Official Journal of the American Society for Investigative Pathology ajp.amjpathol.org Discoveries in Basic and Translational Pathobiology A Digital Reprint Collection for the 2025 Centennial Celebration of The American Journal of Pathology Celebratinŕ © 2026 American Society for Investigative Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
Discoveries in Basic and Translational Pathobiology Editor-in-Chief Martha B. Furie, Stony Brook University Senior Associate Editor Richard N. Mitchell, Brigham and Women’s Hospital and Harvard Medical School Associate Editors Chris Albanese, Georgetown University Medical Center Steven L. Carroll, Medical University of South Carolina Stanley Cohen, Perelman School of Medicine, University of Pennsylvania Zoran Culig, Medical University of Innsbruck Patricia A. D’Amore, Schepens Eye Research Institute dMassachusetts Eye and Ear Wen-Xing Ding, University of Kansas Medical Center Carol F. Farver, University of Michigan Philip Furmanski, Rutgers University Robert J. Homer, Yale School of Medicine Yoshifumi Itoh, University of Oxford Andrei I. Ivanov, Lerner Research Institute, Cleveland Clinic Elaine S. Jaffe, National Cancer Institute, National Institutes of Health Alpdogan Kantarci, Forsyth Institute Thorsten Kirsch, NYU Grossman School of Medicine, NYU Tandon School of Engineering A. Wayne Orr, Louisiana State University Health Sciences Center Shin’ichi Takeda, National Center of Neurology and Psychiatry Astrid Weins, Mass General Brigham; Harvard Medical School Xiao-Ming Yin, Tulane University School of Medicine Director of Scientific Publications Emily H. Essex Production Editor Henry L. Carter, Jr. Senior Editorial Assistant Michael Dustin Theofficial journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. http://ajp.amjpathol.org Editorial Board Rosalyn Adam Malcolm Alison Charles E. Alpers Udayan Apte Leonardo Baiocchi Roberto Barrios Arnold R. Brody L. Maximillian Buja David L. Caudell Dong Feng Chen Lixian Chen Yihe Chen Jerome Cheng William B. Coleman Nicholas Davidson George S. Deepe, Jr. Gabriel E. DiMattia Andrew W. Duncan Motomi Enomoto-Iwamoto Chandrashekhar R. Gandhi Allan Gao Godfrey S. Getz Avrum I. Gotlieb Qiangqiang Gu Ozlem Guzeloglu-Kaysili Meera Hameed Kevan L. Hartshorn Chiung-Kuei Huang Renato V. Iozzo Hartmut Jaeschke Aaron W. James Motoi Kanagawa Bilon Khambu David S. Klimstra Stefan Koch Hans Lassmann Andrew Leask Andrew E. Libby Jody Fromm Longo Robin G. Lorenz Benjamin R. Mitchell George F. Murphy Porfirio Nava Nayden G. Naydenov Shuji Ogino Yasunori Okada Suellen D’Arc Oliveira Liron Pantanowitz Tristrim Parslow Yuri Persidsky Raju C. Reddy Magali Saint-Geniez Joel Saltz Ivy S. Samuels Darryl Shibata Andrzej T. Slominski Pavel A. Solopov Karel Sou cek Douglas B. Stairs Ronen Sumagin Jun Sun Hamid Reza Tizhoosh John E. Tomaszewski Elisavet Vasilopoulou David H. Walker Jia Xu Shengmin Yan Cecelia Yates Mark D. Zarella Qing Zhang EXECUTIVE OFFICER: William B. Coleman PRESIDENT: Pilar Alcaide; Past President: Satdarshan (Paul) Singh Monga; President-Elect: Jonathon W. Homeister; Vice President: David Williams, Jr.; Secretary-Treasurer: John Hanna; Program Chair: Andrei Ivanov; Education Committee Chair: Julie Randolph-Habecker; Committee for Career Development Chair: Veronica Contreras-Shannon; Research and Science Policy Chair: Elaine Bearer; Committee for Equal Representation and Opportunity Chair: Cecelia C. Yates; Councilors: Charleen Chu, Kelsey Dillehay McKillip. PUBLICATIONS COMMITTEE: Heather Francis (Chair), William B. Coleman, Prathana Dalal, Maryknoll Palisoc Linscott, Edward Medina, Charles A. Parkos, Gregory Tsongalis, Joy Winfield, Cecelia Yates.
