Evaluation of cerebral cortex viscoelastic property estimation with nonlinear inversion magnetic resonance elastography

Objective. Magnetic resonance elastography (MRE) of the brain has shown promise as a sensitive neuroimaging biomarker for neurodegenerative disorders; however, the accuracy of performing MRE of the cerebral cortex warrants investigation due to the unique challenges of studying thinner and more complex geometries. Approach. A series of realistic, whole-brain simulation experiments are performed to examine the accuracy of MRE to measure the viscoelasticity (shear stiffness, μ, and damping ratio, ξ) of cortical structures predominantly effected in aging and neurodegeneration. Variations to MRE spatial resolution and the regularization of a nonlinear inversion (NLI) approach are examined. Main results. Higher-resolution MRE displacement data (1.25 mm isotropic resolution) and NLI with a low soft prior regularization weighting provided minimal measurement error compared to other studied protocols. With the optimized protocol, an average error in μ and ξ was 3% and 11%, respectively, when compared with the known ground truth. Mid-line structures, as opposed to those on the cortical surface, generally display greater error. Varying model boundary conditions and reducing the thickness of the cortex by up to 0.67 mm (which is a realistic portrayal of neurodegenerative pathology) results in no loss in reconstruction accuracy. Significance. These experiments establish quantitative guidelines for the accuracy expected of in vivo MRE of the cortex, with the proposed method providing valid MRE measures for future investigations into cortical viscoelasticity and relationships with health, cognition, and behavior

Overexpression of CD44 in acquired tamoxifen-resistant breast cancer cells augments their migratory response to heregulin beta 1

Background Acquired endocrine resistance in breast cancer cells is accompanied by altered growth factor receptor signalling [1] and a highly migratory cell phenotype [2]. Interestingly, in tamoxifen-resistant (TamR) MCF7 cells, our microarray analysis has demonstrated elevated levels of CD44, a transmembrane glycoprotein known to interact with, and modulate the function of, growth factor receptors [3]. Here we have explored the role of CD44 as a modulator of heregulin beta-1-induced migratory signalling in TamR cells. Methods Expression of CD44 (standard and v3 isoforms) were confirmed by RT-PCR and western blotting and their association with erbB family members determined by both immunofluorescence microscopy and immunoprecipitation. Activation of intracellular signalling following heregulin beta 1 treatment (10 ng/ml) in the presence or absence of CD44 (using siRNA-mediated inhibition) was determined by western blotting using phosphospecific antibodies. Cellular migration was determined by seeding cells (control and CD44 siRNA-treated) into fibronectin-coated transwell chambers (8.0 μm pore size) in the presence or absence of heregulin beta 1. After 24 hours, migratory cells were fixed, stained with crystal violet and counted. Results Both standard and v3 isoforms of CD44 were overexpressed in TamR cells at both gene and protein levels (mean fold increase in CD44s protein (TamR versus MCF7): 4.26 ± 1.2, P < 0.05). Moreover, CD44s and v3 colocalised with Her2 and Her3 receptors at the cell surface and were also detectable in Her2/Her3 cellular immunoprecipitates. Treatment of TamR cells with heregulin resulted in phosphorylation of erbB receptors together with a number of downstream signalling intermediates, including Akt, Src and FAK, and resulted in enhanced cellular migration. Significantly, heregulin-induced intracellular signalling was dramatically reduced in cells in which the expression of CD44 was suppressed (via siRNA), with a corresponding loss of heregulin-induced migratory behaviour (mean fold change in cell migration versus untreated control: 6.7 ± 1.1, P < 0.05 (heregulin beta 1); 1.8 ± 0.9 (CD44 siRNA); 1.47 ± 0.6, P < 0.05 (heregulin beta 1 + CD44 siRNA)). Conclusion These data demonstrate a role for CD44 as a modulator of erbB receptor function in endocrine-resistant breast cancer cells, where it augments heregulin beta 1 migratory signalling

Magnetic resonance elastography (MRE) of the human brain: technique, findings and clinical applications

Neurological disorders are one of the most important public health concerns in developed countries. Established brain imaging techniques such as magnetic resonance imaging (MRI) and x-ray computerised tomography (CT) have been essential in the identification and diagnosis of a wide range of disorders, although usually are insufficient in sensitivity for detecting subtle pathological alterations to the brain prior to the onset of clinical symptoms—at a time when prognosis for treatment is more favourable. The mechanical properties of biological tissue provide information related to the strength and integrity of the cellular microstructure. In recent years, mechanical properties of the brain have been visualised and measured non-invasively with magnetic resonance elastography (MRE), a particularly sensitive medical imaging technique that may increase the potential for early diagnosis. This review begins with an introduction to the various methods used for the acquisition and analysis of MRE data. A systematic literature search is then conducted to identify studies that have specifically utilised MRE to investigate the human brain. Through the conversion of MRE-derived measurements to shear stiffness (kPa) and, where possible, the loss tangent (rad), a summary of results for global brain tissue and grey and white matter across studies is provided for healthy participants, as potential baseline values to be used in future clinical investigations. In addition, the extent to which MRE has revealed significant alterations to the brain in patients with neurological disorders is assessed and discussed in terms of known pathophysiology. The review concludes by predicting the trends for future MRE research and applications in neuroscience

Change in prevalence of post-traumatic stress disorder in the two years following trauma:a meta-analytic study

