Arterial spin labeling MR image denoising and reconstruction using unsupervised deep learning

Arterial spin labeling (ASL) imaging is a powerful magnetic resonance imaging technique that allows to quantitatively measure blood perfusion non-invasively, which has great potential for assessing tissue viability in various clinical settings. However, the clinical applications of ASL are currently limited by its low signal-to-noise ratio (SNR), limited spatial resolution, and long imaging time. In this work, we propose an unsupervised deep learning-based image denoising and reconstruction framework to improve the SNR and accelerate the imaging speed of high resolution ASL imaging. The unique feature of the proposed framework is that it does not require any prior training pairs but only the subject's own anatomical prior, such as T1-weighted images, as network input. The neural network was trained from scratch in the denoising or reconstruction process, with noisy images or sparely sampled k-space data as training labels. Performance of the proposed method was evaluated using in vivo experiment data obtained from 3 healthy subjects on a 3T MR scanner, using ASL images acquired with 44-min acquisition time as the ground truth. Both qualitative and quantitative analyses demonstrate the superior performance of the proposed txtc framework over the reference methods. In summary, our proposed unsupervised deep learning-based denoising and reconstruction framework can improve the image quality and accelerate the imaging speed of ASL imaging.     

黄芩苷改善肿瘤缺氧微环境抑制乳腺癌移植瘤的生长＊

目的 通过观察黄芩苷对乳腺癌组织毛细血管通透性（Capillary Vessel Permeability，CVP）、赖氨酰氧化酶（Lysyl Oxidase，LOX）及血清丙二醛（Malondialdehyde，MDA）等相关指标的影响，探讨黄芩苷可能的抗乳腺癌作用机制。方法 通过在裸鼠皮下接种MDA-MB-231乳腺癌细胞株建立乳腺癌移植瘤模型；实验分为模型组、黄芩苷组、阿霉素组、黄芩苷+阿霉素组。于接种第7日开始：黄芩苷组每天灌胃黄芩苷水溶液（100 mg·kg^-1），连续14天；阿霉素组每3天腹腔注射一次阿霉素（5mg·kg^-1），共用药5次；模型组每天灌胃生理盐水（10 mL·kg^-1），连续14天；黄芩苷+阿霉素组每天灌胃黄芩苷水溶液（100 mg·kg^-1），连续14天，并每3天腹腔注射一次阿霉素5 mg·kg^-1，共5次。给药期间监测移植瘤体积；紫外可见分光光度计620 nm下测OD值来反映黄芩苷对肿瘤毛细血管通透性的影响；硫代巴比妥酸（Thiobarbituric acid，TBA）比色法检测黄芩苷对裸鼠血清中丙二醛（MDA）的影响；免疫组化染色法检测乳腺癌组织中赖氨酰氧化酶（LOX）的表达情况。结果 ①与模型组比较，黄芩苷组、阿霉素组、黄芩苷+阿霉素组瘤体重量均明显减轻（P<0.05）；黄芩苷+阿霉素组瘤体重量较阿霉素组明显减轻（P<0.05）。②与模型组比较，黄芩苷组降低乳腺癌组织毛细血管的通透性，而阿霉素组则增加肿瘤组织中毛细血管的通透性，差异均具有统计学意义（P<0.05）。③黄芩苷组能够明显抑制荷瘤裸鼠血清MDA的表达，与模型组比较差异有显著统计学意义（P<0.01）；阿霉素组促进MDA的表达，与模型组比较差异有统计学意义；黄芩苷+阿霉素组促进MDA的表达，与模型组比较差异无统计学意义。④与模型组比较，黄芩苷组裸鼠乳腺癌组织LOX的表达显著下调（P<0.01），阿霉素组肿瘤组织中LOX表达增加（P<0.05）；黄芩苷+阿霉素组能下调裸鼠乳腺癌组织LOX的表达，与模型组比较差异无统计学意义。结论 黄芩苷能够明显抑制乳腺癌移植瘤的生长，其机制可能与黄芩苷降低肿瘤组织毛细血管的通透性，抑制裸鼠血清中丙二醛、乳腺癌组织中赖氨酰氧化酶的表达，从而改变肿瘤缺氧微环境有关。     

Nonlinear elasticity of biological basement membrane revealed by rapid inflation and deflation