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Official Journal of the American Society for Investigative Pathology Discoveries in Basic and Translational Pathobiology Table of Contents A Digital Reprint Collection for the 2025 Centennial Celebration of The American Journal of Pathology This digital reprint collection features special Editorials written to celebrate the 100th anniversary of The American Journal of Pathology. These pieces, written primarily by members of the American Society for Investigative Pathology who also have a strong relationship with AJP, reflect on paradigm shifting discoveries first published in AJP, highly impactful manuscripts over time, and future facing content for the next century of publishing AJP. CONTENTS 1 Celebrating the First 100 Years of Publishing Significant Scientific Discoveries in The American Journal of Pathology Mark E. Sobel and Martha B. Furie Reprinted from: Volume 195, Issue 1, January 2025, Pages 2-4 2 Highlights of the First 100 Years of Publications on Kidney Disease in The American Journal of Pathology Michael S. Goligorsky Reprinted from: Volume 195, Issue 2, February 2025, Pages 158-162 3 Reinterpreting the True Cause and Nature of Unexpected Liver Lumps George K. Michalopoulos Reprinted from: Volume 195, Issue 3, March 2025, Pages 338-340 4 Insights from the Seminal Findings from Puhr et al on the Mechanisms of Docetaxel Resistance in Prostate Cancer Zoran Culig Reprinted from: Volume 195, Issue 4, April 2025, Pages 612-614 5 Blowing Dust Off the Archives: Seminal Eponymous Contributions from Women Pathologists in The American Journal of Pathology Richard N. Mitchell Reprinted from: Volume 195, Issue 5, May 2025, Pages 812-813 6 The American Journal of Pathology’s Contribution to Advancing the Understanding of the Pathogenesis of Atherosclerosis Avrum I. Gotlieb Reprinted from: Volume 195, Issue 6, June 2025, Pages 1032-1035 7 From Disruption of Muscle Membrane to Muscle Membrane Repair Shin’ichi Takeda Reprinted from: Volume 195, Issue 7, July 2025, Pages 1190-1192 8 Discovery and Mechanistic Insights into Vascular Permeability Factor/Vascular Endothelial Growth Factor through the Work of Harold F. Dvorak and Ann M. Dvorak Stephen J. Galli Reprinted from: Volume 195, Issue 8, August 2025, Pages 1360-1362 9 Navigating the Road to Progress in Neurodegeneration Yomna Badawi and Christi L. Kolarcik Reprinted from: Volume 195, Issue 9, September 2025, Pages 1572-1574 10 FromThe American Journal of Pathology’s Archives: Pioneering Studies on the Mechanisms of Metastatic Prostate Cancer Chris Albanese and Olga C. Rodriguez Reprinted from: Volume 195, Issue 10, October 2025, Pages 1756-1757
11 A Century of Progress Toward Gut Barrier Targeting Therapies in Inflammatory Diseases Manuel B. Braga-Neto and Andrei I. Ivanov Reprinted from: Volume 195, Issue 11, November 2025, Pages 1964-1966 12 Advancing Breast Cancer Management Through an Enhanced Understanding of Disease Heterogeneity from Initiation to Metastasis Dennis Jones Reprinted from: Volume 195, Issue 11, November 2025, Pages 1967-1971 13 The American Journal of Pathology and the American Society for Investigative Pathology: Forging the Next Century of Insights into Mechanisms of Disease Martha B. Furie, Pilar Alcaide, William B. Coleman, and Emily H. Essex Reprinted from: Volume 195, Issue 12, December 2025, Pages 2248-2250 14 A Seminal Work That Defined the Pathology of Frontotemporal Dementias and the Concept of TDP-43 Proteinopathies Steven L. Carroll Reprinted from: Volume 195, Issue 12, December 2025, Pages 2251-2253 15 The Future of Ocular Pathobiology: Opportunities and Innovations in the Next Century of Investigative Pathology Daisy Y. Shu Reprinted from: Volume 195, Issue 12, December 2025, Pages 2254-2257 The American Journal of Pathology
