Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable ...success in clinical trials. In this Review, we discuss the potential mechanisms of action of the clinical agents that target two of these receptors, programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3). We also suggest correlative studies that may define the predominant mechanisms of action and identify predictive biomarkers.
Abstract
Most of the existing chest X-ray datasets include labels from a list of findings without specifying their locations on the radiographs. This limits the development of machine learning ...algorithms for the detection and localization of chest abnormalities. In this work, we describe a dataset of more than 100,000 chest X-ray scans that were retrospectively collected from two major hospitals in Vietnam. Out of this raw data, we release 18,000 images that were manually annotated by a total of 17 experienced radiologists with 22 local labels of rectangles surrounding abnormalities and 6 global labels of suspected diseases. The released dataset is divided into a training set of 15,000 and a test set of 3,000. Each scan in the training set was independently labeled by 3 radiologists, while each scan in the test set was labeled by the consensus of 5 radiologists. We designed and built a labeling platform for DICOM images to facilitate these annotation procedures. All images are made publicly available in DICOM format along with the labels of both the training set and the test set.
This paper reports the study of optical and magnetic properties of HoFeO3 nanocrystals prepared by a simple co-precipitation method using ethanol. Single-phase HoFeO3 was formed after calcination of ...the precipitate at 650, 750 and 850 °C during 1 h. The XRD and TEM results showed that the average crystallite sizes of all HoFeO3 samples were in the range of 25–30 nm. The UV-Vis spectra showed strong UV and Vis absorption with a small optical energy gap (Eg = 1.8019 eV). The soft ferromagnetic behavior of HoFeO3 nanoparticles with magnetization ∼0.7–0.8 emu/g, coercivity ∼8–23 Oe, remanent magnetization less than 0.005 emu/g.
•Orthorhombic HoFeO3 nanocrystals prepared by a simple co-precipitation method in hot ethanol.•Samples have been studied by TG-DSC, XRD, EDX, EDX-mapping, HRTEM, UV-Vis, VSM techniques.•Average crystallite and particle sizes ∼25–30 nm.•Optical energy gap (Eg) ∼ 1.8019 eV.•The magnetic characteristics (Ms,Mr and Hc) show increasing with calcination temperature of the samples.
Background and aims Extreme climate events, including flooding and prolonged drought, may establish long-lasting (legacy) effects on soil abiotic and biotic properties, potentially influencing soil ...N-cycling, microbial communities, and plant productivity. Nitrogen (N) fertilizer often stimulates plant growth, but it remains unknown whether N addition can alleviate the impact of legacy drought or waterlogging events on crops. Our aim was to assess the interactive effects of legacy extreme climate events and N-addition on these processes. Methods Using cotton as a model system, soils previously exposed to waterlogging and prolonged drought were used to examine potential legacy impacts of extreme climate on soil N process rates, abundance and structure of associated microbial communities, and cotton growth and productivity under different levels of N fertilizer application (0, 100, 200 and 300 kg N/ha). Results The deleterious legacy effects of prolonged drought on plant productivity were due to negative impacts on microbial abundance and community structure, and soil nutrient availability, thereby negatively influencing the rate of nitrification, and consequently plant available N. The legacy impacts of prolonged drought persisted throughout the experiment despite fertiliser applications of up to 300 kg of N/ha. The only observed legacy impacts of waterlogging were low NO3− levels in soils without N-addition and shifts in the abundance and structure of the N2O-reducing community. Conclusions There were strong legacy impacts of prolonged drought, but minor legacy impacts of waterlogging, on soils and crop yields which could not be fully counteracted by the high rates of N fertilizer application. This study provides critical knowledge contributing to the development of adaptation and soil N management strategies to minimize the loss of farm productivity, within the context of increased frequencies and intensities of extreme weather events.
Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq
) is approved for the treatment of progressive metastatic medullary ...thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63-81 % or 7-30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34-38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76-77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.
A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid ...bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 N-terminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated "hairpin" structure of α-synuclein.
The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state ...that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain ramped up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology.
The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. The validity of this model in the mouse has been questioned; however, ...little is known about the lineage potential of human progenitors. Here we provide a comprehensive analysis of the human hematopoietic hierarchy by clonally mapping the developmental potential of seven progenitor classes from neonatal cord blood and adult bone marrow. Human multilymphoid progenitors, identified as a distinct population of Thy-1(neg-lo)CD45RA(+) cells in the CD34(+)CD38(-) stem cell compartment, gave rise to all lymphoid cell types, as well as monocytes, macrophages and dendritic cells, which indicated that these myeloid lineages arise in early lymphoid lineage specification. Thus, as in the mouse, human hematopoiesis does not follow a rigid model of myeloid-lymphoid segregation.
The world has been undergoing the most ever unprecedented circumstances caused by the coronavirus pandemic, which is having a devastating global effect in different aspects of life. Since there are ...not effective antiviral treatments for Covid-19 yet, it is crucial to early detect and monitor the progression of the disease, thereby helping to reduce mortality. While different measures are being used to combat the virus, medical imaging techniques have been examined to support doctors in diagnosing the disease. In this paper, we present a practical solution for the detection of Covid-19 from chest X-ray (CXR) and lung computed tomography (LCT) images, exploiting cutting-edge Machine Learning techniques. As the main classification engine, we make use of EfficientNet and MixNet, two recently developed families of deep neural networks. Furthermore, to make the training more effective and efficient, we apply three transfer learning algorithms. The ultimate aim is to build a reliable expert system to detect Covid-19 from different sources of images, making it be a multi-purpose AI diagnosing system. We validated our proposed approach using four real-world datasets. The first two are CXR datasets consist of 15,000 and 17,905 images, respectively. The other two are LCT datasets with 2,482 and 411,528 images, respectively. The five-fold cross-validation methodology was used to evaluate the approach, where the dataset is split into five parts, and accordingly the evaluation is conducted in five rounds. By each evaluation, four parts are combined to form the training data, and the remaining one is used for testing. We obtained an encouraging prediction performance for all the considered datasets. In all the configurations, the obtained accuracy is always larger than 95.0%. Compared to various existing studies, our approach yields a substantial performance gain. Moreover, such an improvement is statistically significant.
•EfficientNet and MixNet are suitable for detection of Covid-19 from chest X-ray and lung CT images.•Transfer learning is beneficial to the detection of Covid-19.•The proposed system significantly outperforms various state-of-the-art approaches.•It has been evaluated using different quality metrics.
Evidence supporting any one treatment for plunging ranula is limited. Standard treatment—complete excision of the sublingual gland and ranula—is invasive and morbid given the close operative ...proximity to the submandibular duct and lingual nerve. OK‐432 (Picibanil; Chugai Pharmaceutical Co., Tokyo, Japan) sclerotherapy has been studied as a less invasive treatment but is inaccessible in the United States. This report illustrates the successful management of a plunging ranula using ultrasound‐guided percutaneous ethanol injection. Within 2 months of the procedure, the patient had complete resolution of the plunging ranula, with no associated side effects. We propose that ultrasound‐guided percutaneous ethanol injection be considered for the management of plunging ranula. Laryngoscope, 127:2239–2241, 2017
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