Differences in the frequency of macrophage and t cell markers between focal and crescentic classes of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis

Funding/Support This study was supported by Tenovus Scotland/Tayside grant award to DK (Grant # T13/15).Peer reviewedPublisher PD

The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma

BackgroundMalignant mesothelioma is a tumour that is strongly associated with a history of asbestos exposure, and which derives from mesothelial cells that line the serous cavities of the body. The tumour most commonly arises in the pleural cavity, but can also arise in the pericardium, peritoneum, and tunica vaginalis. At present the lesion has a very poor prognosis and is an incurable form of cancer with median survival times of up to 19 months being quoted for some histological subtypes. A large proportion of mesotheliomas have been shown to be arginine auxotrophic, leading to new research for therapeutics which might exploit this potential vulnerability.MethodsWe measured the levels of General Control Non-derepressible 2 (GCN2) protein in malignant mesothelioma tumour samples and determined whether these levels correlate with clinical outcomes.ResultsWe observed that the expression levels of GCN2 correlated with patient survival and was an independent prognostic variable in pairwise comparisons with all available clinical data.ConclusionThese findings suggest that GCN2 levels provides prognostic information and may allow for stratification of care pathways. It may suggest that targeting GCN2 is a viable strategy for mesothelioma therapy development

Multimodality Characterization of Cancer-Associated Fibroblasts in Tumor Microenvironment and Its Correlation With Ultrasound Shear Wave-Measured Tissue Stiffness in Localized Prostate Cancer

INTRODUCTION: Growing evidence suggests that the tumor microenvironment (TME) represented by cellular and acellular components plays a key role in the multistep process of metastases and response to therapies. However, imaging and molecular characterization of the TME in prostate cancer (PCa) and its role in predicting aggressive tumor behavior and disease progression is largely unexplored. The study explores the PCa TME through the characterization of cancer-associated fibroblasts (CAFs) using both immunohistochemistry (IHC) and genomics approaches. This is then correlated with transrectal ultrasound shear wave elastography (USWE)-measured tissue stiffness. PATIENTS AND METHODS: Thirty patients with clinically localized PCa undergoing radical prostatectomy for different risk categories of tumor (low, intermediate, and high) defined by Gleason score (GS) were prospectively recruited into this study. Prostatic tissue stiffness was measured using USWE prior to surgery. The CAFs within the TME were identified by IHC using a panel of six antibodies (FAP, SMAα, FSP1, CD36, PDGFRα, and PDGFRβ) as well as gene expression profiling using TempO-sequence analysis. Whether the pattern and degree of immunohistochemical positivity (measured by Quick score method) and expression of genes characterizing CAFs were correlated with USWE- and GS-measured tissue stiffnesses were tested using Spearman’s rank correlation and Pearson correlation. RESULTS: There was a statistically significant correlation between GS of cancers, the pattern of staining for CAFs by immunohistochemical staining, and tissue stiffness measured in kPa using USWE (p < 0.001). Significant differences were also observed in immunohistochemical staining patterns between normal prostate and prostatic cancerous tissue. PDGFRβ and SMAα immunostaining scores increased linearly with increasing the USWE stiffness and the GS of PCa. There was a significant positive correlation between increasing tissue stiffness in tumor stroma and SMAα and PDGFRβ gene expression in the fibromuscular stroma (p < 0.001). CONCLUSION: USWE-measured tissue stiffness correlates with increased SMAα and PDGFRβ expressing CAFs and PCa GSs. This mechanistic correlation could be used for predicting the upgrading of GS from biopsies to radical surgery and response to novel treatments

IL-15 and PIM kinases direct the metabolic programming of intestinal intraepithelial lymphocytes

Intraepithelial lymphocytes (IEL) respond to IL-15 complexed with IL-15Ra but how this intrinsically affects IEL is unclear. Here the authors use proteomics analyses of the main mouse IEL subsets and identify PIM kinases as essential for IEL proliferation, metabolism and effector function downstream of IL-15

Cluster analyses of the TCGA and a TMA dataset using the coexpression of HSP27 and CRYAB improves alignment with clinical-pathological parameters of breast cancer and suggests different epichaperome influences for each sHSP

