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This Month in AJP

        Understanding Alcohol-Exacerbated COVID-19

        Chronic alcohol use complicates the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related acute respiratory distress syndrome (ARDS). To further study this link, Solopov et al (Am J Pathol 2022, 990–1000) developed a combined ARDS and chronic alcohol abuse mouse model. A subunit of SARS-CoV-2 spike protein was intratracheally introduced in an ethanol-fed transgenic mouse model expressing the human angiotensinconverting enzyme 2 (ACE2) receptor for SARS-CoV-2. This combinatorial model may help understand the underlying mechanisms as well as explore therapeutic interventions for alcohol-exacerbated COVID-19.

        Managing Cardiac Fibrosis

        The role of the key subunit of the Mediator complex—mediator 1 (MED1)—in cardiac remodeling is unclear. Fatima et al (Am J Pathol 2022, 1016–1027) generated a macrophage-specific Med1 conditional deletion mouse model to understand this role. Cardiac fibrosis was chemically induced in the transgenic mice. Macrophage Med1 deficiency increased chemical-induced cardiac fibrosis via transforming growth factor-β–Smad2/3 pathway. MED1 may be targeted to manage cardiac fibrosis.

        Studying Antibody-Mediated Allograft Vasculopathy

        Our understanding of cardiac allograft vasculopathy (CAV) is limited by the lack of appropriate animal models. Tsuda et al (Am J Pathol 2022, 1053–1065) generated a novel mouse model of CAV to understand underlying mechanisms. This model allowed studying contributions of different cell types to vasculopathy and performing molecular analysis on graft specimens. This novel mouse model may help study the role of allograft- and recipient-derived cells in the development of arterial CAV lesions.

        Diagnosing Chronic Myeloid Leukemia

        Morphological evaluation is a key step in diagnosing chronic myeloid leukemia (CML). Using hematoxylin and eosin–stained bone marrow biopsies, Zhang and Huang et al (Am J Pathol 2022, 1083–1091) developed a conditional generative adversarial network (cGAN)–based model, CMLcGAN, to segment megakaryocytes from myeloid cells. The performance of CMLcGAN was compared to the existing deep learning–based segmentation models. The model was validated on whole slide images. CMLcGAN may outperform existing deep learning–based segmentation models for multiclass segmentation of bone marrow cells.

        Linking Atherosclerosis and Hypercholesterolemia

        Though low density lipoprotein receptor adaptor protein-1 (LDLRAP1) has been implicated in hypercholesteremia and atherosclerosis, direct causality remains unclear. Using Ldlrap1−/− mice, Leigh et al (Am J Pathol 2022, 1092–1108) studied the role of Ldlrap1 in atherosclerosis and insulin resistance. Loss of Ldlrap1 caused a significant increase in serum cholesterol, promoted the development of atherosclerosis, increased insulin resistance and weight gain, and deceased glucose uptake in adipocytes. LDLRAP1 may be targeted to treat diseases that jointly drive metabolic syndrome.

        Linked Article

        • Molecular Signature of Antibody-Mediated Chronic Vasculopathy in Heart Allografts in a Novel Mouse Model
          The American Journal of PathologyVol. 192Issue 7
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            Cardiac allograft vasculopathy (CAV) limits the long-term success of heart transplants. Generation of donor-specific antibodies (DSAs) is associated with increased incidence of CAV clinically, but mechanisms underlying development of this pathology remain poorly understood. Major histocompatibility complex–mismatched A/J cardiac allografts in B6.CCR5−/− recipients have been reported to undergo acute rejection with little T-cell infiltration, but intense deposition of C4d in large vessels and capillaries of the graft accompanied by high titers of DSA.
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        • Deletion of LDLRAP1 Induces Atherosclerotic Plaque Formation, Insulin Resistance, and Dysregulated Insulin Response in Adipose Tissue
          The American Journal of PathologyVol. 192Issue 7
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            Dyslipidemia, vascular inflammation, obesity, and insulin resistance often overlap and exacerbate each other. Mutations in low density lipoprotein receptor adaptor protein-1 (LDLRAP1) lead to LDLR malfunction and are associated with the autosomal recessive hypercholesterolemia disorder in humans. However, direct causality on atherogenesis in a defined preclinical model has not been reported. The objective of this study was to test the hypothesis that deletion of LDLRAP1 will lead to hypercholesteremia and atherosclerosis.
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        • Alcohol Increases Lung Angiotensin-Converting Enzyme 2 Expression and Exacerbates Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein Subunit 1–Induced Acute Lung Injury in K18-hACE2 Transgenic Mice
          The American Journal of PathologyVol. 192Issue 7
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            During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, alcohol consumption increased markedly. Nearly one in four adults reported drinking more alcohol to cope with stress. Chronic alcohol abuse is now recognized as a factor complicating the course of acute respiratory distress syndrome and increasing mortality. To investigate the mechanisms behind this interaction, a combined acute respiratory distress syndrome and chronic alcohol abuse mouse model was developed by intratracheally instilling the subunit 1 (S1) of SARS-CoV-2 spike protein (S1SP) in K18–human angiotensin-converting enzyme 2 (ACE2) transgenic mice that express the human ACE2 receptor for SARS-CoV-2 and were kept on an ethanol diet.
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          Open Access
        • The Diagnosis of Chronic Myeloid Leukemia with Deep Adversarial Learning
          The American Journal of PathologyVol. 192Issue 7
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            Chronic myeloid leukemia (CML) is a clonal proliferative disorder of granulocytic lineage, with morphologic evaluation as the first step for a definite diagnosis. This study developed a conditional generative adversarial network (cGAN)–based model, CMLcGAN, to segment megakaryocytes from myeloid cells in bone marrow biopsies. After segmentation, the statistical characteristics of two types of cells were extracted and compared between patients and controls. At the segmentation phase, the CMLcGAN was evaluated on 517 images (512 × 512) which achieved a mean pixel accuracy of 95.1%, a mean intersection over union of 71.2%, and a mean Dice coefficient of 81.8%.
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        • MED1 Deficiency in Macrophages Aggravates Isoproterenol-Induced Cardiac Fibrosis in Mice
          The American Journal of PathologyVol. 192Issue 7
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            Mediator 1 (MED1), a key subunit of the mediator complex, interacts with various nuclear receptors and functions in lipid metabolism and energy homeostasis. Dilated cardiomyopathy–related ventricular dilatation and heart failure have been reported in mice with cardiomyocyte-specific Med1 deficiency. However, the contribution of macrophage-specific MED1 in cardiac remodeling remains unclear. In this study, macrophage-specific Med1 knockout (Med1ΔMac) mice were generated and exposed to isoproterenol (ISO) to induce cardiac fibrosis; these mice showed aggravated cardiac fibrosis compared with Med1fl/fl mice.
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