Introduction: Autofiction

Autofiction is a literary genre that combines the traditional genres of fiction and autobiography. The three autofictional texts in this section stem from a class on “Autofiction,” taught by Lujain Youssef in the summer term 2022, which engaged with the genre and encouraged students to produce their own creative writing

Computed tomographic atlas for the new international lymph node map for lung cancer: A radiation oncologist perspective

International audiencePurpose : To develop a reproducible definition for each mediastinal lymph node station based on the new TNM classification for lung cancer. Methods and Materials : This paper proposes an atlas using the new international lymph node map used in the seventh edition of the TNM classification for lung cancer. Four radiation oncologists and 1 diagnostic radiologist were involved in the project to put forward a reproducible radiologic description for the lung lymph node stations.Results : The International Association for the Study of Lung Cancer lymph node definitions for stations 1 to 11 have been described and illustrated on axial computed tomographic scan images using a certified radiotherapy planning system. Conclusions : This atlas will assist both diagnostic radiologists and radiation oncologists in accurately defining the lymph node stations on computed tomographic scan in patients diagnosed with lung cancer

Dengue Virus-Induced Inflammation of the Endothelium and the Potential Roles of Sphingosine Kinase-1 and MicroRNAs

Copyright © 2015 Amanda L. Aloia et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.One of the main pathogenic effects of severe dengue virus (DENV) infection is a vascular leak syndrome. There are no available antivirals or specific DENV treatments and without hospital support severe DENV infection can be life-threatening. The cause of the vascular leakage is permeability changes in the endothelial cells lining the vasculature that are brought about by elevated vasoactive cytokine and chemokines induced following DENV infection. The source of these altered cytokine and chemokines is traditionally believed to be from DENV-infected cells such as monocyte/macrophages and dendritic cells. Herein we discuss the evidence for the endothelium as an additional contributor to inflammatory and innate responses during DENV infection which may affect endothelial cell function, in particular the ability to maintain vascular integrity. Furthermore, we hypothesise roles for two factors, sphingosine kinase-1 and microRNAs (miRNAs), with a focus on several candidate miRNAs, which are known to control normal vascular function and inflammatory responses. Both of these factors may be potential therapeutic targets to regulate inflammation of the endothelium during DENV infection

CIB1 contributes to oncogenic signalling by Ras via modulating the subcellular localisation of sphingosine kinase 1

CIB1 (calcium and integrin binding protein 1) is a small intracellular protein with numerous interacting partners, and hence has been implicated in various cellular functions. Recent studies have revealed emerging roles of CIB1 in regulating cancer cell survival and angiogenesis, although the mechanisms involved have remained largely undefined. In investigating the oncogenic function of CIB1, we initially found that CIB1 is widely up-regulated across a diverse range of cancers, with this up-regulation frequently correlating with oncogenic mutations of KRas. Consistent with this, we found that ectopic expression of oncogenic KRas and HRas in cells resulted in elevated CIB1 expression. We previously described the Ca2+-myristoyl switch function of CIB1, and its ability to facilitate agonist-induced plasma membrane localisation of sphingosine kinase 1 (SK1), a location where SK1 is known to elicit oncogenic signalling. Thus, we examined the role this may play in oncogenesis. Consistent with these findings, we demonstrated here that over-expression of CIB1 by itself is sufficient to drive localisation of SK1 to the plasma membrane and enhance the membrane associated enzymatic activity of SK1, as well as its oncogenic signalling. We subsequently demonstrated that elevated levels of CIB1 resulted in full neoplastic transformation, in a manner dependent on SK1. In agreement with our previous findings that SK1 is a downstream mediator of oncogenic signalling by Ras, we found that targeting CIB1 also inhibited neoplastic growth of cells induced by oncogenic Ras, suggesting an important pro-tumorigenic role for CIB1. Thus, we have demonstrated for the first time a role for CIB1 in neoplastic transformation, and revealed a novel mechanism facilitating oncogenic signalling by Ras and SK1

Proteasomal degradation of sphingosine kinase 1 and inhibition of dihydroceramide desaturase by the sphingosine kinase inhibitors, SKi or ABC294640, induces growth arrest in androgen-independent LNCaP-AI prostate cancer cells

Sphingosine kinases (two isoforms termed SK1 and SK2) catalyse the formation of the bioactive lipid sphingosine 1-phosphate. We demonstrate here that the SK2 inhibitor, ABC294640 (3-(4-chlorophenyl)-adamantane-1-carboxylic acid (pyridin-4-ylmethyl)amide) or the SK1/SK2 inhibitor, SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole)) induce the proteasomal degradation of SK1a (Mr = 42 kDa) and inhibit DNA synthesis in androgen-independent LNCaP-AI prostate cancer cells. These effects are recapitulated by the dihydroceramide desaturase (Des1) inhibitor, fenretinide. Moreover, SKi or ABC294640 reduce Des1 activity in Jurkat cells and ABC294640 induces the proteasomal degradation of Des1 (Mr = 38 kDa) in LNCaP-AI prostate cancer cells. Furthermore, SKi or ABC294640 or fenretinide increase the expression of the senescence markers, p53 and p21 in LNCaP-AI prostate cancer cells. The siRNA knockdown of SK1 or SK2 failed to increase p53 and p21 expression, but the former did reduce DNA synthesis in LNCaP-AI prostate cancer cells. Moreover, N-acetylcysteine (reactive oxygen species scavenger) blocked the SK inhibitor-induced increase in p21 and p53 expression but had no effect on the proteasomal degradation of SK1a. In addition, siRNA knockdown of Des1 increased p53 expression while a combination of Des1/SK1 siRNA increased the expression of p21. Therefore, Des1 and SK1 participate in regulating LNCaP-AI prostate cancer cell growth and this involves p53/p21-dependent and -independent pathways. Therefore, we propose targeting androgen-independent prostate cancer cells with compounds that affect Des1/SK1 to modulate both de novo and sphingolipid rheostat pathways in order to induce growth arrest