Background: Understanding the course of post-traumatic stress disorder (PTSD) and the factors that impact this is essential to inform decisions about when and for whom screening and intervention are likely to be beneficial. Objective: To provide meta-analytic evidence of the course of recovery from PTSD in the first year following trauma, and the factors that influence that recovery. Method: We conducted a meta-analysis of observational studies of adult PTSD prevalence which included at least two assessments within the first 12 months following trauma exposure, examining prevalence statistics through to 2 years post-trauma. We examined trauma intentionality (intentional or non-intentional), PTSD assessment method (clinician or self-report), sample sex distribution, and age as moderators of PTSD prevalence over time. Results: We identified 78 eligible studies including 16,484 participants. Pooled prevalence statistics indicated that over a quarter of individuals presented with PTSD at 1 month post-trauma, with this proportion reducing by a third between 1 and 3 months. Beyond 3 months, any prevalence changes were detected over longer intervals and were small in magnitude. Intentional trauma, younger age, and female sex were associated with higher PTSD prevalence at 1 month. In addition, higher proportions of females, intentional trauma exposure, and higher baseline PTSD prevalence were each associated with larger reductions in prevalence over time. Conclusions: Recovery from PTSD following acute trauma exposure primarily occurs in the first 3 months post-trauma. Screening measures and intervention approaches offered at 3 months may better target persistent symptoms than those conducted prior to this point. HIGHLIGHTS: PTSD rates in the immediate aftermath of trauma exposure decline from 27% at 1 month to 18% at 3 months post-trauma, showing significant spontaneous recovery.Problems appear to stabilize after 3 months.Screening/intervention for PTSD at 3 months post-trauma is indicated

Aging brain mechanics: Progress and promise of magnetic resonance elastography

Neuroimaging techniques that can sensitivity characterize healthy brain aging and detect subtle neuropathologies have enormous potential to assist in the early detection of neurodegenerative conditions such as Alzheimer's disease. Magnetic resonance elastography (MRE) has recently emerged as a reliable, high-resolution, and especially sensitive technique that can noninvasively characterize tissue biomechanical properties (i.e., viscoelasticity) in vivo in the living human brain. Brain tissue viscoelasticity provides a unique biophysical signature of neuroanatomy that are representative of the composition and organization of the complex tissue microstructure. In this article, we detail how progress in brain MRE technology has provided unique insights into healthy brain aging, neurodegeneration, and structure-function relationships. We further discuss additional promising technical innovations that will enhance the specificity and sensitivity for brain MRE to reveal considerably more about brain aging as well as its potentially valuable role as an imaging biomarker of neurodegeneration. MRE sensitivity may be particularly useful for assessing the efficacy of rehabilitation strategies, assisting in differentiating between dementia subtypes, and in understanding the causal mechanisms of disease which may lead to eventual pharmacotherapeutic development

Zip4 (Slc39a4) Expression is Activated in Hepatocellular Carcinomas and Functions to Repress Apoptosis, Enhance Cell Cycle and Increase Migration

Background: The zinc transporter ZIP4 (Slc39a4) is important for proper mammalian development and is an essential gene in mice. Recent studies suggest that this gene may also play a role in pancreatic cancer. Methods/Principal Findings: Herein, we present evidence that this essential zinc transporter is expressed in hepatocellular carcinomas. Zip4 mRNA and protein were dramatically elevated in hepatocytes in the majority of human hepatocellular carcinomas relative to noncancerous surrounding tissues, as well as in hepatocytes in hepatocellular carcinomas occurring in farnesoid X receptor-knockout mice. Interestingly, meta-analysis of microarray data in the Geo and Oncomine databases suggests that Zip4 mRNA may also be elevated in many types of cancer. Potential mechanisms of action of ZIP4 were examined in cultured cell lines. RNAi knockdown of Zip4 in mouse Hepa cells significantly increased apoptosis and modestly slowed progression from G0/G1 to S phase when cells were released from hydroxyurea block into zinc-deficient medium. Cell migration assays revealed that RNAi knockdown of Zip4 in Hepa cells depressed in vitro migration whereas forced over-expression in Hepa cells and MCF-7 cells enhanced in vitro migration. Conclusions: ZIP4 may play a role in the acquisition of zinc by hepatocellular carcinomas, and potentially many different cancerous cell-types, leading to repressed apoptosis, enhanced growth rate and enhanced invasive behavior

Sex-based contributors to and consequences of post-traumatic stress disorder

Purpose of Review Women are twice as likely to develop post-traumatic stress disorder (PTSD) compared to men after a traumatic experience. The purpose of this mini review was to explore recent research on biological contributors to this sex difference. Recent Findings We identified 51 studies published since 2019. Studies found that beyond the influence of sex on the prevalence and symptoms of PTSD, there is evidence for and against sex-based differences in genetic and epigenetic factors (n = 8), brain structure and function (n = 11), neuroendocrine and inflammatory responses (n = 5), and in the role of sleep on emotional memory processing (n = 1). Sex differences were also observed in recovery and during PTSD treatment (n = 16). Finally, there is emerging evidence of sex-differentiated risk for medical and psychiatric comorbidities in PTSD (n = 10). Summary Rapid advances are being made using integrated multidisciplinary approaches to understand why females are at a heightened risk for developing PTSD