Basement membrane (BM) is a thin layer of extracellular matrix that surrounds most animal tissues, serving as a physical barrier while allowing nutrient exchange. Although they have important roles in tissue structural integrity, physical properties of BMs remain largely uncharacterized, which limits our understanding of their mechanical functions. Here, we perform pressure-controlled inflation and deflation to directly measure the nonlinear mechanics of BMs in situ. We show that the BMs behave as a permeable, hyperelastic material whose mechanical properties and permeability can be measured in a model-independent manner. Furthermore, we find that BMs exhibit a remarkable nonlinear stiffening behavior, in contrast to the reconstituted Matrigel. This nonlinear stiffening behavior helps the BMs to avoid the snap-through instability (or structural softening) widely observed during the inflation of most elastomeric balloons and thus maintain sufficient confining stress to the enclosed tissues during their growth.

Basement membrane (BM) is a thin layer of fibrous matrix separating cells from the connecting tissues, which functions as a physical barrier and widely exists across multicellular organisms (1). The BM is typically composed of laminins, collagen IV, nidogens, and proteoglycans; laminin and collagen IV are the major components that constitute networks forming the structure of the BM, and nidogen and proteoglycans are associated with the laminin and collagen IV networks. As a physical barrier, the structural and mechanical properties of BM are important in the organization and morphogenesis of tissues and organs as well as in the maintenance of adult functions (2); abnormal BM has been associated with a variety of diseases such as cancer (3). For example, in metastasis, cancer cells must invade through BMs to escape from the primary tumor—a process that causes 90% of cancer-related death (4). Indeed, breaks in BMs can be observed in malignant tumors (5). Thus, mechanical properties of the BM are considered to play important roles in regulating cancer cell invasion (6, 7). Furthermore, as a physical barrier differentiating different parts of tissues, BMs are required to be permeable to small molecules to allow exchange of water and nutrients; the permeability of BM is thus one of the essential kinetic parameters regulating biomolecule exchange and activities of internal cells (8, 9). Given the importance of BMs as a semipermeable barrier maintaining tissue structural integrity, however, their permeability and mechanical properties remain largely unknown, mainly due to the lack of direct measurement methods, especially in situ. This limits our understanding of the physical role of BMs in various physiological and pathological processes such as tumor development and angiogenesis.Determining the mechanical properties of intact BMs in situ is challenging because of their irregular shape, small thickness, and tight connection to the cells inside. Due to these limitations, conventional mechanical tests such as tensile, compression, and bending tests are difficult to be applied to characterize the mechanical behavior of the BM in situ. Instead, previous measurements had been carried out on fragmented BMs isolated from various tissues (e.g., via atomic force microscopy [AFM] indentation) and found that the BM stiffness ranges from ∼kPa to ∼MPa (10–17). In addition, a constitutive relationship is required to extract the material parameters such as elastic modulus and permeability from these experimental measurements. However, like most biological tissues, a reliable constitutive model for the BM is not yet available, causing additional difficulties in obtaining its mechanical parameters from most traditional experiments.In this work, we demonstrate an in situ method to simultaneously measure both the elastic properties and permeability of intact BM in breast cancer spheroid by recording the deflation process of an inflated BM filled with phosphate buffered saline (PBS) by microinjection without requiring complex sample preparation and post-data processing. During the deflation of the BM, its elastic retraction generates a pressure difference to drive the liquid flow through the membrane; the liquid flux can be calculated from the reduction of the intact BM diameter. With the BM thickness measured by transmission electron microscopy (TEM), we can determine the shear modulus, permeability, and diffusivity of the intact BM. Moreover, we find from our measurements that the elasticity of BM is highly nonlinear with a strong strain-stiffening effect. Furthermore, we discuss the possible impact of the strain-stiffening effects of BM on its functions.     

Studies on the structure-activity relationship of caffeate derivatives as neuroprotective agents

In the present study, novel ester derivatives of CAPE were designed and synthesized as neuroprotective agents. The anti-inflammatory and antioxidant activities of these compounds were evaluated at the cellular level, while the blood-brain barrier (BBB) permeability was predicted by parallel artificial membrane permeability assay (PAMPA). The results revealed that phenolic hydroxyl groups and double bonds in the structure of CAPE had important effects on neuroprotective activities. Accordingly,a preliminary structure-activity relationship was summarized in this paper. In addition, we observed a significant improvement on BBB permeability. These results provided important references for the structural modification and optimization of CAPE in the future.     

