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This Month in AJP

    Open AccessPublished:March 19, 2012DOI:https://doi.org/10.1016/j.ajpath.2012.03.002

        Diagnosing Bladder Cancer via Urinary Samples

        Altered miRNA expression may occur early in bladder cancer, directing carcinogenesis and tumor behavior. Puerta-Gil et al (Am J Pathol 2012, 180:1808–1815) evaluated whether alterations in miRNA expression could improve disease stratification and outcome. Tumor miRNA expression correlated with tumor grade, size, and presence of carcinoma in situ (miR-222), recurrence (miR-222 and miR-143), progression (miR-222 and miR-143), disease-specific survival (miR-222), and overall survival (miR-222). Expression patterns of miRNA targets (BCL2, VEGF, ERBB3, and ERBB4) also correlated with tumor progression and/or several outcome endpoints. Furthermore, miR-452 and miR-222 detection in urine provided high accuracies for bladder cancer diagnosis, demonstrating the utility of examining miRNA expression in urinary specimens for noninvasive diagnosis.

        Age Influences Injury and Repair in MS

        Accumulating evidence suggests that age affects the course and prognosis of multiple sclerosis (MS). Hampton et al (Am J Pathol 2012, 180:1897–1905) used a novel MS model of focal immune-mediated demyelinating injury to show that aged adult mice exhibit both an increased vulnerability to axonal injury as well as a reduced efficiency of remyelination compared to younger animals. More importantly, remyelination in the aged animals was predominantly Schwann-cell mediated, in contrast to central oligodendrocyte-mediated remyelination in the younger rodents. Together, these findings establish an experimental platform to further study the influence of age on both injury and repair in a biologically relevant model of MS.

        B-Cell Response Distinguishes Outcome in Leishmania spp. Co-Infection

        Co-infection of C3HeB/FeJ (C3H) mice with both Leishmania major and L. amazonensis leads to a healed footpad lesion, whereas co-infection of C57Bl/6 (B6) mice leads to non-healing lesions, likely via deficient B cell responses. To clarify the mechanisms involved, Gibson-Corley et al (Am J Pathol 2012, 180:2009–2017) analyzed the draining lymph node germinal center B-cell response between co-infected C3H and B6 mice. C3H mice had more germinal center B cells, more antibody isotype-switched germinal center B cells, more memory B cells, and more antigen-specific antibody-producing cells following co-infection compared to B6 mice. These data establish a fundamental difference between these two mouse strains in the immune response to Leishmania infection, namely presence/absence of productive B-cell germinal center response.

        CFTR Mutation Impacts Bone Formation

        The cystic fibrosis transmembrane conductance regulator (CFTR) F508del mutation may be an independent risk factor for CF-related bone disease. Therefore, Le Henaff et al (Am J Pathol 2012, 180:2068–2075) evaluated bone formation and bone mass in F508del-Cftr homozygous mice (F508del Cftrtm1Eur) and Cftr+/+ littermate controls. F508del Cftrtm1Eur mice displayed reduced bone mineral density, lower femoral bone mass, and altered trabecular bone architecture, as well as decreased bone formation rate, compared to controls at all ages. Severe osteopenia and altered bone architecture were also found in young and mature adult F508del Cftrtm1Eur mice. These findings demonstrate that the F508del Cftrtm1Eur model may represent a valuable tool to examine emerging targets for the treatment of CF-related bone disease.

        Redefining Glioblastoma Gene Expression Class

        The Cancer Genome Atlas (TCGA) project assigns glioblastoma (GBM) to four transcriptional classes (proneural, neural, classical, and mesenchymal), but Cooper et al (Am J Pathol 2012, 180:2108–2119) hypothesized that the tumor microenvironment also has an impact. They found that the mesenchymal GBM class was enriched with samples displaying a high degree of necrosis, with transcriptional regulators of the mesenchymal transition tightly correlating with the extent of necrosis. Non-mesenchymal GBMs became more similar to the mesenchymal class with increasing levels of necrosis. In addition, C/EBP-β and C/EBP-δ were specifically expressed by hypoxic, perinecrotic pseudopalisading cells, accounting for their association with necrosis and poor prognosis and suggesting key signaling nodes for targeted therapies.

