Susceptibility differences between tissues can be utilized as a new type of contrast in MRI that is different from spin density, T 1 -, or T 2 -weighted imaging. Signals from substances with different magnetic susceptibilities compared to their neighboring tissue will become out of phase with these tissues at sufficiently long echo times (TEs). Thus, phase imaging offers a means of enhancing contrast in MRI. Specifically, the phase images themselves can provide excellent contrast between gray matter (GM) and white matter (WM), iron-laden tissues, venous blood vessels, and other tissues with susceptibilities that are different from the background tissue. Also, for the first time, projection phase images are shown to demonstrate tissue (vessel) continuity. In this work, the best approach for combining magnitude and phase images is discussed. The phase images are high-pass-filtered and then transformed to a special phase mask that varies in amplitude between zero and unity. This mask is multiplied a few times into the original magnitude image to create enhanced contrast between tissues with different susceptibilities.
A highly efficient drug vector for photodynamic therapy (PDT) drug delivery was developed by synthesizing PEGylated gold nanoparticle conjugates, which act as a water-soluble and biocompatible "cage" that allows delivery of a hydrophobic drug to its site of PDT action. The dynamics of drug release in vitro in a two-phase solution system and in vivo in cancer-bearing mice indicates that the process of drug delivery is highly efficient, and passive targeting prefers the tumor site. With the Au NP-Pc 4 conjugates, the drug delivery time required for PDT has been greatly reduced to less than 2 h, compared to 2 days for the free drug.
BACKGROUND Noncigarette tobacco products are evolving rapidly, with increasing popularity in the United States. METHODS We present prevalence estimates for 12 types of tobacco products, using data from 45,971 adult and youth participants (≥12 years of age) from Wave 1 (September 2013 through December 2014) of the Population Assessment of Tobacco and Health (PATH) Study, a large, nationally representative, longitudinal study of tobacco use and health in the United States. Participants were asked about their use of cigarettes, e-cigarettes, traditional cigars, cigarillos, filtered cigars, pipe tobacco, hookah, snus pouches, other smokeless tobacco, dissolvable tobacco, bidis, and kreteks. Estimates of the prevalence of use for each product were determined according to use category (e.g., current use or use in the previous 30 days) and demographic subgroup, and the prevalence of multiple-product use was explored. RESULTS More than a quarter (27.6%) of adults were current users of at least one type of tobacco product in 2013 and 2014, although the prevalence varied depending on use category. A total of 8.9% of youths had used a tobacco product in the previous 30 days; 1.6% of youths were daily users. Approximately 40% of tobacco users, adults and youths alike, used multiple tobacco products; cigarettes plus e-cigarettes was the most common combination. Young adults (18 to 24 years of age), male adults and youths, members of racial minorities, and members of sexual minorities generally had higher use of tobacco than their counterparts. CONCLUSIONS During this study, 28% of U.S. adults were current users of tobacco, and 9% of youths had used tobacco in the previous 30 days. Use of multiple products was common among tobacco users. These findings will serve as baseline data to examine between-person differences and within-person changes over time in the use of tobacco products. (Funded by the National Institute on Drug Abuse and the Food and Drug Administration.)
Pre-trained language models such as BERT have proven to be highly effective for natural language processing (NLP) tasks. However, the high demand for computing resources in training such models hinders their application in practice. In order to alleviate this resource hunger in large-scale model training, we propose a Patient Knowledge Distillation approach to compress an original large model (teacher) into an equally-effective lightweight shallow network (student). Different from previous knowledge distillation methods, which only use the output from the last layer of the teacher network for distillation, our student model patiently learns from multiple intermediate layers of the teacher model for incremental knowledge extraction, following two strategies: (i) PKD-Last: learning from the last k layers; and (ii) PKD-Skip: learning from every k layers. These two patient distillation schemes enable the exploitation of rich information in the teacher's hidden layers, and encourage the student model to patiently learn from and imitate the teacher through a multilayer distillation process. Empirically, this translates into improved results on multiple NLP tasks with significant gain in training efficiency, without sacrificing model accuracy. 1
Programmed cell death (apoptosis) is a normal process in the developing nervous system. Recent data suggest that certain features seen in the process of programmed cell death may be favored in the developing versus the adult brain in response to different brain injuries. In a well characterized model of neonatal hypoxia-ischemia, we demonstrate marked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activation, which is required in many cases of apoptotic cell death, also followed a delayed time course after hypoxia-ischemia. Administration of boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was significantly neuroprotective when given by intracerebroventricular injection 3 h after cerebral hypoxia-ischemia. In addition, systemic injections of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fashion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonged therapeutic window after hypoxic-ischemic events in the developing brain, a major contributor to static encephalopathy and cerebral palsy.
Purpose Glioblastoma (GBM) is the most common form of malignant glioma in adults. Although protected by both the blood brain- and blood tumor-barriers, T cells actively infiltrate GBM. Previous work has shown that IDO, CTLA-4 and PD-L1 are dominant molecular participants in the suppression of GBM immunity. This includes IDO-mediated regulatory T cell (Treg; CD4+CD25+FoxP3+) accumulation, the interaction of T cell-expressed, CTLA-4, with dendritic cell-expressed, CD80, as well as the interaction of tumor- and/or macrophage-expressed, PD-L1, with T cell-expressed, PD-1. The individual inhibition of each pathway has been shown to increase survival in the context of experimental GBM. However, the impact of simultaneously targeting all three pathways in blood tumor-barriers, GBMs are actively infiltrated by T cells. Experimental Design and Results In this report, we demonstrate that, when dually-challenged, IDO-deficient tumors provide a selectively competitive survival advantage against IDO-competent tumors. Next, we provide novel observations regarding tryptophan catabolic enzyme expression, before showing that the therapeutic inhibition of IDO, CTLA-4 and PD-L1 in a mouse model of well-established glioma maximally decreases tumor-infiltrating Tregs, coincident with a significant increase in T cell-mediated long-term survival. In fact, 100% of mice bearing intracranial tumors were long-term survivors following triple combination therapy. The expression and/or frequency of T cell-expressed CD44, CTLA-4, PD-1 and IFN-γ depended on timing after immunotherapeutic administration. Conclusions Collectively, these data provide strong pre-clinical evidence that combinatorially-targeting immunosuppression in malignant glioma is a strategy that has high potential value for future clinical trials in patients with GBM.
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