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American Journal of Pathology

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September 18, 2018: American Journal of Pathology
Surendra Sharma
This commentary highlights the article by Aoki et al that shows that Atg7 deficiencyâ€"mediated placental autophagy imbalance may contribute towards preeclampsia.
September 18, 2018: American Journal of Pathology
Haoshen Shi, Abdul Shukkur Ebrahim, Elizabeth A Berger
Ischemia is associated with the pathogenesis of retinal disease, including diabetic retinopathy and glaucoma. As a result, the retinal ischemia-reperfusion (I/R) injury model has been used to study neurovascular changes. Historically, murine models of retinal disease are established in C57BL/6J (B6) mice, which have been described as type 1-dominant responders. In bacterial keratitis models, B6 are susceptible, whereas BALB/c (type 2-dominant) exhibit a resistant phenotype. As such, we questioned whether the type 1/type 2 paradigm could be extrapolated to events associated with retinal pathogenesis...
September 17, 2018: American Journal of Pathology
Cheng-Mao Lin, Paul M Titchenell, Jason M Keil, Adolfo Garcia-Ocaña, Mark T Bolinger, Steven F Abcouwer, David A Antonetti
Changes in permeability of retinal blood vessels contribute to macular edema and the pathophysiology of numerous ocular diseases, including diabetic retinopathy, retinal vein occlusions, and macular degeneration. Vascular endothelial growth factor (VEGF) induces retinal permeability and macular thickening in these diseases. However, inflammatory agents, such as tumor necrosis factor-α (TNF-α), also may drive vascular permeability, specifically in patients unresponsive to anti-VEGF therapy. Recent evidence suggests VEGF and TNF-α induce permeability through distinct mechanisms; however, both require the activation of atypical protein kinase C (aPKC)...
September 12, 2018: American Journal of Pathology
Elizabeth A Pearsall, Kip M Connor
This commentary highlights the article by Lin et al that demonstrates the therapeutic potential of small-molecule atypical protein kinase C inhibitors in inflammatory ocular disease.
September 12, 2018: American Journal of Pathology
Ruizhong Zhang, Zefeng Lin, Ming Fu, Xisi Guan, Jiakang Yu, Wei Zhong, Jixiao Zeng, Vincent Ch Lui, Paul Kh Tam, Jonathan R Lamb, Huimin Xia, Yan Chen
Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11b+ Gr-1+ cells in a mouse model of BA and their presence in BA patients. CD11b+ Gr-1+ cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177+ was examined in biopsies from BA patients. The symptoms of BA were ameliorated and survival was prolonged in those mice receiving five to 10 μg of antibody/mouse every three days for 4 times compared to the mice treated with virus alone...
September 7, 2018: American Journal of Pathology
Jinhua Zhang, Yuanqing Ye, David W Chang, Shu-Hong Lin, Maosheng Huang, Nizar M Tannir, Surena Matin, Jose A Karam, Christopher G Wood, Zhi-Nan Chen, Xifeng Wu
About 30% of renal cell carcinoma (RCC) patients undergoing nephrectomy experience disease recurrence. We profiled microRNAs (miRNAs) that are dysregulated in clear cell RCC (ccRCC) tumor tissues and predictive of recurrence. The expression levels of 800 miRNAs were assessed in paired tumor and normal tissues from a discovery cohort of 18 ccRCC patients via the NanoString assay platform. miRNAs found to be differentially expressed were examined in a validation set of 205 patients using quantitative real-time PCR...
September 7, 2018: American Journal of Pathology
Ania Prochnicki, Kerstin Amann, Michael Wegner, Elisabeth Sock, Eva Pfister, Stuart Shankland, Jeffrey Pippin, Christoph Daniel
Mechanisms of glomerular crescent formation and podocyte repair processes are still unclear. Therefore, we investigated the expression of the transcription factor Sox9 as a potential marker of a subpopulation of parietal epithelial cells (PECs) with potential regenerative properties. Glomerular Sox9 expression was characterized in detail in a rat anti-glomerular basement membrane (GBM) nephritis model using immunofluorescence and confocal laser scanning microscopy. In healthy kidneys Sox9 is expressed in a subpopulation of PECs restricted to approximately 20% to 50% of PEC nuclei and was highly conserved in all investigated species...
