Outcomes for metastatic Ewing sarcoma and osteosarcoma are dismal and have not changed for decades. Oxidative stress attenuates melanoma metastasis, and melanoma cells must reduce oxidative stress to metastasize. We explored this in sarcomas by screening for oxidative stress sensitizers, which identified the class I HDAC inhibitor MS‐275 as enhancing vulnerability to reactive oxygen species (ROS) in sarcoma cells. Mechanistically,…
Read More
Characterizing the adaptive landscapes that encompass the emergence of novel enzyme functions can provide molecular insights into both enzymatic and evolutionary mechanisms. Here, we combine ancestral protein reconstruction with biochemical, structural and mutational analyses to characterize the functional evolution of methyl-parathion hydrolase (MPH), an organophosphate-degrading enzyme. We identify five mutations that are necessary and sufficient for the evolution of MPH…
Read More
Background Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease, and gene expression profiling has identified several molecular subtypes with distinct biological and clinicopathological characteristics. While MIBC subtyping has primarily been based on messenger RNA (mRNA), long non-coding RNAs (lncRNAs) may provide additional resolution. Methods LncRNA expression was quantified from microarray data of a MIBC cohort treated with neoadjuvant chemotherapy (NAC)…
Read More
Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. Results We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with…
Read More
The latency phenomenon produced by human immunodeficiency virus (HIV‐1) prevents viral clearance by current therapies, and consequently development of a cure for HIV‐1 disease represents a formidable challenge. Research over the past decade has resulted in identification of small molecules that are capable of exposing HIV‐1 latent reservoirs, by reactivation of viral transcription, which is intended to render these infected…
Read More
Chlamydia trachomatis and C. muridarum are intracellular bacterial pathogens of mucosal epithelial cells. CD4 T cells and major histocompatibility complex (MHC) class II molecules are essential for protective immunity against them. Antigens presented by dendritic cells (DCs) expand naïve pathogen-specific T cells (inductive phase), while antigens presented by epithelial cells identify infected epithelial cells as targets during the effector phase. We previously showed…
Read More
DNA methylation is the most studied modification in human population epigenetics. Its information content can be explored in 2 principal ways—epigenome-wide association studies and epigenetic age. The latter likely reflects cellular/biological age and works with impressive accuracy across most tissues. In adults, it associates with various environments and health. However, current epigenetic clocks are not very accurate in the pediatric…
Read More
The airway epithelium forms the interface between the inhaled environment and the lung. The airway epithelium is dysfunctional in asthma and epigenetic mechanisms are considered a contributory factor. We hypothesised that the DNA methylation profiles of cultured primary airway epithelial cells (AECs) would differ between cells isolated from individuals with asthma (n = 17) versus those without asthma (n = 16). AECs were isolated…
Read More
Scientists have shown that we can harness the search-and-destroy functions of cytotoxic T cells (CTLs) to help our bodies fight off cancer, but finding these cancer-fighting cells is like searching for a needle in a haystack. A new method takes advantage of the CTLs’ granzyme-mediated cell killing to identify disease antigens. To do this, the scientists generate a library of cells, each displaying a different antigen. Only a small fraction of these antigens will signal disease, and the goal is to find them.
Read More
The authors evaluated operating characteristics, particularly specificity and positive predictive value (PPV), by mapping plasma miR371 expression to actual clinical events in patients with a history of germ cell tumour. Plasma miR371 expression predicted aGCM with high specificity and positive predictive value. Although other operating characteristics of miR371 awaited longer follow-up for more complete definition, the findings of a highly...
Read More