Clinical Utility of Molecular Profiling in Recurrent Glioblastoma Multiforme

Introduction: Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor found in adults. GBM has limited therapeutic options. Initial tumor sampling establishes the histopathologic diagnosis, identifies prognostic and therapeutic biomarkers, and provides an opportunity for molecular profiling. By contrast, the utility of repeat tumor sampling and molecular profiling in recurrent GBM is not well established. Clinical Findings: We present a 69-year-old woman with GBM whose tumor recurred after standard treatment with temozolomide (TMZ) and concurrent radiation, followed by adjuvant TMZ. This patient had a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, which ordinarily predicts a favorable response to TMZ. Main Diagnosis, Therapeutic Interventions, and Outcomes: Our patient’s recurrent tumor was rechallenged with TMZ based on persistent methylation of the MGMT promoter. However, her tumor was refractory to TMZ, and she floridly progressed through multiple treatments. We performed retrospective molecular profiling using next-generation sequencing (NGS) on her recurrent tumor. The NGS results showed a TMZ hypermutation signature that confers resistance to TMZ. This signature impacted our patient’s treatment plan in real time and prompted an immediate discontinuation of TMZ. Conclusions: Advances in NGS provide further insight into the molecular landscape of GBM. As NGS becomes more timely and cost-effective, molecular profiling of recurrent tumors could impact treatment decisions through either avoiding a particular treatment paradigm or identifying a potential targetable mutation. For this reason, we suggest that clinical practice routinely consider repeat biopsy and molecular profiling for recurrent GBM

Harnessing the Therapeutic Potential of Th17 Cells

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases

A distinct subset of podoplanin (gp38) expressing F4/80+ macrophages mediate phagocytosis and are induced following zymosan peritonitis

AbstractMacrophages are important tissue resident cells that regulate the dynamics of inflammation. However, they are strikingly heterogeneous. During studies looking at podoplanin (gp38) expression on stromal cells in the murine spleen and peritoneal cavity we unexpectedly discovered that podoplanin was expressed on a subset of F4/80+ macrophages; a subset which we have termed fibroblastic macrophages (FM). These cells function as phagocytes in vitro as measured by bead mediated phagocytosis assays. FM also exist at high frequency in the peritoneal cavity and in zymosan induced peritonitis in vivo. These FM represent a unique subgroup of F4/80+ macrophages and their presence in the inflamed peritoneum suggests that they play a role in zymosan induced peritonitis

CAR T cells targeting tumor endothelial marker CLEC14A inhibit tumor growth

Engineering T cells to express chimeric antigen receptors (CARs) specific for antigens on hematological cancers has yielded remarkable clinical responses, but with solid tumors, benefit has been more limited. This may reflect lack of suitable target antigens, immune evasion mechanisms in malignant cells, and/or lack of T cell infiltration into tumors. An alternative approach, to circumvent these problems, is targeting the tumor vasculature rather than the malignant cells directly. CLEC14A is a glycoprotein selectively overexpressed on the vasculature of many solid human cancers and is, therefore, of considerable interest as a target antigen. Here, we generated CARs from 2 CLEC14A-specific antibodies and expressed them in T cells. In vitro studies demonstrated that, when exposed to their target antigen, these engineered T cells proliferate, release IFN-γ, and mediate cytotoxicity. Infusing CAR engineered T cells into healthy mice showed no signs of toxicity, yet these T cells targeted tumor tissue and significantly inhibited tumor growth in 3 mouse models of cancer (Rip-Tag2, mPDAC, and Lewis lung carcinoma). Reduced tumor burden also correlated with significant loss of CLEC14A expression and reduced vascular density within malignant tissues. These data suggest the tumor vasculature can be safely and effectively targeted with CLEC14A-specific CAR T cells, offering a potent and widely applicable therapy for cancer

TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20.