CENTENNIAL EDITORIAL Celebrating the First 100 Years of Publishing Significant Scientific Discoveries in The American Journal of Pathology Mark E. Sobel* and Martha B. Furiey From the American Society for Investigative Pathology,* Rockville, Maryland; and the Department of Pathology,y Stony Brook University, Stony Brook, New York A central tenet of the theory of evolution1 is that species must adapt to external conditions to survive and thrive. The principles of Darwin’s theory can also be applied to the development and advancement of journals that publish scientific discoveries. The first 100 years of The American Journal of Pathology (AJP), the official journal of the American Society for Investigative Pathology (ASIP), are a testament to those principles. ASIP’s core mission is the dissemination of information about the pathogenesis, classification, diagnosis, and manifestations of disease. Since 1901, the Society and its predecessors have published noteworthy scientific discoveries in its designated official journal. The cover of the first issue of AJP in January 1925 noted that it was owned by the American Association of Pathologists and Bacteriologists (AAPB) and was the continuation of The Journal of Medical Research. The Journal of Medical Research had been published from 1901 to 1924 as the official journal of AAPB but in fact had been owned by Dr. Harold C. Ernst, its first editor-in-chief (EIC). After the death of Ernst in 1922, Frank B. Mallory took over the duties of EIC. Because AAPB desired to own its official journal and enhance the diversity of expertise on its editorial board, in 1924 it established AJP with Mallory as EIC, beginning a tradition of editorial leadership of the Journal with outstanding scientists that has continued to this day (Table 1). AAPB merged with the American Society for Experimental Pathology in 1976 to form the American Association of Pathologists, which became ASIP in 1992. AJP also became the official journal of the American Society for Experimental Pathology 6 years before the merger. (AAPB provided not only the Journal, but also originated the GoldHeaded Cane Award in 1919 and the Rous-Whipple Award in 1975; these remain as two of ASIP’s most prestigious honors.) In 1992, ASIP became the owner and self-publisher of AJP, and an editorial office was organized within the ASIP office to manage receipt, review, and publication of manuscripts. For the first time since 1925, the EIC was relieved of some of the business responsibilities of the Journal, which were now the job of the central editorial office. The development of online platforms in the 1990s was a transformative event in scientific publishing. It necessitated significant changes in procedures and a new infrastructure to support dissemination of scientific research. AJP needed to develop an enhanced manuscript submission system that could be linked to a rigorous peer-review system for authors and reviewers. A commitment was made to maintain a stable, permanent online archive and to meet the challenges of scientific misconduct 2 that were facilitated by new software applications. Balancing these time-consuming and expensive consequences were the benefits of providing scientists with increased and facilitated access to the body of literature at decreased cost to the authors of manuscripts. The need to maintain a costly infrastructure that requires frequent enhancements led to the decision to engage in January 2011 with a commercial publisher (Elsevier, Inc.) to provide post-production services. However, ASIP retains full editorial control and copyright ownership. Even with the Accepted for publication October 7, 2024. This Editorial introduces The American Journal of Pathology’s (AJP’s) Centennial Celebration, a collection of pieces that highlight notable publications that have appeared in AJP and the lasting impact that they have had on the shape of the discipline. Address correspondence to Martha B. Furie, Ph.D., Stony Brook University, Room 248 Centers for Molecular Medicine, Stony Brook, NY 11794-5120. E-mail: martha.furie@stonybrook.edu. Copyright ª2025 American Society for Investigative Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. https://doi.org/10.1016/j.ajpath.2024.10.011 ajp.amjpathol.org Reprinted from: The American Journal of Pathology, Vol. 195, No. 1, January 2025
