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This Month in AJP

    Published:September 13, 2021DOI:https://doi.org/10.1016/j.ajpath.2021.09.002

        Healing Corneal Defects

        The role of the aquaporin AQP5 in corneal epithelial wound healing and nerve regeneration is unclear. Using CRISPR/Cas9 technology, Liu et al (Am J Pathol 2021, 1974–1985) generated transgenic Aqp5 knockout mice to study this role. The transgenic mice showed impaired corneal epithelial wound healing due to decreased cell proliferation and a significant delay in both corneal epithelial and nerve regeneration. Inducing AQP5 may help accelerate corneal epithelial regeneration and promote the regeneration of corneal epithelial nerve fibers in corneal defects.

        Understanding Osteoarthritis Progression

        The role of hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) in osteoarthritis (OA) progression is unclear. Using osteoarthritis mouse models lacking the HA depolymerase Hybid, Momoeda et al (Am J Pathol 2021, 1986–1998) studied this role. High molecular weight HA accumulated in OA joint tissues in vivo in the absence of Hybid. Cartilage destruction and osteophyte formation were suppressed in Hybid−/- mice. Inhibiting HYBID may help manage OA progression.

        Managing Renal Cell Carcinoma

        Development of effective treatments for renal cell carcinoma (RCC) is limited by our lack of understanding of cancer cell–intrinsic mTOR-mediated pathways. Using clear cell RCC (ccRCC) cell lines, Lee et al (Am J Pathol 2021, 1999–2008) studied the effect of mTOR regulation on transcription factor E3 (TFE3) and PD-L1 in RCC. TFE3 overexpression correlated with increased expression of PD-L1 as well as enhanced mTOR activity, and the knockdown of TFE3 correlated with reduced PD-L1 expression. mTOR inhibition enhanced TFE3 expression with concomitant increased expression of PD-L1. Both the immune checkpoint and mTOR pathways may be targeted to manage RCC.

        Modeling Myelodysplastic Syndromes

        Aberrant miRNA expression is associated with a myelodysplastic syndrome (MDS) phenotype. Using a stable knockdown of miR-378-3p in transfected human hematopoietic stem cells and promyelocytic leukemia cell lines, Wang et al (Am J Pathol 2021, 2009–2022) generated a novel model for MDS. This model showed characteristics of MDS including aberrant signaling, immunophenotypic changes, morphologic dysplasia, and aberrant growth and function, which could be reversed with azacytidine. The model also mimicked aberrant signal transduction in response to stimulation as seen in MDS patient samples. The novel miRNA-based cell line model of MDS may help understand underlying biology and identify novel therapies for MDS.

        Treating Metastatic Malignant Melanoma

        The role of intussusceptive angiogenesis—characterized by intravascular pillars—in human tumors is unclear. Using human malignant melanomas, patient-derived melanoma xenografts in mice (PDX), and a transgenic mouse model, Pandita et al (Am J Pathol 2021, 2023–2038) studied this role. Intravascular pillars were observed in human metastases, were rare in PDXs, and absent in transgenic mice. MMP9 mRNA expression was higher in human metastases; higher matrix metallopeptidase-9 (MMP9) protein expression and macrophage and T cell infiltration was observed near intravascular pillars. In vitro, MMP chemical inhibition blocked pillar formation. Blocking MMP-9 may help manage intravascular pillars as well as metastatic melanoma.

        Linked Article

        • Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice
          The American Journal of PathologyVol. 191Issue 11
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            Hyaluronan (HA)–binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid−/−) mice compared with wild-type mice.
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          Open Access
        • miR-378-3p Knockdown Recapitulates Many of the Features of Myelodysplastic Syndromes
          The American Journal of PathologyVol. 191Issue 11
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            Myelodysplastic syndromes (MDS) are clonal neoplasms of the hematopoietic stem cell that result in aberrant differentiation of hematopoietic lineages caused by a wide range of underlying genetic, epigenetic, and other causes. Despite the myriad origins, a recognizable MDS phenotype has been associated with miRNA aberrant expression. A model of aberrant myeloid maturation that mimics MDS was generated using a stable knockdown of miR-378-3p. This model exhibited a transcriptional profile indicating aberrant maturation and function, immunophenotypic and morphologic dysplasia, and aberrant growth that characterizes MDS.
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        • Intussusceptive Angiogenesis in Human Metastatic Malignant Melanoma
          The American Journal of PathologyVol. 191Issue 11
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            Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor–driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors.
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        • mTOR Inhibition Increases Transcription Factor E3 (TFE3) Activity and Modulates Programmed Death-Ligand 1 (PD-L1) Expression in Translocation Renal Cell Carcinoma
          The American Journal of PathologyVol. 191Issue 11
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            The efficacy of programmed death ligand (PD-L)-1/PD-1 checkpoint blockade in renal cell carcinoma (RCC) remains unknown. The effects of mTOR inhibitors are uncertain, and patients may develop resistance to them. The limited understanding of cancer cell–intrinsic mTOR-mediated pathways remains a challenge in developing effective treatments. Whether transcription factor (TF)-E3 regulates PD-L1 expression and the tumor microenvironment was investigated, and the effects of an mammalian target of rapamycin (mTOR) inhibitor on translocation RCC were explored.
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        • Aquaporin 5 Facilitates Corneal Epithelial Wound Healing and Nerve Regeneration by Reactivating Akt Signaling Pathway
          The American Journal of PathologyVol. 191Issue 11
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            Aquaporins (AQPs) are a highly conserved group of membrane proteins that play critical roles in water and small solute transport across epithelial and endothelial barriers. The aim of this study was to determine whether AQP5, a well-known water channel protein, also plays a role in corneal epithelial wound healing. AQP5 knockout (AQP5−/−) mice were generated using CRISPR/Cas9. A corneal wound healing model was established using epithelial debridement of corneas. The time to corneal epithelial and nerve regeneration was significantly delayed in the AQP5−/− mice.
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