Advertisement

This Month in AJP

    Open ArchivePublished:August 21, 2019DOI:https://doi.org/10.1016/j.ajpath.2019.08.001

        Managing Colorectal Cancer

        The role of KH-type splicing regulatory protein (KHSRP) in colorectal cancer (CRC) is unclear. Using a combination of in silico, ex vivo, and in vitro approaches, Caiazza et al (Am J Pathol 2019, 1916–1932) studied this role. KHSRP is expressed in the epithelial and stromal compartments of both primary and metastatic tumors, elevated in tumor tissues compared to controls, and is a prognostic indicator of worse overall survival. KHSRP increased cell proliferation in vitro and promoted a pro-angiogenic extracellular environment. KHSRP promotes CRC and may be therapeutically targeted to manage it.

        Understanding Diabetic Retinopathy

        Though lysyl oxidase propeptide (LOX-PP) promotes apoptosis in diseased tissues, its role in vascular cell loss associated with diabetic retinopathy (DR) is unclear. Using in vivo and in vitro studies, Kim et al (Am J Pathol 2019, 1945–1952) examined the effects of high glucose (HG) or diabetes on LOX-PP expression and function. HG increased LOX-PP expression and decreased pro-survival signals in vitro and in vivo. These observations were replicated when recombinant LOX-PP was administered in vitro and in vivo. HG-induced LOX-PP overexpression may be targeted in preventing retinal vascular cell loss associated with DR.

        Resolving Inflammation after Acetaminophen Overdose

        The fibrinolytic enzyme, plasmin, regulates macrophage function; however this regulation has not been studied in the context of acetaminophen (APAP). Using mouse and in vitro models, Roth et al (Am J Pathol 2019, 1986–2001) studied plasmin-mediated macrophage function upon APAP overdose. Chemical inhibition of plasmin in mice delayed the up-regulation of proinflammatory cytokines and prevented phagocytic removal of dead cells. In vitro, plasmin stimulated cytokine production via NF-κB. Plasmin may help resolve inflammation after APAP overdose by promoting macrophage function.

        Understanding Molecular Pathogenesis of Group A Streptococcus

        Serotype M28 group A Streptococcus (GAS) strains collected from human invasive infections show a higher than expected number of polymorphisms in rocA. Bernard et al (Am J Pathol 2019, 2002–2018) hypothesized that RocA polymorphisms may alter RocA function and change the global transcriptome and hence the virulence of serotype M28 GAS. RNA-seq, in vitro virulence factor assays, and mouse and nonhuman primate pathogenesis studies were performed on naturally-occurring clinical isolates with rocA polymorphisms and isogenic mutant strains to study global GAS transcriptome changes and virulence phenotype. Naturally occurring RocA polymorphisms may uniquely alter global GAS transcriptome and GAS virulence.

        Modeling Human Osteomyelitis

        Staphylococcus infection may cause human bacterial chondronecrosis with osteomyelitis (BCO). Using a Staphylococcus-induced chicken BCO model and human osteomyelitis samples, Greene et al (Am J Pathol 2019, 2077–2089) studied the mechanisms underlying virulence. Administration of synthetic or genetic double stranded RNA (dsRNA) induced human osteoblast cell death in vitro. Infection with staphylococci isolated from chicken BCO model and human samples induced DICER1-mediated up-regulation of cytotoxic dsRNA and activated NLRP3 inflammasome in vitro. NLRP3 inflammasome was also activated in the bones of BCO chicken and humans with osteomyelitis compared to healthy controls. The chicken BCO model may help study human osteomyelitis and test therapeutic potential of dsRNA.

        Linked Article

        • Dichotomous Role of Plasmin in Regulation of Macrophage Function after Acetaminophen Overdose
          The American Journal of PathologyVol. 189Issue 10
          • Preview
            Kupffer cells and monocyte-derived macrophages are critical for liver repair after acetaminophen (APAP) overdose. These cells produce promitogenic cytokines and growth factors, and they phagocytose dead cell debris, a process that is critical for resolution of inflammation. The factors that regulate these dynamic functions of macrophages after APAP overdose, however, are not fully understood. We tested the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function after APAP-induced liver injury.
          • Full-Text
          • PDF
          Open Archive
        • Effects of High Glucose–Induced Lysyl Oxidase Propeptide on Retinal Endothelial Cell Survival: Implications for Diabetic Retinopathy
          The American Journal of PathologyVol. 189Issue 10
          • Preview
            Diabetic retinopathy (DR) is characterized by apoptotic cell loss in the retinal vasculature. Lysyl oxidase propeptide (LOX-PP), released during LOX processing, has been implicated in promoting apoptosis in various diseased tissues. However, its role in the development and progression of DR is unknown. We investigated whether high glucose (HG) or diabetes alters LOX-PP expression and thereby influences AKT pathway and affects retinal endothelial cell survival. Rat retinal endothelial cells were grown in normal medium, normal medium and exposed to recombinant LOX-PP (rLOX-PP) or HG medium and examined for LOX-PP expression, AKT and caspase-3 activation.
          • Full-Text
          • PDF
          Open Archive
        • Double-Stranded RNA Is a Novel Molecular Target in Osteomyelitis Pathogenesis: A Translational Avian Model for Human Bacterial Chondronecrosis with Osteomyelitis
          The American Journal of PathologyVol. 189Issue 10
          • Preview
            Osteomyelitis remains a serious inflammatory bone disease that affects millions of individuals worldwide and for which there is no effective treatment. Despite scientific evidence that Staphylococcus bacteria are the most common causative species for human bacterial chondronecrosis with osteomyelitis (BCO), much remains to be understood about the underlying virulence mechanisms. Herein, we show increased levels of double-stranded RNA (dsRNA) in infected bone in a Staphylococcus-induced chicken BCO model and in human osteomyelitis samples.
          • Full-Text
          • PDF
          Open Archive
        • KH-Type Splicing Regulatory Protein Controls Colorectal Cancer Cell Growth and Modulates the Tumor Microenvironment
          The American Journal of PathologyVol. 189Issue 10
          • Preview
            KH-type splicing regulatory protein (KHSRP) is a multifunctional nucleic acid binding protein implicated in key aspects of cancer cell biology: inflammation and cell-fate determination. However, the role KHSRP plays in colorectal cancer (CRC) tumorigenesis remains largely unknown. Using a combination of in silico analysis of large data sets, ex vivo analysis of protein expression in patients, and mechanistic studies using in vitro models of CRC, we investigated the oncogenic role of KHSRP. We demonstrated KHSRP expression in the epithelial and stromal compartments of both primary and metastatic tumors.
          • Full-Text
          • PDF
          Open Access
        • Polymorphisms in Regulator of Cov Contribute to the Molecular Pathogenesis of Serotype M28 Group A Streptococcus
          The American Journal of PathologyVol. 189Issue 10
          • Preview
            Two-component systems (TCSs) are signal transduction proteins that enable bacteria to respond to external stimuli by altering the global transcriptome. Accessory proteins interact with TCSs to fine-tune their activity. In group A Streptococcus (GAS), regulator of Cov (RocA) is an accessory protein that functions with the control of virulence regulator/sensor TCS, which regulates approximately 15% of the GAS transcriptome. Whole-genome sequencing analysis of serotype M28 GAS strains collected from invasive infections in humans identified a higher number of missense (amino acid–altering) and nonsense (protein-truncating) polymorphisms in rocA than expected.
          • Full-Text
          • PDF
          Open Archive