Our cluster analysis of the Cancer Genome Atlas for co-expression of HSP27 and CRYAB in breast cancer patients identified three patient groups based on their expression level combination (high HSP27 + low CRYAB; low HSP27 + high CRYAB; similar HSP27 + CRYAB). Our analyses also suggest that there is a statistically significant inverse relationship between HSP27 and CRYAB and known clinicopathological markers in breast cancer. Screening an unbiased 248 breast cancer patient tissue microarray (TMA) for the protein expression of HSP27 and phosphorylated HSP27 (HSP27-82pS) with CRYAB also identified three patient groups based on HSP27 and CRYAB expression levels. TMA24 also had recorded clinical-pathological parameters, such as ER and PR receptor status, patient survival, and TP53 mutation status. High HSP27 protein levels were significant with ER and PR expression. HSP27-82pS associated with the best patient survival (Log Rank test). High CRYAB expression in combination with wild-type TP53 was significant for patient survival, but a different patient outcome was observed when mutant TP53 was combined with high CRYAB expression. Our data suggest that HSP27 and CRYAB have different epichaperome influences in breast cancer, but more importantly evidence the value of a cluster analysis that considers their coexpression. Our approach can deliver convergence for archival datasets as well as those from recent treatment and patient cohorts and can align HSP27 and CRYAB expression to important clinical-pathological features of breast cancer

Recombination-Mediated Host Adaptation by Avian Staphylococcus aureus

Staphylococcus aureus are globally disseminated among farmed chickens causing skeletal muscle infections, dermatitis, and septicaemia. The emergence of poultry-associated lineages has involved zoonotic transmission from humans to chickens but questions remain about the specific adaptations that promote proliferation of chicken pathogens. We characterized genetic variation in a population of genome-sequenced S. aureus isolates of poultry and humanorigin. Genealogical analysis identified a dominant poultry-associated sequence cluster within the CC5 clonal complex. Poultry and human CC5 isolates were significantly distinct from each other and more recombination events were detected in the poultry isolates. We identified 44 recombination events in 33 genes along the branch extending to the poultry-specific CC5 cluster, and 47 genes were found more often in CC5 poultry isolates compared with those from humans. Many of these gene sequences were common in chicken isolates from other clonal complexes suggesting horizontal gene transfer among poultry associated lineages. Consistent with functional predictions for putative poultry-associated genes, poultry isolates showed enhanced growth at 42 degrees C and greater erythrocyte lysis on chicken blood agar in comparison with human isolates. By combining phenotype information with evolutionary analyses of staphylococcal genomes, we provide evidence of adaptation, following a human-to-poultry host transition. This has important implications for the emergence and dissemination of new pathogenic clones associated with modern agriculture.Peer reviewe

MAGE-A cancer/testis antigens inhibit MDM2 ubiquitylation function and promote increased levels of MDM4

Melanoma antigen A (MAGE-A) proteins comprise a structurally and biochemically similar sub-family of Cancer/Testis antigens that are expressed in many cancer types and are thought to contribute actively to malignancy. MAGE-A proteins are established regulators of certain cancer-associated transcription factors, including p53, and are activators of several RING finger-dependent ubiquitin E3 ligases. Here, we show that MAGE-A2 associates with MDM2, a ubiquitin E3 ligase that mediates ubiquitylation of more than 20 substrates including mainly p53, MDM2 itself, and MDM4, a potent p53 inhibitor and MDM2 partner that is structurally related to MDM2. We find that MAGE-A2 interacts with MDM2 via the N-terminal p53-binding pocket and the RING finger domain of MDM2 that is required for homo/hetero-dimerization and for E2 ligase interaction. Consistent with these data, we show that MAGE-A2 is a potent inhibitor of the E3 ubiquitin ligase activity of MDM2, yet it does not have any significant effect on p53 turnover mediated by MDM2. Strikingly, however, increased MAGE-A2 expression leads to reduced ubiquitylation and increased levels of MDM4. Similarly, silencing of endogenous MAGE-A expression diminishes MDM4 levels in a manner that can be rescued by the proteasomal inhibitor, bortezomid, and permits increased MDM2/MDM4 association. These data suggest that MAGE-A proteins can: (i) uncouple the ubiquitin ligase and degradation functions of MDM2; (ii) act as potent inhibitors of E3 ligase function; and (iii) regulate the turnover of MDM4. We also find an association between the presence of MAGE-A and increased MDM4 levels in primary breast cancer, suggesting that MAGE-A-dependent control of MDM4 levels has relevance to cancer clinically