        Linked Article

        • Focal Immune-Mediated White Matter Demyelination Reveals an Age-Associated Increase in Axonal Vulnerability and Decreased Remyelination Efficiency
          The American Journal of PathologyVol. 180Issue 5
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            In addition to being an established risk factor for neurodegenerative diseases, age is increasingly recognized as adversely influencing regeneration. Accumulating evidence also suggests that age plays important, although poorly understood, roles with respect to course and prognosis in the degenerative and untreatable later phase of multiple sclerosis. Two experimental models of multiple sclerosis have been particularly influential in modeling the different aspects of neuronal injury and regeneration: global experimental autoimmune encephalomyelitis and focal toxin-mediated injury.
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        • The F508del Mutation in Cystic Fibrosis Transmembrane Conductance Regulator Gene Impacts Bone Formation
          The American Journal of PathologyVol. 180Issue 5
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            The F508del mutation in the cystic fibrosis transmembrane conductance regulator (Cftr) gene is believed to be an independent risk factor for cystic fibrosis–related bone disease. In this study, we evaluated the bone mineral density as well as the histomorphometric parameters of bone formation and bone mass in both F508del-Cftr homozygous mice (F508del Cftrtm1Eur) and Cftr+/+ littermate controls at 6 (prepubertal), 10 (pubertal), and 14 (young adult) weeks of age in both sexes. The bone architecture of F508del Cftrtm1Eur and wild-type (WT) littermate mice was evaluated by bone densitometry, microcomputed tomography, and analysis of the dynamic parameters of bone formation.
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        • The Tumor Microenvironment Strongly Impacts Master Transcriptional Regulators and Gene Expression Class of Glioblastoma
          The American Journal of PathologyVol. 180Issue 5
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            The Cancer Genome Atlas (TCGA) project has generated gene expression data that divides glioblastoma (GBM) into four transcriptional classes: proneural, neural, classical, and mesenchymal. Because transcriptional class is only partially explained by underlying genomic alterations, we hypothesize that the tumor microenvironment may also have an impact. In this study, we focused on necrosis and angiogenesis because their presence is both prognostically and biologically significant. These features were quantified in digitized histological images of TCGA GBM frozen section slides that were immediately adjacent to samples used for molecular analysis.
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          Open Access
        • miR-143, miR-222, and miR-452 Are Useful as Tumor Stratification and Noninvasive Diagnostic Biomarkers for Bladder Cancer
          The American Journal of PathologyVol. 180Issue 5
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            Altered microRNA (miRNA) expression may occur early in bladder cancer and may play a role in carcinogenesis and tumor behavior. We evaluated whether alterations in miRNA expression could improve disease stratification and outcome prognosis in bladder tumors and noninvasive diagnosis in urinary samples. miR-143, miR-222, and miR-452 expression levels were analyzed by quantitative RT-PCR (RT-qPCR) in paired urinary and matching tumors and in two independent prospective series of tumors and urinary specimens.
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        • Promotion of a Functional B Cell Germinal Center Response after Leishmania Species Co-Infection Is Associated with Lesion Resolution
          The American Journal of PathologyVol. 180Issue 5
          • Preview
            Co-infection of C3HeB/FeJ (C3H) mice with both Leishmania major and Leishmania amazonensis leads to a healed footpad lesion, whereas co-infection of C57BL/6 (B6) mice leads to non-healing lesions. This inability to heal corresponds to a deficiency in B cell stimulation of the macrophage-mediated killing of L. amazonensis in vitro and a less robust antibody response. The mechanism that leads to healing of these lesions is not completely known, although our studies implicate the B cell response as having an important effector function in killing L.
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          Open Access