Microvascular invasion (MVI) in hepatocellular carcinoma (HCC) is an independent predictor of poor outcomes subsequent to surgical resection or liver transplantation (LT); however, MVI currently ...cannot be adequately determined preoperatively. Radiogenomic venous invasion (RVI) is a contrast‐enhanced computed tomography (CECT) biomarker of MVI derived from a 91‐gene HCC “venous invasion” gene expression signature. Preoperative CECTs of 157 HCC patients who underwent surgical resection (N = 72) or LT (N = 85) between 2000 and 2009 at three institutions were evaluated for the presence or absence of RVI. RVI was assessed for its ability to predict MVI and outcomes. Interobserver agreement for scoring RVI was substantial among five radiologists (κ = 0.705; P < 0.001). The diagnostic accuracy, sensitivity, and specificity of RVI in predicting MVI was 89%, 76%, and 94%, respectively. Positive RVI score was associated with lower overall survival (OS) than negative RVI score in the overall cohort (P < 0.001; 48 vs. >147 months), American Joint Committee on Cancer tumor‐node‐metastasis stage II (P < 0.001; 34 vs. >147 months), and in LT patients within Milan criteria (P < 0.001; 69 vs. >147 months). Positive RVI score also portended lower recurrence‐free survival at 3 years versus negative RVI score (P = 0.001; 27% vs. 62%). Conclusion: RVI is a noninvasive radiogenomic biomarker that accurately predicts histological MVI in HCC surgical candidates. Its presence on preoperative CECT is associated with early disease recurrence and poor OS and may be useful for identifying patients less likely to derive a durable benefit from surgical treatment. (Hepatology 2015;62:792–800)
Photoacoustic (PA) imaging is an emerging imaging modality that utilizes optical excitation and acoustic detection to enable high resolution at centimeter depths. The development of activatable PA ...probes can expand the utility of this technology to allow for detection of specific stimuli within live-animal models. Herein, we report the design, development, and evaluation of a series of Acoustogenic Probe(s) for Nitric Oxide (APNO) for the ratiometric, analyte-specific detection of nitric oxide (NO) in vivo. The best probe in the series, APNO-5, rapidly responds to NO to form an N-nitroso product with a concomitant 91 nm hypsochromic shift. This property enables ratiometric PA imaging upon selective irradiation of APNO-5 and the corresponding product, tAPNO-5. Moreover, APNO-5 displays the requisite photophysical characteristics for in vivo PA imaging (e.g., high absorptivity, low quantum yield) as well as high biocompatibility, stability, and selectivity for NO over a variety of biologically relevant analytes. APNO-5 was successfully applied to the detection of endogenous NO in a murine lipopolysaccharide-induced inflammation model. Our studies show a 1.9-fold increase in PA signal at 680 nm and a 1.3-fold ratiometric turn-on relative to a saline control.
Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their ...abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.
shows a strict host tropism for reticulocytes. We identified transferrin receptor 1 (TfR1) as the receptor for
reticulocyte-binding protein 2b (PvRBP2b). We determined the structure of the N-terminal ...domain of PvRBP2b involved in red blood cell binding, elucidating the molecular basis for TfR1 recognition. We validated TfR1 as the biological target of PvRBP2b engagement by means of TfR1 expression knockdown analysis. TfR1 mutant cells deficient in PvRBP2b binding were refractory to invasion of
but not to invasion of
Using Brazilian and Thai clinical isolates, we show that PvRBP2b monoclonal antibodies that inhibit reticulocyte binding also block
entry into reticulocytes. These data show that TfR1-PvRBP2b invasion pathway is critical for the recognition of reticulocytes during
invasion.
We introduce Digital microfluidic Isolation of Single Cells for -Omics (DISCO), a platform that allows users to select particular cells of interest from a limited initial sample size and connects ...single-cell sequencing data to their immunofluorescence-based phenotypes. Specifically, DISCO combines digital microfluidics, laser cell lysis, and artificial intelligence-driven image processing to collect the contents of single cells from heterogeneous populations, followed by analysis of single-cell genomes and transcriptomes by next-generation sequencing, and proteomes by nanoflow liquid chromatography and tandem mass spectrometry. The results described herein confirm the utility of DISCO for sequencing at levels that are equivalent to or enhanced relative to the state of the art, capable of identifying features at the level of single nucleotide variations. The unique levels of selectivity, context, and accountability of DISCO suggest potential utility for deep analysis of any rare cell population with contextual dependencies.