Elsevier arrangement, the editorial office has five full-time employees, and additional support for the Journal is provided by the ASIP Executive Officer and Society staff. A timeline of the history of the Journal can be found in Table 2, and further details have been published previously.3e9 As the governance and organization of AJPhave evolved to meet changing needs, so its scope has been redefined to reflect trends in the discipline of pathology. For its first halfcentury, AJP’s content aligned with the broad discipline of pathology, including both descriptive and mechanistic studies. In 1982, under the leadership of EIC Vincent Marchesi, the Journal began to prioritize “.material that is more experimental than observational.” 10 The swing toward the present-day emphasis on mechanistic research was cemented by EIC Nelson Fausto, with a redefined scope appearing in 1994. It began, “AJP.seeks to publish the highest quality, original articles on the cellular and molecular mechanisms of disease. AJP reports important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific Table 1 Editors-in-Chief of The American Journal of Pathology Year(s) Editor-in-Chief Senior Associate Editors 1925 to 1940 Frank B. Mallory 1941 to 1956 Carl V. Weller 1957 Ernest W. Goodpasture 1957 to 1967 Edward A. Gall 1967 to 1977 Thomas D. Kinney Donald B. Hackel (AE) 1977 to 1982 Donald B. Hackel F. Stephen Vogel (SE) 1982 to 1992 Vincent T. Marchesi Jon Morrow (SE) 1992 to 2000 Nelson Fausto Steven Kunkel (SE) 2000 to 2003 James L. Madara Charles A. Parkos 2003 to 2008 Jay M. McDonald Gene P. Siegal 2008 to 2012 Michael P. Lisanti Herbert Tanowitz 2013 to 2017 Kevin A. Roth Martha B. Furie 2018 to present Martha B. Furie William B. Coleman and Richard N. Mitchell Goodpasture was acting editor-in-chief (EIC). Kinney was the first EIC to appoint an AE, who shared some responsibilities and served as second in command. Under Fausto, the number of AEs was expanded, and the second in command was designated SE. Since 2000, the second in command has the title of Senior Associate Editor. AE, associate editor; SE, senior editor. Table 2 Timeline of Significant Events in the First 100 Years of AJP Year Event 1924 AAPB Council votes to form a successor journal to The Journal of Medical Research that will be owned by AAPB 1925 Volume 1 of AJP is published by Harvard University Press and appears bimonthly (6 issues per volume) 1941 Ann Arbor Press succeeds Harvard University Press as publisher 1958 AJP is published monthly (12 issues per volume) 1960 AJP is published monthly with two volumes per year (6 issues per volume) 1960 Paul B. Hoeber (which subsequently became Harper & Row) succeeds Ann Arbor Press as publisher 1969 AJP is published monthly with four volumes per year (3 issues per volume) 1970 ASEP agrees to cosponsor AJP with AAPB; AJP is now the official journal of AAPB and ASEP 1976 AAPB and ASEP merge to form AAP 1976 US Congress passes The Copyright Revision Act of 1976 (authors transfer copyright to the Journal starting 1978) 1981 Page size is increased by 50% 1986 First color cover and increase in page size to the current 8.5 11 inches 1988 J.B. Lippincott (a subsidiary of Harper & Row) succeeds Paul B. Hoeber as publisher 1989 AJP returns to publishing two volumes a year (6 issues per volume) 1992 An Editorial Office is established in the Society’s office in preparation for self-publishing of AJP 1993 AAP changes its name to ASIP, and ASIP begins an 18-year period as self-publisher of AJP 1995 The tagline Cellular and Molecular Biology of Disease is added to the AJP cover 1999 Full-text online publishing (Stanford University’s HighWire Press is online publisher) of AJP starts with back content from July 1988 (volume 153) 1999 JMD is launched as AJP Part B with the Association for Molecular Pathology as co-owner and publisher 2001 JMD goes solo (volume 3) 2004 Public access policy is established, giving free access to articles published at least 12 months prior 2004 Position of full-time scientific editor is established 2006 AJP CME Program in Pathogenesis is launched and continues through 2014 2007 ASIP enters into an agreement with PMC to provide online content of AJParticles authored by US federally funded scientists 2007 PMC provides digital versions of AJPvolumes 1e152 (1925e1998), accessible at https://www.ncbi.nlm.nih.gov/pmc/journals/ 338 (last accessed October 4, 2024) 2010 ASIP enters into a managed publishing agreement with Elsevier, Inc., with ASIP retaining ownership and copyright 2011 Elsevier, Inc., serves as the publisher of AJP 2013 AJP published monthly with one volume per year (12 issues per volume) 2018 Tagline changed to Discoveries in Basic and Translational Pathobiology 2025 AJP celebrates 100 years of publishing seminal advances in investigative pathobiology AAP, American Association of Pathologists; AAPB, American Association of Pathologists and Bacteriologists; AJP, The American Journal of Pathology; ASEP, American Society for Experimental Pathology; ASIP, American Society for Investigative Pathology; CME, continuing medical education; JMD, The Journal of Molecular Diagnostics; PMC, PubMed Central. Celebrating the First 100 Years of AJP The American Journal of Pathology - ajp.amjpathol.org 3
