Directionally Sensitive Fractal Radiomics Compatible With Irregularly Shaped Magnetic Resonance Tumor Regions of Interest: Association With Osteosarcoma Chemoresistance.

BACKGROUND: Computational analysis of routinely acquired MRI has potential to improve the tumor chemoresistance prediction and to provide decision support in precision medicine, which may extend patient survival. Most radiomic analytical methods are compatible only with rectangular regions of interest (ROIs) and irregular tumor shape is therefore an important limitation. Furthermore, the currently used analytical methods are not directionally sensitive. PURPOSE: To implement a tumor analysis that is directionally sensitive and compatible with irregularly shaped ROIs. STUDY TYPE: Retrospective. SUBJECTS: A total of 54 patients with histopathologic diagnosis of primary osteosarcoma on tubular long bones and with prechemotherapy MRI. FIELD STRENGTH/SEQUENCE: A 1.5 T, T2-weighted-short-tau-inversion-recovery-fast-spin-echo. ASSESSMENT: A model to explore associations with osteosarcoma chemo-responsiveness included MRI data obtained before OsteoSa MAP neoadjuvant cytotoxic chemotherapy. Osteosarcoma morphology was analyzed in the MRI data by calculation of the nondirectional two-dimensional (2D) and directional and nondirectional one-dimensional (1D) Higuchi dimensions (Dh). MAP chemotherapy response was assessed by histopathological necrosis. STATISTICAL TESTS: The area under the receiver operating characteristic (ROC) curve (AUC) evaluated the association of the calculated features with the actual chemoresponsiveness, using tumor histopathological necrosis (95%) as the endpoint. Least absolute shrinkage and selection operator (LASSO) machine learning and multivariable regression were used for feature selection. Significance was set at <0.05. RESULTS: The nondirectional 1D Dh reached an AUC of 0.88 in association with the 95% tumor necrosis, while the directional 1D analysis along 180 radial lines significantly improved this association according to the Hanley/McNeil test, reaching an AUC of 0.95. The model defined by variable selection using LASSO reached an AUC of 0.98. The directional analysis showed an optimal predictive range between 90° and 97° and revealed structural osteosarcoma anisotropy manifested by its directionally dependent textural properties. DATA CONCLUSION: Directionally sensitive radiomics had superior predictive performance in comparison to the standard nondirectional image analysis algorithms with AUCs reaching 0.95 and full compatibility with irregularly shaped ROIs. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

Determination of Heart Rate Changes using Simulated Head Up Tilt Test for Syncope Patient Assessment.

Home-based self-training can be beneficial to neurocardiogenic patients, particularly for those who experience a decreased heart rate during the clinical head up tilt test (HUT). Many patients, however, may not be able to attend a clinic and/or attend clinics which lack HUT devices. Individualized heart rate prediction based on a simulated HUT (sHUT) model may address this gap in clinical practice. The proposed sHUT model aims to predict whether home-based self-training is an appropriate beneficial intervention based on the calculated decrease in heart rate from the model. The results obtained with the model are in agreement with previous clinical findings with greater than 80% accuracy in identifying patients who could benefit from home training. The predicted home-based training efficacy of syncope against the control group had a corresponding p-value of p<0.0001. Based on these results, physicians may be able to recommend home training as part of online or telemedicine consultation.Clinical Relevance- The simulated Head Up Tilt model predicts the patient-specific efficacy of tilt-training for patients at home diagnosed with syncope.

GIRK1 triggers multiple cancer-related pathways in the benign mammary epithelial cell line MCF10A.

Excessive expression of subunit 1 of GIRK1 in ER+ breast tumors is associated with reduced survival times and increased lymph node metastasis in patients. To investigate possible tumor-initiating properties, benign MCF10A and malign MCF7 mammary epithelial cells were engineered to overexpress GIRK1 neoplasia associated vital parameters and resting potentials were measured and compared to controls. The presence of GIRK1 resulted in resting potentials negative to the controls. Upon GIRK1 overexpression, several cellular pathways were regulated towards pro-tumorigenic action as revealed by comparison of transcriptomes of MCF10AGIRK1 with the control (MCF10AeGFP). According to transcriptome analysis, cellular migration was promoted while wound healing and extracellular matrix interactions were impaired. Vital parameters in MCF7 cells were affected akin the benign MCF10A lines, but to a lesser extent. Thus, GIRK1 regulated cellular pathways in mammary epithelial cells are likely to contribute to the development and progression of breast cancer.

Fractal analysis of cervical intraepithelial neoplasia.

INTRODUCTION: Cervical intraepithelial neoplasias (CIN) represent precursor lesions of cervical cancer. These neoplastic lesions are traditionally subdivided into three categories CIN 1, CIN 2, and CIN 3, using microscopical criteria. The relation between grades of cervical intraepithelial neoplasia (CIN) and its fractal dimension was investigated to establish a basis for an objective diagnosis using the method proposed. METHODS: Classical evaluation of the tissue samples was performed by an experienced gynecologic pathologist. Tissue samples were scanned and saved as digital images using Aperio scanner and software. After image segmentation the box counting method as well as multifractal methods were applied to determine the relation between fractal dimension and grades of CIN. A total of 46 images were used to compare the pathologist's neoplasia grades with the predicted groups obtained by fractal methods. RESULTS: Significant or highly significant differences between all grades of CIN could be found. The confusion matrix, comparing between pathologist's grading and predicted group by fractal methods showed a match of 87.1%. Multifractal spectra were able to differentiate between normal epithelium and low grade as well as high grade neoplasia. CONCLUSION: Fractal dimension can be considered to be an objective parameter to grade cervical intraepithelial neoplasia.

