Vasculogenic Mimicry: Role of melanoma differentiation associated gene-9/syntenin

Malignant melanoma (MM) is the most aggressive skin cancer and the most frequent skin disorder in Caucasians. MM is associated with aggressive and progressive disease states, leading to major cancer-related morbidity and mortality. Recent investigations identify a new non-angiogenesis-dependent pathway vasculogenic mimicry (VM), which is considered a cancer hallmark that can independently facilitate tumor neovascularization by the formation of fluid-conducting and vascular endothelial cells. MM cells undergoing VM can dedifferentiate into numerous cellular phenotypes and acquire endothelial-like features, resulting in the formation of the de novo matrix-rich vascular-like network, such as plasma and red blood cells. The co-generation of endothelial cells, channels, laminar structures, and heparin sulfate proteoglycans are the main pathophysiological characteristics of VM in human melanoma patients. In highly aggressive melanoma cells downregulation of vascular endothelial cadherin and upregulation of ECM components promote the perfusion of the VM pathway. We investigated whether mda-9/syntenin, a pro-metastatic gene, affects VM in MM. The expression of mda-9/syntenin was modulated using gain-of-function and loss-of-function strategies to determine its potential role in VM. Downregulation of mda-9/syntenin in aggressive melanoma cells decreases VM, while over expressing mda-9/syntenin in immortalized melanoma cells increases VM. These findings shed light on a novel role and molecular mechanism of action of mda-9/syntenin in VM, which may contribute significantly to the metastatic phenotype of these aggressive cancers.https://scholarscompass.vcu.edu/gradposters/1137/thumbnail.jp

Postconditioning inhibits myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway

<p>Abstract</p> <p>Background</p> <p>Postconditioning (PostC) inhibits myocardial apoptosis after ischemia-reperfusion (I/R) injury. The JAK2-STAT3 pathway has anti-apoptotic effects and plays an essential role in the late protection of preconditioning. Our aim was to investigate the anti-apoptotic effect of PostC after prolonged reperfusion and the role of the JAK2-STAT3 pathway in the anti-apoptotic effect of PostC.</p> <p>Methods</p> <p>Wistar rats were subjected to 30 minutes ischemia and 2 or 24 hours (h) reperfusion, with or without PostC (three cycles of 10 seconds reperfusion and 10 seconds reocclusion at the onset of reperfusion). Separate groups of rats were treated with a JAK2 inhibitor (AG490) or a PI3K inhibitor (wortmannin) 5 minutes before PostC. Immunohistochemistry was used to analyze Bcl-2 protein levels after reperfusion. mRNA levels of Bcl-2 were detected by qRT-PCR. TTC staining was used to detect myocardial infarction size. Myocardial apoptosis was evaluated by TUNEL staining. Western-blot was used to detect p-STAT3 and p-Akt levels after reperfusion.</p> <p>Results</p> <p>There was more myocardial apoptosis at 24 h <it>vs </it>2 h after reperfusion in all groups. PostC significantly reduced myocardial apoptosis and elevated Bcl-2 levels at both 2 and 24 hours after reperfusion. PostC increased p-STAT3 and p-Akt levels after reperfusion. Administration of AG490 reduced p-STAT3 and p-Akt levels and attenuated the anti-apoptotic effect of PostC. Wortmannin also reduced p-Akt levels and attenuated the anti-apoptotic effect of PostC but had no effect on p-STAT3 levels. AG490 abrogated the up-regulation of Bcl-2 by PostC.</p> <p>Conclusion</p> <p>PostC may reduce myocardial apoptosis during prolonged reperfusion via a JAK2-STAT3-Bcl-2 pathway. As a downstream target of JAK2 signaling, activation of PI3K/Akt pathway may be necessary in the protection of PostC.</p

Memory in quantum dot blinking

The photoluminescence intermittency (blinking) of quantum dots is interesting because it is an easily-measured quantum process whose transition statistics cannot be explained by Fermi's Golden Rule. Commonly, the transition statistics are power-law distributed, implying that quantum dots possess at least trivial memories. By investigating the temporal correlations in the blinking data, we demonstrate with high statistical confidence that quantum dot blinking data has non-trivial memory, which we define to be statistical complexity greater than one. We show that this memory cannot be discovered using the transition distribution. We show by simulation that this memory does not arise from standard data manipulations. Finally, we conclude that at least three physical mechanisms can explain the measured non-trivial memory: 1) Storage of state information in the chemical structure of a quantum dot; 2) The existence of more than two intensity levels in a quantum dot; and 3) The overlap in the intensity distributions of the quantum dot states, which arises from fundamental photon statistics.Comment: Added supplementary quantum dot plots in source director