This is a pre-copyedited, author-produced version of an article accepted for publication in Rheumatology following peer review. The version of record:Mohammed Al-Bogami, Jonas Bystrom, Felix Clanchy, Taher E Taher, Pamela Mangat, Richard O Williams, Ali S Jawad, Rizgar A Mageed, TNFα inhibitors reduce bone loss in rheumatoid arthritis independent of clinical response by reducing osteoclast precursors and IL-20, Rheumatology, keaa551, https://doi.org/10.1093/rheumatology/keaa551 is available online at:  https://doi.org/10.1093/rheumatology/keaa551OBJECTIVES: About half of RA patients treated with TNFα inhibitors either do not respond or lose their initial therapeutic response over time. The clinical response is measured by reduction in DAS28, which primarily reflects inflammation. However, other effects of TNFα inhibitors, such as impact on bone erosion, are not assessed by DAS28. We aimed to examine the effect of TNFα inhibitors on bone density, bone biomarkers and cytokine production in responder and non-responder patients and assessed mechanisms of action. METHODS: BMD in the lumbar spine and femur neck of 117 RA patients was measured by DEXA scan. Bone turnover biomarkers CTX, osteoprotegerin (OPG), osteocalcin and RANKL were measured by ELISA. Levels of 16 cytokines in plasma and in tissue culture supernatants of ex vivo T cells were measured by multiplex assays and ELISA. The effect of treatment with TNFα inhibitors on blood mononuclear cell (MNC) differentiation to osteoclast precursors (OCP) was measured flow cytometry and microscopy. RESULTS: TNFα inhibitors improved lumbar spine BMD but had modest effects on blood bone biomarkers, irrespective of patients' clinical response. Blood OCP numbers and the ability of monocytes to differentiate to OCP in vitro declined after treatment. Treatment also reduced RANK expression and IL-20 production. BMD improvement correlated with reduced levels of IL-20 in responder patients. CONCLUSION: This study reveals that TNFα inhibitors reduce lumbar spine bone loss in RA patients irrespective of changes in DAS28. The reduction in bone loss is associated with reduction in IL-20 levels in responder patients

Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.

Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses

Lament as Transitional Justice

Works of human rights literature help to ground the formal rights system in an informal rights ethos. Writers have developed four major modes of human rights literature: protest, testimony, lament, and laughter. Through interpretations of poetry in Carolyn Forché’s anthology, Against Forgetting, and novels from Rwanda, the United States, and Bosnia, I focus on the mode of lament, the literature of mourning. Lament is a social and ritualized form, the purposes of which are congruent with the aims of transitional justice institutions. Both laments and truth commissions employ grieving narratives to help survivors of human rights trauma bequeath to the ghosts of the past the justice of a monument while renewing the survivors’ capacity for rebuilding civil society in the future. Human rights scholars need a broader, extra-juridical meaning for “transitional justice” if we hope to capture its power

What is an intelligent building? Analysis of recent interpretations from an international perspective

In recent years, the notion of intelligent buildings (IBs) has become increasingly popular due to their potentials for deploying design initiatives and emerging technologies towards maximized occupants’ comfort and well-being with sustainable design. However, various definitions, interpretations, and implications regarding the essence of IBs exist. Various key performance indicators of IBs have been proposed in different contexts. This study explores the notion of IBs and presents an analysis of their main constituents. Through a comparison of these constituents in different contexts, this study aims to extract the common features of IBs leading to an evolved definition which could be useful as a reference framework for design, evaluation, and development of future IBs. Findings also scrutinize the long run benefits of IBs, while demonstrating the constraints and challenges of the current international interpretations

Extrusion of Endodontic Filling Materials: Medico-Legal Aspects. Two Cases

The Authors describe two cases of alleged malpractice due to overfilling. The aim of this article is to underline some medico-legal aspects regarding the quantity of extruded material which may be considered acceptable and the consequent damage to the patient

Co-ordinated Gene Expression in the Liver and Spleen during Schistosoma japonicum Infection Regulates Cell Migration

Determining the molecular events induced in the spleen during schistosome infection is an essential step in better understanding the immunopathogenesis of schistosomiasis and the mechanisms by which schistosomes modulate the host immune response. The present study defines the transcriptional and cellular events occurring in the murine spleen during the progression of Schistosoma japonicum infection. Additionally, we compared and contrasted these results with those we have previously reported for the liver. Microarray analysis combined with flow cytometry and histochemistry demonstrated that transcriptional changes occurring in the spleen were closely related to changes in cellular composition. Additionally, the presence of alternatively activated macrophages, as indicated by up-regulation of Chi3l3 and Chi3l4 and expansion of F4/80+ macrophages, together with enhanced expression of the immunoregulatory genes ANXA1 and CAMP suggests the spleen may be an important site for the control of S. japonicum-induced immune responses. The most striking difference between the transcriptional profiles of the infected liver and spleen was the contrasting expression of chemokines and cell adhesion molecules. Lymphocyte chemokines, including the homeostatic chemokines CXCL13, CCL19 and CCL21, were significantly down-regulated in the spleen but up-regulated in the liver. Eosinophil (CCL11, CCL24), neutrophil (CXCL1) and monocyte (CXCL14, CCL12) chemokines and the cell adhesion molecules VCAM1, NCAM1, PECAM1 were up-regulated in the liver but unchanged in the spleen. Chemokines up-regulated in both organs were expressed at significantly higher levels in the liver. Co-ordinated expression of these genes probably contributes to the development of a chemotactic signalling gradient that promotes recruitment of effector cells to the liver, thereby facilitating the development of hepatic granulomas and fibrosis. Together these data provide, for the first time, a comprehensive overview of the molecular events occurring in the spleen during schistosomiasis and will substantially further our understanding of the local and systemic mechanisms driving the immunopathogenesis of this disease