September 7, 2018: American Journal of Pathology
Vinod Kumar, Himanshu Vashistha, Xiqian Lan, Nirupama Chandel, Kamesh Ayasolla, Seyedeh Shadafarin Marashi Shoshtari, Rukhsana Aslam, Nitpriya Paliwal, Frank Abbruscato, Joanna Mikulak, Waldemar Popik, Mohamed G Atta, Praveen N Chander, Ashwani Malhotra, Catherine Meyer-Schwesinger, Karl Skorecki, Pravin C Singhal
Human parietal epithelial cells (PECs) are one of the progenitor cells that sustain podocyte homeostasis. We hypothesized that the lack of apolipoprotein (APO) L1 assures the PEC phenotype but its induction initiates PECs' transition (expression of podocyte markers). APOL1 expression and down-regulation of miR193a coincided with the expression of podocyte markers during the transition. The induction of APOL1 also stimulated transition markers in human embryonic kidney cells (cells with undetectable APOL1 protein expression)...
September 7, 2018: American Journal of Pathology
Sandra Mattu, Christian Saliba, Pia Sulas, Patrizia Zavattari, Andrea Perra, Marta A Kowalik, Satdarshan P Monga, Amedeo Columbano
Activation of Wnt/β-catenin signaling is frequent in human and rodent hepatocarcinogenesis. Although in mice, the tumor promoting activity of agonists of constitutive androstane receptor (CAR) occurs via selection of carcinogen-initiated cells harboring β-catenin mutations, the molecular alterations leading to hepatocellular carcinoma (HCC) development by the CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), in the absence of genotoxic injury are unknown. Here we show that CAR activation per se induced HCC in mice and that 91% of them carried β-catenin point mutations or large in-frame deletions/exon skipping targeting Ctnnb1 exon 3...
September 7, 2018: American Journal of Pathology
Joseph Jessee, Jeffrey B Kopp
This commentary highlights the article by Kumar et al that reports an essential role of APOL1 in maintaining podocyte phenotype.
September 7, 2018: American Journal of Pathology
Aiko Aoki, Akitoshi Nakashima, Tae Kusabiraki, Yosuke Ono, Osamu Yoshino, Masanaga Muto, Keiichi Kumasawa, Tamotsu Yoshimori, Masahito Ikawa, Shigeru Saito
Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes utilizing trophoblast-specific Atg7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not labyrinth layer, which significantly elevated blood pressure in dams...
August 27, 2018: American Journal of Pathology
Wei-Ling Tu, Li-Ru You, Ann-Ping Tsou, Chun-Ming Chen
The aim of this study was to shed light on the molecular and cellular mechanisms responsible for initiation and progression of liver malignancies by examining the role of the tumor suppressor gene Pten in liver tumor progression in microRNA122a (Mir122a)-null mice. We generated and monitored liver tumor initiation in Mir122a-null Pten heterozygous (Mir122a-/- ;Pten+/- and Mir122a-/- ;Alb-Cre;Ptenfx/+ ) mice and compared the results to those in Mir122a-/- mice. Both Mir122a-/- ;Pten+/- and Mir122a-/- ;Alb-Cre;Ptenfx/+ mice developed visible liver tumor nodules at six months of age...
August 27, 2018: American Journal of Pathology
Shawn J Loder, Shailesh Agarwal, Michael T Chung, David Cholok, Charles Hwang, Noelle Visser, Kaetlin Vasquez, Michael Sorkin, Joe Habbouche, Hsiao Hsin Sung, Joshua Peterson, David Fireman, Kavitha Ranganathan, Christopher Breuler, Caitlin Priest, John Li, Xue Bai, Shuli Li, Paul S Cederna, Benjamin Levi
Heterotopic ossification (HO) occurs secondary to trauma, causing pain and functional limitations. Identification of the cells that contribute to HO is critical to the development of therapies. Given that innate immune cells and mesenchymal stem cells (MSCs) are known contributors to HO, we sought to define the contribution of these populations to HO and to identify what, if any, contribution circulating population have to HO. A shared circulation was obtained using a parabiosis model, established between an eGFP+ /luciferase+ donor and a same-strain non-reporter recipient mouse...
August 21, 2018: American Journal of Pathology
Clement Delacroix, Janek Hyzewicz, Megane Lemaitre, Bertrand Friguet, Zhenlin Li, Arnaud Klein, Denis Furling, Onnik Agbulut, Arnaud Ferry
Dystrophin deficiency in mdx mice, a model for Duchenne muscular dystrophy (DMD), leads to muscle weakness revealed by a reduced specific maximal force as well as fragility, ie, higher susceptibility to contraction-induced injury as shown by a greater force drop following lengthening contractions. Both symptoms could be improved with dystrophin restoration-based therapies and long-term (months) voluntary exercise. Here, we evaluated the effect of short-term (one-week) voluntary wheel running. We found that running improved fragility of tibialis anterior muscle (TA), but not plantaris muscle, independently of utrophin up-regulation, without affecting weakness...