Examining the role of sphingosine kinase-2 in the regulation of endothelial cell barrier integrity

A key mediator of vascular EC barrier integrity, S1P, is derived from phosphorylation of sphingosine by the SK-1 and SK-2. While previous work indicates that SK-1 can regulate EC barrier integrity, whether SK-2 has a similar role remains to be determined.A cell impedance assay was used to assess human umbilical vein EC and bone marrow EC barrier integrity in vitro, with application of the SK inhibitors ABC294640, PF543, SKi, and MP-A08. In vivo studies were conducted using intravital microscopy to assess EC barrier integrity in SK-1 (Sphk1(-/-) ) and SK-2 (Sphk2(-/-) ) knock-out mice.Only ABC294640 and MP-A08, which can both inhibit SK-2, caused a decrease in EC barrier integrity in vitro in both cell types. Intravital microscopy revealed that Sphk1(-/-) mice had reduced EC barrier integrity compared to WT mice, whereas no change was evident in Sphk2(-/-) mice.Our data suggest that in vitro inhibition of SK-2, can compromise the integrity of the EC monolayer, while SK-1 exerts a more dominant control in vivo. These data may have clinical implications and could aid in the development of new treatments for disorders of vascular barrier function.David P. Dimasi, Stuart M. Pitson, and Claudine S. Bonde

The Role of the Extracellular Matrix and Its Molecular and Cellular Regulators in Cancer Cell Plasticity

The microenvironment encompasses all components of a tumor other than the cancer cells themselves. It is highly heterogenous, comprising a cellular component that includes immune cells, fibroblasts, adipocytes, and endothelial cells, and a non-cellular component, which is a meshwork of polymeric proteins and accessory molecules, termed the extracellular matrix (ECM). The ECM provides both a biochemical and biomechanical context within which cancer cells exist. Cancer progression is dependent on the ability of cancer cells to traverse the ECM barrier, access the circulation and establish distal metastases. Communication between cancer cells and the microenvironment is therefore an important aspect of tumor progression. Significant progress has been made in identifying the molecular mechanisms that enable cancer cells to subvert the immune component of the microenvironment to facilitate tumor growth and spread. While much less is known about how the tumor cells adapt to changes in the ECM nor indeed how they influence ECM structure and composition, the importance of the ECM to cancer progression is now well established. Plasticity refers to the ability of cancer cells to modify their physiological characteristics, permitting them to survive hostile microenvironments and resist therapy. Examples include the acquisition of stemness characteristics and the epithelial-mesenchymal and mesenchymal-epithelial transitions. There is emerging evidence that the biochemical and biomechanical properties of the ECM influence cancer cell plasticity and vice versa. Outstanding challenges for the field remain the identification of the cellular mechanisms by which cancer cells establish tumor-promoting ECM characteristics and delineating the key molecular mechanisms underlying ECM-induced cancer cell plasticity. Here we summarize the current state of understanding about the relationships between cancer cells and the main stromal cell types of the microenvironment that determine ECM characteristics, and the key molecular pathways that govern this three-way interaction to regulate cancer cell plasticity. We postulate that a comprehensive understanding of this dynamic system will be required to fully exploit opportunities for targeting the ECM regulators of cancer cell plasticity

Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways

Copyright: © 2017 Al-Shujairi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.We have previously reported that the absence of sphingosine kinase 1 (SK1) affects both dengue virus (DENV) infection and innate immune responses in vitro. Here we aimed to define SK1-dependancy of DENV-induced disease and the associated innate responses in vivo. The lack of a reliable mouse model with a fully competent interferon response for DENV infection is a challenge, and here we use an experimental model of DENV infection in the brain of immunocompetent mice. Intracranial injection of DENV-2 into C57BL/6 mice induced body weight loss and neurological symptoms which was associated with a high level of DENV RNA in the brain. Body weight loss and DENV RNA level tended to be greater in SK1-/- compared with wildtype (WT) mice. Brain infection with DENV-2 is associated with the induction of interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression including viperin, Ifi27l2a, IRF7, and CXCL10 without any significant differences between WT and SK1-/- mice. The SK2 and sphingosine-1-phosphate (S1P) levels in the brain were unchanged by DENV infection or the lack of SK1. Histological analysis demonstrated the presence of a cellular infiltrate in DENV-infected brain with a significant increase in mRNA for CD8 but not CD4 suggesting this infiltrate is likely CD8+ but not CD4+ T-lymphocytes. This increase in T-cell infiltration was not affected by the lack of SK1. Overall, DENV-infection in the brain induces IFN and T-cell responses but does not influence the SK/S1P axis. In contrast to our observations in vitro, SK1 has no major influence on these responses following DENV-infection in the mouse brain

Pleural myxoid liposarcoma: features of 2 cases and associated literature review

Primary pleural myxoid liposarcoma is a rare entity and no agreed treatment options have been formulated once diagnosis has been made. We report two cases with subsequent management and make recommendations for treatment pathways in these rare cases