We present the design and implementation of an automated data calibration and reduction pipeline for very long baseline interferometric (VLBI) observations taken at millimeter wavelengths. These ...short radio wavelengths provide the best imaging resolution available from ground-based VLBI networks such as the Event Horizon Telescope (EHT) and the Global Millimeter VLBI Array (GMVA) but require specialized processing owing to the strong effects from atmospheric opacity and turbulence, as well as the heterogeneous nature of existing global arrays. The pipeline builds on a calibration suite (HOPS) originally designed for precision geodetic VLBI. To support the reduction of data for astronomical observations, we have developed an additional framework for global phase and amplitude calibration that provides output in a standard data format for astronomical imaging and analysis. The pipeline was successfully used toward the reduction of 1.3 mm observations from the EHT 2017 campaign, leading to the first image of a black hole "shadow" at the center of the radio galaxy M87. In this work, we analyze observations taken at 3.5 mm (86 GHz) by the GMVA, joined by the phased Atacama Large Millimeter/submillimeter Array in 2017 April, and demonstrate the benefits from the specialized processing of high-frequency VLBI data with respect to classical analysis techniques.
Purpose
Pseudoprogression (PsP) occurs in 20–30% of patients with glioblastoma multiforme (GBM) after receiving the standard treatment. PsP exhibits similarities in shape and intensity to the true ...tumor progression (TTP) of GBM on the follow‐up magnetic resonance imaging (MRI). These similarities pose challenges to the differentiation of these types of progression and hence the selection of the appropriate clinical treatment strategy.
Methods
To address this challenge, we introduced a novel feature learning method based on deep convolutional generative adversarial network (DCGAN) and AlexNet, termed DC‐AL GAN, to discriminate between PsP and TTP in MRI images. Due to the adversarial relationship between the generator and the discriminator of DCGAN, high‐level discriminative features of PsP and TTP can be derived for the discriminator with AlexNet. We also constructed a multifeature selection module to concatenate features from different layers, contributing to more powerful features used for effectively discriminating between PsP and TTP. Finally, these discriminative features from the discriminator are used for classification by a support vector machine (SVM). Tenfold cross‐validation (CV) and the area under the receiver operating characteristic (AUC) were applied to evaluate the performance of this developed algorithm.
Results
The accuracy and AUC of DC‐AL GAN for discriminating PsP and TTP after tenfold CV were 0.920 and 0.947. We also assessed the effects of different indicators (such as sensitivity and specificity) for features extracted from different layers to obtain a model with the best classification performance.
Conclusions
The proposed model DC‐AL GAN is capable of learning discriminative representations from GBM datasets, and it achieves desirable PsP and TTP classification performance superior to other state‐of‐the‐art methods. Therefore, the developed model would be useful in the diagnosis of PsP and TTP for GBM.
Each taste modality is generally encoded by a single, molecularly defined, population of sensory cells. However, salt stimulates multiple taste pathways in mammals and insects, suggesting a more ...complex code for salt taste. Here, we examine salt coding in
. After creating a comprehensive molecular map comprised of five discrete sensory neuron classes across the fly labellum, we find that four are activated by salt: two exhibiting characteristics of 'low salt' cells, and two 'high salt' classes. Behaviorally, low salt attraction depends primarily on 'sweet' neurons, with additional input from neurons expressing the ionotropic receptor IR94e. High salt avoidance is mediated by 'bitter' neurons and a population of glutamatergic neurons expressing Ppk23. Interestingly, the impact of these glutamatergic neurons depends on prior salt consumption. These results support a complex model for salt coding in flies that combinatorially integrates inputs from across cell types to afford robust and flexible salt behaviors.
Nontuberculous mycobacteria (NTM) are environmental microbes that cause a variety of human diseases, particularly chronic lung infections. Despite the fact that NTM are widespread in the environment, ...relatively few people develop NTM lung disease, suggesting intrinsic vulnerability in some individuals. This paper reviews the evidence that underlying disorders predispose to NTM lung disease, in particular primary conditions that result in bronchiectasis, chronic obstructive pulmonary disease, α-1-antitrypsin anomalies, pneumoconiosis, pulmonary alveolar proteinosis, and frank immunosuppressive states such as that associated with the use of anti-tumor necrosis factor-α biologics, posttransplantation immunosuppression, and HIV infection. Over the past several decades, NTM lung disease has been increasingly identified in postmenopausal women with slender body habitus. Thus we will also review the clinical and experimental evidence which supports the observation that such individuals are predisposed to NTM lung disease.
Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive ...function.
A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.
Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.
Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.
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