August 21, 2018: American Journal of Pathology
Ye Feng, Lin-Li Lv, Wei-Jun Wu, Zuo-Lin Li, Jun Chen, Hai-Feng Ni, Le-Ting Zhou, Tao-Tao Tang, Feng-Mei Wang, Bin Wang, Ping-Sheng Chen, Steven D Crowley, Bi-Cheng Liu
Immunoglobulin A nephropathy (IgAN) features variable renal pathology and a heterogeneous clinical course. Our aim was to search noninvasive biomarkers from urinary exosomes for IgAN patients; membrane nephropathy and minimal change disease were included as other glomerulopathy controls. Transmission electron microscopy and nanoparticle tracking analysis confirmed the size and morphology characteristic of urinary exosomes. Exosome markers (Alix, CD63) as well as renal cell markers (AQP2 and Nephrin) were detected which indicate the renal origin of urinary exosomes...
August 21, 2018: American Journal of Pathology
Duy T Dao, Lorenzo Anez-Bustillos, Rosalyn M Adam, Mark Puder, Diane R Bielenberg
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family. It contains an EGF-like domain as well as a heparin-binding domain that allows for interactions with heparin and cell-surface heparan sulfate. Soluble mature HB-EGF, a ligand of human epidermal growth factor receptor 1 and 4, is cleaved from the membrane-associated pro-HB-EGF by matrix metalloproteinase or a disintegrin and metalloproteinase (ADAM) in a process called ectodomain shedding. Signaling through HER1 and 4 results in a variety of effects, including cellular proliferation, migration, adhesion, and differentiation...
August 21, 2018: American Journal of Pathology
Alyaksandr V Nikitski, Susan L Rominski, Mamta Wankhede, Lindsey M Kelly, Federica Panebianco, Guillermo Barila, Daniel L Altschuler, Yuri E Nikiforov
Chromosomal rearrangements of the ALK gene, which lead to constitutive activation of ALK tyrosine kinase, are found in various cancers. In thyroid cancers, ALK fusions, most commonly the STRN-ALK fusion, are detected in papillary thyroid cancer and with higher frequency in poorly differentiated and anaplastic thyroid cancers. Our aim was to establish a mouse model of thyroid-specific expression of STRN-ALK and to test whether this fusion drives the development of thyroid cancer with a propensity for dedifferentiation...
August 17, 2018: American Journal of Pathology
Yoon Seok Roh, Jong Won Kim, Surim Park, Changho Shon, Sokho Kim, Seong Kug Eo, Jung Kee Kwon, Chae Woong Lim, Bumseok Kim
Toll-like receptor 7 (TLR7) signaling regulates the production of type I interferons (IFNs) and proinflammatory cytokines such as tumor necrosis factor (TNF)-α implicated in the control of regulatory T (Treg) cell activity. However, the mechanistic interplay between TLR7 signaling and Treg cells in non-alcoholic steatohepatitis (NASH) has not been elucidated. Our aim was to clarify the role of TLR7 signaling in the pathogenesis of NASH. Steatohepatitis was induced in wild-type (WT), TLR7-deficient, IFN-α/β receptor-1 (IFNAR1)-deficient, and Treg cell-depleted (DEREG) mice...
August 17, 2018: American Journal of Pathology
Cinzia Antognelli, Francesca Mancuso, Roberta Frosini, Iva Arato, Mario Calvitti, Riccardo Calafiore, Vincenzo Nicola Talesa, Giovanni Luca
As SCs play a central role in germ cesurvival, their death may results in marked germ cell loss and infertility (Eid et al., 2012; Oliveira et al., 2015). As SCs play a central role in germ cell survival, their death may result in marked germ cell loss and infertility (Eid et al., 2012; Oliveira et al., 2015). As SCs play a central role in germ cell survival, their death may result in marked germ cell loss and infertility (Eid et al., 2012; Oliveira et al., 2015). Sertoli cells (SCs) are the only somatic cells within the seminiferous tubules and are essential for regulating spermatogenesis...
August 17, 2018: American Journal of Pathology
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