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This Month in AJP

    Open ArchivePublished:May 16, 2019DOI:https://doi.org/10.1016/j.ajpath.2019.05.001

        USP15 Promotes Wound Healing

        The regulatory role of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15), in wound healing is unclear. Using Usp15 knockout mice and USP15-silenced human dermal fibroblasts, Zhao et al (Am J Pathol 2019, 189:1351–1362) studied this role. Loss of USP15 suppressed the transforming growth factor-β signaling pathway, significantly delayed wound closure, and inhibited cell proliferation and migration. USP15 may be targeted in the treatment of refractory wounds.

        CD55 Regulates Peripheral Tolerance

        The tolerogenic role of the complement inhibitory protein CD55 (decay accelerating factor (DAF)) is unclear. Using two independent mouse models of tolerance, Strainic and Liu et al (Am J Pathol 2019, 189:1386–1401) studied this role in two immune-privileged sites (the gut and the eye) that continuously elicit immunosuppressive responses. DAF deficiency lowered induction of immune tolerance by manipulating the expression levels of the effector molecules in the dendritic and T cells in both the models. DAF plays a critical role in programming immune tolerance.

        Automating Signal Identification

        Automated detection and thresholding of multiplexed, fluorescent images has been challenging. Barnett et al (Am J Pathol 2019, 189:1402–1412) report a software to meet this need. The novel SignalFinder program used a newly-developed algorithm called Segment-Fit Thresholding. The performance of SignalFinder for automated signal identification faired well with several current methods on various operating systems. SignalFinder allows quantification and mapping of relationships between unlimited numbers of markers and produces composite images of the signals/colocalization on brightfield heamtoxylin and eosin images. The high-throughput, unbiased rigorous analyses of whole-slide and multimarker data by SignalFinder may open new avenues in clinical research.

        Understanding Osteoarthritis Progression

        The role of high temperature requirement A1 (HTRA1)—the most abundant protease in human osteoarthritis (OA) cartilage—in OA progression is unclear. Using established aging and post-traumatic mouse models of OA, Chen et al (Am J Pathol 2019, 189:1423–1434) explored this causal relationship. HtrA1 was genetically removed in these mouse models and OA progression studied histologically. HTRA1 delayed OA progression by protecting the pericellular matrix of chondrocytes. HTRA1 may be therapeutically targeted in the development of disease-modifying OA drugs.

        Predicting Prostate Cancer Aggressiveness

        The secreted protein CCN3 has clear implications in breast cancer metastasis; however, its role in the metastasis of prostate cancer remains debatable. Using in vivo and in vitro models of prostate cancer as well as tissue microarrays from primary prostate cancer patient radical prostatectomy specimen, Dankner and Ouellet et al (Am J Pathol 2019, 189:1451–1461) studied this role. CCN3 mediates metastasis to bone through its C-terminal domain. The expression of CCN3 correlates with aggressive disease and negatively correlates with the expression of prostate specific antigen, a marker of androgen receptor signaling. CCN3 may serve as a prognostic biomarker to predict prostate cancer recurrence to bone in prospective cohorts.

        Linked Article

        • Ubiquitin-Specific Protease 15 Maintains Transforming Growth Factor-β Pathway Activity by Deubiquitinating Transforming Growth Factor-β Receptor I during Wound Healing
          The American Journal of PathologyVol. 189Issue 7
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            Wound healing is a process of cutaneous barrier reconstruction that occurs after skin injury and involves diverse cytokines and cell types. Similar to several deubiquitinating enzymes, ubiquitin-specific protease 15 (USP15) can remove ubiquitin chains from specific proteins to rescue them from degradation. However, the regulatory role of USP15 in wound healing remains unclear. We investigated the dynamic function of USP15 in wound healing. First, in USP15 knockout mice, we observed a significant delay in wound closure.
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        • CD55 Is Essential for CD103+ Dendritic Cell Tolerogenic Responses that Protect against Autoimmunity
          The American Journal of PathologyVol. 189Issue 7
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            Recent studies traced inflammatory bowel disease in some patients to deficiency of CD55 [decay-accelerating factor (DAF)], but the mechanism underlying the linkage remained unclear. Herein, we studied the importance of DAF in enabling processes that program tolerance in the gut and the eye, two immune-privileged sites where immunosuppressive responses are continuously elicited. Unlike oral feeding or ocular injection of ovalbumin in wild-type (WT) mice, which induced dominant immune tolerance, identical treatment of DAF–/– mice or DAF–/– to WT bone marrow chimeras did not.
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        • CCN3/Nephroblastoma Overexpressed Is a Functional Mediator of Prostate Cancer Bone Metastasis That Is Associated with Poor Patient Prognosis
          The American Journal of PathologyVol. 189Issue 7
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            Prostate cancer (PC) commonly metastasizes to the bone, resulting in pathologic fractures and poor prognosis. CCN3/nephroblastoma overexpressed is a secreted protein with a known role in promoting breast cancer metastasis to bone. However, in PC, CCN3 has been ascribed conflicting roles; some studies suggest that CCN3 promotes PC metastasis, whereas others argue a tumor suppressor role for CCN3 in this disease. Indeed, in the latter context, CCN3 has been shown to sequester the androgen receptor (AR) and suppress AR signaling.
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        • Automated Identification and Quantification of Signals in Multichannel Immunofluorescence Images: The SignalFinder-IF Platform
          The American Journal of PathologyVol. 189Issue 7
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            Multimarker fluorescence analysis of tissue specimens offers the opportunity to probe the expression levels and locations of multiple markers in a single sample. Software is needed to fully capitalize on the advantages of this technology for sensitive, quantitative, and multiplexed data collection. A major challenge has been the automated identification and quantification of signals. We report on the software SignalFinder-IF, which meets that need. SignalFinder-IF uses a newly developed algorithm called Segment-Fit Thresholding, which showed robust performance for automated signal identification in side-by-side comparisons with several current methods.
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        • High-Temperature Requirement A1 Protease as a Rate-Limiting Factor in the Development of Osteoarthritis
          The American Journal of PathologyVol. 189Issue 7
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            Preserving the mature articular cartilage of joints is a critical focus in the prevention and treatment of osteoarthritis. We determined whether the genetic inactivation of high-temperature requirement A1 (HtrA1) can significantly attenuate the degradation of articular or condylar cartilage. Two types of mouse models of osteoarthritis were used, a spontaneous mutant mouse model [type XI collagen–haploinsufficient (Col11a1+/−) mice] and two post-traumatic mouse models [destabilization of the medial meniscus (DMM) on the knee and a partial discectomy (PDE) on the temporomandibular joint].
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