Constructing an In Silico Three-Class Predictor of Human Intestinal Absorption With Caco-2 Permeability and Dried-DMSO Solubility

Absorption of drugs is the first step after dosing, and it largely affects drug bioavailability. Hence, estimating the fraction of absorption (Fa) in humans is important in the early stages of drug discovery. To achieve correct exclusion of low Fa compounds and retention of potential compounds, we developed a freely available model to classify compounds into 3 levels of Fa capacity using only the chemical structure. To improve Fa prediction, we added predicted binary classification results of membrane permeability measured using Caco-2 cell line (Papp) and dried–dimethyl sulfoxide solubility (accuracy, 0.836; kappa, 0.560). The constructed models can be accessed via a web application.     

Increased bladder permeability in interstitial cystitis/painful bladder syndrome

The definition of interstitial cystitis (IC) has evolved over the years from being a well-defined entity characterized by diagnostic lesion (Hunner’s ulcer) in the urothelium to a clinical diagnosis by exclusion [painful bladder syndrome (PBS)]. Although the etiology is unknown, a central theme has been an association with increased permeability of the bladder. This article reviews the evidence for increased permeability being important to the symptoms of interstitial cystitis/painful bladder syndrome (IC/PBS) and in treating the disorder. Recent work showing cross-communication among visceral organs is also reviewed to provide a basis for understanding IC/PBS as a systemic disorder of a complex, interconnected system consisting of the bladder, bowel and other organs, nerves, cytokine-responding cells and the nervous system.     

Multiparametric MRI as an early biomarker of individual therapy effects during concomitant treatment of brain tumours

The aim of this study was to determine the ability of multiparametric MRI to identify the early effects of individual treatment, during combined chemo‐radiotherapy on brain tumours. Eighty male rats bearing 9L gliosarcomas were randomized into four groups: untreated, anti‐angiogenic therapy (SORA group), microbeam radiation therapy (MRT group) and both treatments (MRT+SORA group). Multiparametric MRI (tumour volume, diffusion‐weighted MR imaging (ADC), blood volume fraction (BVf), microvessel index (VSI), vessel wall integrity (AUC_P846) and tissue oxygen saturation (StO₂)) was performed 1 day before and 2, 5 and 8 days after treatment initiation. Unpaired t‐tests and one‐way ANOVA were used for statistical analyses. Each MR parameter measured in our protocol was revealed to be sensitive to tumour changes induced by any of the therapies used (individually or combined). When compared with untreated tumours, SORA induced a decrease in BVf, VSI, StO₂ and AUC_P846, MRT generated an increase in ADC and AUC_P846 and combined therapies yielded mixed effects: an increase in ADC and AUC_P846 and a decrease in BVf, StO₂ and AUC_P846. MRT and MRT+SORA significantly slowed tumour growth. Despite these two groups presenting with similar tumour sizes, the information yielded from MR multiparameter assessment indicated that, when used concomitantly, each therapy induced distinguishable and appreciable physiological changes in the tumour. Our results suggest that multiparametric MRI can monitor the effects of individual treatments, used concomitantly, on brain tumours. Such monitoring would be useful for the detection of tumour resistance to drug/radiotherapy in patients undergoing concomitant therapies. Copyright © 2015 John Wiley & Sons, Ltd.     

Intestinal permeability of mitragynine in rats using in situ absorption model

The intestinal permeability of mitragynine was investigated in situ using a single pass intestinal perfusion (SPIP) absorption model, in small intestine of rat using mitragynine in the absence/presence of the permeability markers, P-gp and/or CYP3A4 inhibitors. Mitragynine demonstrated high intestinal permeability (P_eff of 1.11 × 10^?4 cm/s) that is in the range of highly permeable drugs such as propranolol (P_eff of 1.27 × 10^?4 cm/s) indicating that it readily crosses the intestine. The addition of azithromycin (P-glycoprotein inhibitor) and ciprofloxacin (CYP3A4 inhibitor) or combination of both has no effect on intestinal permeability of mitragynine across the rat small intestine.