Physician Executive Leadership: Student-Led Curriculum to Fill Gaps in Traditional Medical Education

Students at Sidney Kimmel Medical College (SKMC) have identified a gap in the traditional medical curriculum surrounding topics such as telehealth, the patient experience, health policy, medical malpractice, and health care entrepreneurship and innovation, and in response have initiated a student-centered, student-led, student-driven program called Physician Executive Leadership (PEL). PEL provides students with a variety of avenues to engage with these topics, such as lectures from leaders in each of these fields, easy access to weekly news articles on current events in health care, targeted review sessions on the US health care system, and the opportunity to voice and develop ideas through an online publication. To identify the gaps in medical education PEL is best suited to fill, we administered a survey to 174 students at Sidney Kimmel Medical College.The survey contained 20 multiple-choice questions to assess general knowledge on health insurance and reimbursement, health care policy and reform, and care quality and patient experience. It also included a subjective self-assessment of students’ understanding of and interest in these topics. Overall, we found that although the traditional medical school curriculum improved students\u27 understanding of these topics from year to year, it is not sufficient on it\u27s own: on average, students failed to achieve a passing score of 70% in any of the categories tested. Further illustrating the importance of this program, students self-identified a gap between their current level of understanding and what they want to know. Please visit our website www.physicianexecutiveleadership.com to learn more!https://jdc.jefferson.edu/pel/1000/thumbnail.jp

Candidate plasma biomarkers for predicting ascending aortic aneurysm in bicuspid aortic valve disease.

BACKGROUND: Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1-2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients. METHODS: Plasma samples were collected pre-operatively from BAV patients undergoing aortic valve surgery. Maximum ascending aortic diameter was measured on pre-operative transoesophageal echocardiography. Maximum diameter ≥ 45 mm was classified as aneurysmal. Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH-MS), an advanced mass spectrometry technique, was used to identify and quantify all proteins within the samples. Protein abundance and aortic diameter were correlated using logistic regression. Levene's test was used to identify proteins demonstrating low abundance variability in the aneurysmal patients (consistent expression in disease), and high variability in the non-aneurysmal patients (differential expression between 'at risk' and not 'at risk' patients). RESULTS: Fifteen plasma samples were collected (seven non-aneurysmal and 8 aneurysmal BAV patients). The mean age of the patients was 55.5 years and the majority were female (10/15, 67%). Four proteins (haemoglobin subunits alpha, beta and delta and mannan-binding lectin serine protease) correlated significantly with maximal ascending aortic diameter (p < 0.05, r = 0.5-0.6). Five plasma proteins demonstrated significantly lower variability in the aneurysmal group and may indicate increased risk of aneurysm in non-aneurysmal patients (DNA-dependent protein kinase catalytic subunit, lumican, tetranectin, gelsolin and cartilage acidic protein 1). A further 7 proteins were identified only in the aneurysmal group (matrin-3, glucose-6-phosphate isomerase, coactosin-like protein, peptidyl-prolyl cis-trans isomerase A, golgin subfamily B member 1, myeloperoxidase and 2'-deoxynucleoside 5'-phosphate N-hydrolase 1). CONCLUSIONS: This study is the first to identify candidate plasma biomarkers for predicting aortic diameter and risk of future aneurysm in BAV patients. It provides valuable pilot data and proof of principle that could be used to design a large-scale prospective investigation. Ultimately, a more affordable 'off-the-shelf' follow-on blood assay could then be developed in place of SWATH-MS, for use in the healthcare setting

Sacrificial crystal templating of hyaluronic acid-based hydrogels

Natural tissues have intricate structures organized in a hierarchical fashion over multiple length scales (Å to cm). These tissues commonly incorporate pores as a key feature that may regulate cell behavior. To enable the development of tissues scaffolds with biomimetic pore structures, it is important to investigate methods to impart pores to biomaterials, such as the use of novel sacrificial porogens. Here we report the use of sacrificial crystals to impart pores to biopolymer hydrogels (based on a methacrylated hyaluronic acid derivative) with macroscopic crystal templated pores embedded within them. The pore structure was investigated using microscopy (cryoSEM and confocal), and the specific sacrificial porogen used was found not only to impact the pore structure, but also swelling and mechanical properties. Such templated hydrogels have prospects for application as instructive tissue scaffolds (where the pore structure controls cell alignment, migration, etc.)

Risk factors for hospital admission with RSV bronchiolitis in England: a population-based birth cohort study.

