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This Month in AJP

    Published:October 16, 2021DOI:https://doi.org/10.1016/j.ajpath.2021.10.001

        Molecularly Profiling COVID-19 Patients

        Our understanding of COVID-19 pathophysiology is currently limited. Using rapid autopsy tissues from infected and uninfected individuals, Pujadas and Beaumont et al (Am J Pathol 2021, 2064–2071) studied the underlying mechanisms. Comparison of COVID-19 tissues with control tissues revealed four main regulatory pathways: blood vessel development, cytokine production, cell activation, and structure and degradation. Effectors within the identified pathways may be targeted to manage COVID-19.

        Reversing Aging Lacrimal Dysfunction

        Aging affects the lacrimal glands and the microbiota; however, the underlying mechanisms are unclear. Using a mouse model, Jiao and Pei et al (Am J Pathol 2021, 2091–2116) studied these mechanisms. Mice were divided into three groups: young, old, and fecal microbiota transplant–treated old groups. Reconstitution of old mice with the microbiome of young mice over time shifted the microbial communities to young donors and significantly reduced the chronic inflammation, lipid deposition, and abnormal neural response of the aging lacrimal glands. Microbiome-based intervention may help reverse age-related dysfunction of the lacrimal glands.

        Understanding Endometriosis

        The role of casein kinase 1α (CK1α)—a widely expressed protein in the endometrium that regulates autophagy—in endometriosis is unclear. Using patient and control clinical samples and cultured cells, Zhou et al (Am J Pathol 2021, 2195–2202) studied this role. CK1α, phosphatase and tensin homolog (PTEN), and autophagy-related 7 (Atg7) were expressed at lower levels in the ectopic endometrium and a positive correlation was observed between CK1α and PTEN, CK1α and Atg7, and PTEN and Atg7. CK1α, PTEN, and autophagy-related markers were repressed in the endometrial stromal cells. CK1α regulates PTEN/Atg7-mediated autophagy in human endometrial stromal cells.

        Managing Bladder Cancer

        The role of the arginine derivative nitric oxide (NO) in bladder cancer invasion is unclear. Using patient samples, cultured cells, and a zebrafish model, Sahu et al (Am J Pathol 2021, 2203–2218) studied this role. A stage-associated increase was observed in the expression of NO-generating enzymes, endothelial NOS (eNOS) and inducible NOS (iNOS), in human bladder cancer. Reducing NOS activity decreased cancer cell invasion; whereas, increasing NOS activity enhanced invasion. In vivo, reducing NOS activity decreased bladder cancer cell metastasis. The invasive tips of bladder cancer cells, invadopodia, were enriched in NOS proteins as well as mTORC2 activity, which in turn regulated invadopodia formation, eNOS and iNOS expression, and cyclicGMP production in the invadopodia. Blocking NO may help manage bladder cancer.

        Attenuating the Growth of Abdominal Aortic Aneurysm

        The role of the cytokine B cell activating factor (BAFF) in aortic aneurysms is unclear. By performing prevention and intervention studies in a mouse model of abdominal aortic aneurysm (AAA), Spinosa et al (Am J Pathol 2021, 2231–2244) studied this role. The formation of AAA was attenuated by injecting BAFF antagonists before and after the induction of AAA in prevention and intervention studies, respectively. In the intervention group, BAFF antagonism enhanced resolution of inflammation in AAA. BAFF antagonism may deplete mature B cells, promote resolution of inflammation in aorta, and attenuate the growth of AAA.

        Linked Article

        • Down-Regulation of Casein Kinase 1α Contributes to Endometriosis through Phosphatase and Tensin Homolog/Autophagy-Related 7–Mediated Autophagy
          The American Journal of PathologyVol. 191Issue 12
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            The present study aimed to explore the roles of casein kinase 1α (CK1α) in endometriosis and its underlying mechanisms. Endometrial specimen were collected from the patients and healthy volunteers. The expression patterns of CK1α, phosphatase and tensin homolog (PTEN), and autophagy-related proteins were determined using immunohistochemistry staining, Western blot analysis, and quantitative RT-PCR. Besides, the CK1α-overexpressing cells and PTEN knockdown cells were constructed in the endometrial stromal cells isolated from endometriosis patients.
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        • Molecular Profiling of Coronavirus Disease 2019 (COVID-19) Autopsies Uncovers Novel Disease Mechanisms
          The American Journal of PathologyVol. 191Issue 12
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            Current understanding of coronavirus disease 2019 (COVID-19) pathophysiology is limited by disease heterogeneity, complexity, and a paucity of studies assessing patient tissues with advanced molecular tools. Rapid autopsy tissues were evaluated using multiscale, next-generation RNA-sequencing methods (bulk, single-nuclei, and spatial transcriptomics) to provide unprecedented molecular resolution of COVID-19-induced damage. Comparison of infected/uninfected tissues revealed four major regulatory pathways.
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        • B Cell–Activating Factor Antagonism Attenuates the Growth of Experimental Abdominal Aortic Aneurysm
          The American Journal of PathologyVol. 191Issue 12
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            B cell–activating factor (BAFF), part of a tumor necrosis factor family of cytokines, was recently identified as a regulator of atherosclerosis; however, its role in aortic aneurysm has not been determined. Here, the study examined the effect of selective BAFF antagonism using an anti-BAFF antibody (blocks binding of BAFF to receptors BAFF receptor 3, transmembrane activator and CAML interactor, and B-cell maturation antigen) and mBaffR-mFc (blocks binding of BAFF to BAFF receptor 3) on a murine model of abdominal aortic aneurysm (AAA).
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        • Microbial Reconstitution Improves Aging-Driven Lacrimal Gland Circadian Dysfunction
          The American Journal of PathologyVol. 191Issue 12
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            Lacrimal glands are highly susceptible to aging and exhibit age-related structural and functional alterations. However, the mechanisms by which aging affects the lacrimal glands are not well-established. The current study explores the crosstalk between the aging process, gut microbiota, and circadian rhythm in age-associated lacrimal gland dysfunction. C57BL/6J mice were divided into young, old, and fecal microbiota transplant (FMT)-treated old groups. The gut bacterial community diversity was analyzed by 16S rRNA sequencing.
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        • Bladder Cancer Invasion Is Mediated by Mammalian Target of Rapamycin Complex 2–Driven Regulation of Nitric Oxide and Invadopodia Formation
          The American Journal of PathologyVol. 191Issue 12
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            Bladder cancer invasion depends on mammalian target of rapamycin complex 2 (mTORC2) activity, although the downstream mTORC2 effectors that mediate this effect have not been fully defined. One potential downstream effector is the arginine derivative nitric oxide (NO). This study identified a stage-associated increase in the expression of the NO-generating enzymes endothelial NO synthase (eNOS) and inducible NOS (iNOS) in human bladder cancer. Reduction of NOS activity by pharmacologic inhibition or silencing of NOS enzymes reduced cancer cell invasion, with similar effects observed using the NO scavenger cobinamide.
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