Disasters are not natural

Steve, Lee and Ksenia argue for a greater understanding that disasters arising from hazardous events are not natural and that we should therefore avoid using the term ‘natural disaster’

Eccrine porocarcinoma of the head: An important differential diagnosis in the elderly patient

Background: Eccrine porocarcinoma is a rare malignant tumor of the sweat gland, characterized by a broad spectrum of clinicopathologic presentations. Surprisingly, unlike its benign counterpart eccrine poroma, eccrine porocarcinoma is seldom found in areas with a high density of eccrine sweat glands, like the palms or soles. Instead, eccrine porocarcinoma frequently occurs on the lower extremities, trunk and abdomen, but also on the head, resembling various other skin tumors, as illustrated in the patients described herein. Observations: We report 5 cases of eccrine porocarcinoma of the head. All patients were initially diagnosed as having epidermal or melanocytic skin tumors. Only after histopathologic examination were they classified as eccrine porocarcinoma, showing features of epithelial tumors with abortive ductal differentiation. Characteristic clinical, histopathologic and immunohistochemical findings of eccrine porocarcinomas are illustrated. Conclusion: Eccrine porocarcinomas are potentially fatal adnexal malignancies, in which extensive metastatic dissemination may occur. Porocarcinomas are commonly overlooked, or misinterpreted as squamous or basal cell carcinomas as well as other common malignant and even benign skin tumors. Knowledge of the clinical pattern and histologic findings, therefore, is crucial for an early therapeutic intervention, which can reduce the risk of tumor recurrence and serious complications. Copyright (c) 2008 S. Karger AG, Basel

Further education sector governors as ethnographers: five case studies

This paper considers how governors in the English Further Education and Skills (FE) sector examined their practice as ethnographers. The paper locates both FE governance and ethnography within the challenges of the performative and Panoptic environments facing English education. In doing so, the paper explores how the informants’ mobilisation of ethnographic methods revealed a novel lens on both governance and the role of ethnographer. Employing Grounded Theory, the paper considers how the participants negotiated philosophical questions regarding evidence, objectivity and truth. The paper suggests that despite the deep-seated complexities inherent in conducting ethnography in performative contexts, the participants generated data which painted a unique and revealing picture upon their practice as governor and researcher

EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study

Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with Cu-64 through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-Cu-64 images were qualitatively and quantitatively compared to the current clinical standards of [F-18] FDOPA and gadolinium (Gd) contrast-enhanced MRI. We show that EphA2-4B3-NOTA-Cu-64 effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-Cu-64 images than in [F-18] FDOPA images and Gd contrast-enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG

Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity

MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution

Biodegradable core crosslinked star polymer nanoparticles as 19F MRI contrast agents for selective imaging

With the aim of developing stimuli-responsive imaging agents, we report here the synthesis of core crosslinked star (CCS) polymers and their evaluation as pH-sensitive 19F magnetic resonance imaging (19F MRI) contrast agents. Block copolymers consisting of poly(ethylene glycol)methyl ether methacrylate (PPEGMA) as the first block and a copolymer of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and 2,2,2-trifluoroethyl methacrylate (TFEMA) as the second block were synthesised using RAFT polymerisation. The polymerisation kinetics were studied in detail. The block copolymers were then used as arm precursors for the arm-first synthesis of CCS polymers through RAFT dispersion polymerisation. The synthetic conditions were investigated and optimised. CCS polymers with a degradable core were also synthesised and evaluated as 19F MRI contrast agents. The degradation of the core was confirmed by treatment with various reducing agents. The particle size, 19F NMR signal and relaxation times as well as 19F MRI imaging performance of the CCS polymers were studied at a range of value of solution pH. Significant enhancement of the image intensity was observed when the pH was decreased from 8 to 5, indicating that the CCS nanoparticles could be used as 19F MRI contrast agents for the detection of the acidic environment within tumour tissue

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)$^{1,2}$. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive$^{1,2}$. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma$^{3}$. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response