
sn
-glycero-3-phospho-
l
-serine (DOPS). A strong linear relationship was noted between zeta potential values and the mole percentage of charged lipids within a liposome (e.g., cationic DOTAP or anionic DOPS). This finding could be used to formulate similar liposomes to a specific zeta potential, potentially of importance for systems sensitive to highly charged species. In addition, cationic and anionic liposomes were titrated with up to two mole percent of the neutral lipid 1,2-distearoyl-
sn
-glycero-3-phosphoethanolamine-
N
-methoxy(polyethylene glycol)-2000 (lipid-PEG; LP). Very small amounts of the lipid-PEG (<0.2 mol%) were found to impart stability to the DOTAP- and DOPS-containing liposomes without significantly affecting other physicochemical properties of the formulation, providing a simple approach to making stable liposomes with cationic and anionic surface charge.
Inferring astrophysical information from gravitational waves emitted by compact binaries is one of the key science goals of gravitational-wave astronomy. In order to reach the full scientific ...potential of gravitational-wave experiments, we require techniques to mitigate the cost of Bayesian inference, especially as gravitational-wave signal models and analyses become increasingly sophisticated and detailed. Reduced-order models (ROMs) of gravitational waveforms can significantly reduce the computational cost of inference by removing redundant computations. In this paper, we construct the first reduced-order models of gravitational-wave signals that include the effects of spin precession, inspiral, merger, and ringdown in compact object binaries and that are valid for component masses describing binary neutron star, binary black hole, and mixed binary systems. This work utilizes the waveform model known as "IMRPhenomPv2." Our ROM enables the use of a fast reduced-orderquadrature(ROQ) integration rule which allows us to approximate Bayesian probability density functions at a greatly reduced computational cost. We find that the ROQ rule can be used to speed-up inference by factors as high as 300 without introducing systematic bias. This corresponds to a reduction in computational time from around half a year to half a day for the longest duration and lowest mass signals. The ROM and ROQ rules are available with the main inference library of the LIGO Scientific Collaboration, LALInference.
We present the first surrogate model for gravitational waveforms from the coalescence of precessing binary black holes. We call this surrogate model NRSur4d2s. Our methodology significantly extends ...recently introduced reduced-order and surrogate modeling techniques, and is capable of directly modeling numerical relativity waveforms without introducing phenomenological assumptions or approximations to general relativity. Motivated by GW150914, LIGO’s first detection of gravitational waves from merging black holes, the model is built from a set of 276 numerical relativity (NR) simulations with mass ratios q≤2, dimensionless spin magnitudes up to 0.8, and the restriction that the initial spin of the smaller black hole lies along the axis of orbital angular momentum. It produces waveforms which begin ∼30 gravitational wave cycles before merger and continue through ringdown, and which contain the effects of precession as well as all ℓ∈{2,3} spin-weighted spherical-harmonic modes. We perform cross-validation studies to compare the model to NR waveforms not used to build the model and find a better agreement within the parameter range of the model than other, state-of-the-art precessing waveform models, with typical mismatches of 10−3. We also construct a frequency domain surrogate model (called NRSur4d2s_FDROM) which can be evaluated in 50 ms and is suitable for performing parameter estimation studies on gravitational wave detections similar to GW150914.
Abstract Background Targeted molecular therapies (TMTs) previously have demonstrated oncologic activity in renal cell carcinoma (RCC) by reducing the size of primary tumors and metastases. Objective ...To assess the cytoreductive effect of TMTs on inferior vena cava tumor thrombi. Design, setting, and participants A multi-institutional database of patients treated with TMTs for RCC was reviewed. The subset with in situ level II or higher caval thrombi (above renal vein) was assessed for radiographic response in thrombus size and level. Pre- and posttreatment characteristics of this population were assessed for predictors of response in height, diameter, and level of the tumor thrombi. Measurements The main outcome measured was a change in the clinical level of tumor thrombus following TMT. We also measured radiographic responses in thrombus size and location before and after TMT. Results and limitations Twenty-five patients met the inclusion criteria. Before TMT, thrombus level was II in 18 patients (72%), III in 5 patients (20%), and IV in 2 patients (8%). The first-line therapy was sunitinib in 12 cases; alternative TMTs were administered in 13. The median duration of therapy was two cycles (range: one to six cycles). Following TMT, 7 patients (28%) had a measurable increase in thrombus height, 7 (28%) had no change, and 11 (44%) had a decrease. One patient (4%) had an increase in thrombus-level classification, 21 (84%) had stable thrombi, and in 3 (12%) the thrombus level decreased. There was only one case (4%) where the surgical approach was potentially affected by tumor thrombus regression (level IV to III). No statistically significant predictors of tumor thrombus response to TMTs were found. Limitations include the descriptive and retrospective study design. Because TMTs were initiated according to physician and/or patient preferences, and not all patients were treated in anticipation of surgery, no conclusions could be drawn regarding selection and duration of therapy. Thus it may not be appropriate to extrapolate our experience to all patients with locally advanced RCC. Although this is the largest reported experience with in situ caval tumor thrombi treated with TMT, this series lacks sufficient statistical power to assess the usefulness of TMTs adequately in tumor thrombus cytoreduction. Conclusions TMT had a minimal clinical effect on RCC tumor thrombi. Only patients treated with sunitinib had clinical thrombus regression; however, the clinical magnitude and relevance of this effect is not clear and should be investigated prospectively.
The growing need for baseline data against which efforts to reduce the rate of biodiversity loss can be judged highlights the importance of long-term datasets, some of which are as old as ecology ...itself. We review methods of evaluating change in biodiversity at the community level using these datasets, and contrast whole-community approaches with those that combine information from different species and habitats. As all communities experience temporal turnover, one of the biggest challenges is distinguishing change that can be attributed to external factors, such as anthropogenic activities, from underlying natural change. We also discuss methodological issues, such as false alerts and modifications in design, of which users of these data sets need to be aware.
Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab ...vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas.
In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility.
The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.
Inferring the astrophysical parameters of coalescing compact binaries is a key science goal of the upcoming advanced LIGO-Virgo gravitational-wave detector network and, more generally, ...gravitational-wave astronomy. However, current approaches to parameter estimation for these detectors require computationally expensive algorithms. Therefore, there is a pressing need for new, fast, and accurate Bayesian inference techniques. In this Letter, we demonstrate that a reduced order modeling approach enables rapid parameter estimation to be performed. By implementing a reduced order quadrature scheme within the LIGO Algorithm Library, we show that Bayesian inference on the 9-dimensional parameter space of nonspinning binary neutron star inspirals can be sped up by a factor of ∼30 for the early advanced detectors' configurations (with sensitivities down to around 40 Hz) and ∼70 for sensitivities down to around 20 Hz. This speedup will increase to about 150 as the detectors improve their low-frequency limit to 10 Hz, reducing to hours analyses which could otherwise take months to complete. Although these results focus on interferometric gravitational wave detectors, the techniques are broadly applicable to any experiment where fast Bayesian analysis is desirable.
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