OBJECTIVE: To examine the timing and duration of RSV bronchiolitis hospital admission among term and preterm infants in England and to identify risk factors for bronchiolitis admission. DESIGN: A population-based birth cohort with follow-up to age 1 year, using the Hospital Episode Statistics database. SETTING: 71 hospitals across England. PARTICIPANTS: We identified 296618 individual birth records from 2007/08 and linked to subsequent hospital admission records during the first year of life. RESULTS: In our cohort there were 7189 hospital admissions with a diagnosis of bronchiolitis, 24.2 admissions per 1000 infants under 1 year (95%CI 23.7-24.8), of which 15% (1050/7189) were born preterm (47.3 bronchiolitis admissions per 1000 preterm infants (95% CI 44.4-50.2)). The peak age group for bronchiolitis admissions was infants aged 1 month and the median was age 120 days (IQR = 61-209 days). The median length of stay was 1 day (IQR = 0-3). The relative risk (RR) of a bronchiolitis admission was higher among infants with known risk factors for severe RSV infection, including those born preterm (RR = 1.9, 95% CI 1.8-2.0) compared with infants born at term. Other conditions also significantly increased risk of bronchiolitis admission, including Down's syndrome (RR = 2.5, 95% CI 1.7-3.7) and cerebral palsy (RR = 2.4, 95% CI 1.5-4.0). CONCLUSIONS: Most (85%) of the infants who are admitted to hospital with bronchiolitis in England are born at term, with no known predisposing risk factors for severe RSV infection, although risk of admission is higher in known risk groups. The early age of bronchiolitis admissions has important implications for the potential impact and timing of future active and passive immunisations. More research is needed to explain why babies born with Down's syndrome and cerebral palsy are also at higher risk of hospital admission with RSV bronchiolitis

Sacrificial crystal templated hyaluronic acid hydrogels as biomimetic 3D tissue scaffolds for nerve tissue regeneration

Pores are key features of natural tissues and the development of tissues scaffolds with biomimetic properties (pore structures and chemical/mechanical properties) offers a route to engineer implantable biomaterials for specific niches in the body. Here we report the use of sacrificial crystals (potassium dihydrogen phosphate or urea) that act as templates to impart pores to hyaluronic acid-based hydrogels. The mechanical properties of the hydrogels were analogous to the nervous system (in the Pascal regime), and we investigated the use of the potassium dihydrogen phosphate crystal-templated hydrogels as scaffolds for neural progenitor cells (NPCs), and the use of urea crystal-templated hydrogels as scaffolds for Schwann cells. For NPCs cultured inside the porous hydrogels, assays for the expression of Nestin are inconclusive, and assays for GFAP and BIII-tubulin expression suggest that the NPCs maintain their undifferentiated phenotype more effectively than the controls (with glial fibrillary acidic protein (GFAP) and BIII-tubulin expression at ca. 50% relative to the chemically/mechanically equivalent not templated control hydrogels). For Schwann cells cultured within these hydrogels, assays for the expression of S100 protein or Myelin basic protein confirm the expression of both proteins, albeit at lower levels on the templated hydrogels (ca. 50%) than on the chemically/mechanically equivalent not templated control hydrogels. Such sacrificial crystal templated hydrogels represent platforms for biomimetic 3D tissue scaffolds for the nervous system

The dilemma of arranged marriages in people with epilepsy. An expert group appraisal

INTRODUCTION: Matrimony remains a challenging psychosocial problem confronting people with epilepsy (PWE). People with epilepsy are less likely to marry; however, their marital prospects are most seriously compromised in arranged marriages. AIMS: The aim of this study was to document marital prospects and outcomes in PWE going through arranged marriage and to propose optimal practices for counseling PWE contemplating arranged marriage. METHODS: A MEDLINE search and literature review were conducted, followed by a cross-disciplinary meeting of experts to generate consensus. RESULTS: People with epilepsy experience high levels of felt and enacted stigma in arranged marriages, but the repercussions are heavily biased against women. Hiding epilepsy is common during marital negotiations but may be associated with poor medication adherence, reduced physician visits, and poor marital outcome. Although divorce rates are generally insubstantial in PWE, divorce rates appear to be higher in PWE undergoing arranged marriages. In these marriages, hiding epilepsy during marital negotiations is a risk factor for divorce. CONCLUSIONS: In communities in which arranged marriages are common, physicians caring for PWE are best-equipped to counsel them about their marital prospects. Marital plans and aspirations should be discussed with the family of the person with epilepsy in a timely and proactive manner. The benefits of disclosing epilepsy during marital negotiations should be underscored