Lack of acyl-CoA:diacylglycerol acyltransferase 1 reduces intestinal cholesterol absorption and attenuates atherosclerosis in apolipoprotein E knockout mice.

Triacylglycerols (TG) are the major storage molecules of metabolic energy and fatty acids in several tissues. The final step in TG biosynthesis is catalyzed by acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes. Lack of whole body DGAT1 is associated with reduced lipid-induced inflammation. Since one major component of atherosclerosis is chronic inflammation we hypothesized that DGAT1 deficiency might ameliorate atherosclerotic lesion development. We therefore crossbred Apolipoprotein E-deficient (ApoE(-/-)) mice with Dgat1(-/-) mice. ApoE(-/-) and ApoE(-/-)Dgat1(-/-) mice were fed Western-type diet (WTD) for 9weeks and thereafter examined for plaque formation. The mean atherosclerotic lesion area was substantially reduced in ApoE(-/-)Dgat1(-/-) compared with ApoE(-/-) mice in en face and aortic valve section analyses. The reduced lesion size was associated with decreased cholesterol uptake and absorption by the intestine, reduced plasma TG and cholesterol concentrations and increased cholesterol efflux from macrophages. The expression of adhesion molecules was reduced in aortas of ApoE(-/-)Dgat1(-/-) mice, which might be the reason for less migration capacities of monocytes and macrophages and the observed decreased amount of macrophages within the plaques. From our results we conclude that the lack of DGAT1 is atheroprotective, implicating an additional application of DGAT1 inhibitors with regard to maintaining cholesterol homeostasis and attenuating atherosclerosis.

A new method for morphometric analysis of tissue distribution of mobile cells in relation to immobile tissue structures.

The distribution of cells in stained tissue sections provides information that may be analyzed by means of morphometric computation. We developed an algorithm for automated analysis for the purpose of answering questions pertaining to the relative densities of wandering cells in the vicinity of comparatively immobile tissue structures such as vessels or tumors. As an example, we present the analysis of distribution of CD56-positive cells and of CXCR3-positive cells (relative densities of peri-vascular versus non-vascular cell populations) in relation to the endothelium of capillaries and venules of human parietal decidua tissue of first trimester pregnancy. In addition, the distribution of CD56-positive cells (mostly uterine NK cells) in relation to spiral arteries is analyzed. The image analysis is based on microphotographs of two-color immunohistological stainings. Discrete distances (10-50 µm) from the fixed structures were chosen for the purpose of defining the extent of neighborhood areas. For the sake of better comparison of cell distributions at different overall cell densities a model of random distribution of "cells" in relation to neighborhood areas and rest decidua of a specific sample was built. In the chosen instances, we found increased perivascular density of CD56-positive cells and of CXCR3-positive cells. In contrast, no accumulation of CD56-positive cells was found in the neighborhood of spiral arteries.

Measurement of cell death by oxidative stress in three-dimensional spheroids from trophoblast and in fragments of decidua tissue.

We report a new morphometric method for measurement of the amount of cell death in three-dimensional multicellular spheroids of the trophoblast-like cell line AC1-M59 and of cultured pieces of decidua tissue (decidua spheroids) in response to a cytotoxic agent. The viability of the spheroids was assessed by adding propidium iodide to the culture medium at the end of the toxic treatment. On fluorescence and brightfield images of serial cryosections the areas of propidium iodide fluorescence and the entire corresponding spheroids were measured by applying digital image processing and ratiometrical quantification. As an example, we evaluated the cytotoxic effect of hydrogen peroxide on both types of spheroids. The relative potency of hydrogen peroxide to induce tissue damage was assessed quantitatively for determination of the minimal concentration that leads to an increase in cytotoxicity. The method presented suggests general applicability for in vitro determination of toxicity against tissues.

Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia.

Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7alpha-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists.

The influence of edge detection algorithms on the estimation of the fractal dimension of binary digital images.

The boundary of a fractal object, represented in a two-dimensional space, is theoretically a line with an infinitely small width. In digital images this boundary or contour is limited to the pixel resolution of the image and the width of the line commonly depends on the edge detection algorithm used. The Minkowski dimension was evaluated by using three different edge detection algorithms (Sobel, Roberts, and Laplace operator). These three operators were investigated because they are very widely used and because their edge detection result is very distinct concerning the line width. Very common fractals (Sierpinski carpet and Koch islands) were investigated as well as the binary images from a cancer invasion assay taken with a confocal laser scanning microscope. The fractal dimension is directly proportional to the width of the contour line and the fact, that in practice very often the investigated objects are fractals only within a limited resolution range is considered too.