mechanism of analysis.” 11,p.237 To signify this greater stress on pathogenesis, a tagline was added under the title of the Journal on its cover, reading Cellular and Molecular Basis of Disease. With the advent of the 21st century, the editorial leadership began to recognize that a relatively narrow focus on mechanistic experimentation did not fully reflect the evolution of experimental pathology. Consequently, the decision was made to broaden the scope to include work that might be considered descriptive per se, such as large-scale omics studies, but also has the potential to establish a basis for future mechanistic investigations.8 And in 2019, under the leadership of Associate Editor Stanley Cohen, AJP began to welcome manuscripts that apply artificial intelligence to problems in pathology.12 The topic category of Machine Learning, Computational Pathology, and Biophysical Imaging is now one of AJP’s fastest-growing areas. The Journal’s statement of scope has been revised to reflect these changes, and the tagline is now Discoveries in Basic and Translational Biology. As AJP moves into the next century of scientific publishing, it will need to take advantage of innovative technologies in medicine and science and build on the scientific foundations laid down by the first century. However, it is AJP’s first 100 years that we are reflecting on and celebrating in 2025. Accordingly, we have invited prominent investigators in experimental pathology to showcase highly influential articles that have appeared in AJP. These Centennial Editorials will appear throughout 2025, and we hope that you will enjoy these retrospective views of investigative pathology and the role that AJP has played in shaping the discipline. These editorials will be joined by some forward-looking pieces by younger members of ASIP, who will offer their visions for the future of experimental pathobiology. Finally, multiple Theme Issues of AJPwill be published in 2025. These collections of complementary Review Articles will highlight the importance of AJP as a top source of information from thought leaders in their fields. In closing, we thank the many dedicated readers, authors, editors, reviewers, staff, and ASIP members who have been essential to the Journal’s success for this past century. With your help, we look forward to ensuring that The American Journal of Pathology continues to evolve as science progresses and remains the most frequently cited journal in pathology for another 100 years. Disclosure Statement None declared. References 1. Darwin CR: On the Origin of Species by Means of Natural Selection. London, UK, John Murray, 1859 2. McDonald JM, Cox AE, Siegal GP: The dark side of publishing: promoting ethics in AJP 2003-2008. Am J Pathol 2012, 181:730e732 3. Fausto N: What’s in a name? The American Society for Investigative Pathology. Am J Pathol 1993, 142:1 4. Madara J: A new editor on the occasion of the centennial celebration of the Journal (maybe). Am J Pathol 2001, 159:1183e1185 5. Sobel ME: A new stage in the history of publishing seminal experimental pathology research in the Journal. Am J Pathol 2011, 178:2e3 6. Roth KA: The American Journal of Pathology centennial project: celebrating 100 years of the American Society for Investigative Pathology. Am J Pathol 2012, 180:1337e1339 7. Sobel ME: The American Society for Investigative Pathology in the next century. Am J Pathol 2013, 182:1052e1054 8. Furie MB: A new scope and a new editorial team for The American Journal of Pathology. Am J Pathol 2018, 188:2e3 9. Sobel ME: History of the American Society for Investigative Pathology 1976-2013. Chelsea, MI, Sheridan Books, Inc., 2013 10. Marchesi VT: Editorial statement. Am J Pathol 1982, 108:255 11. Fausto N: Information for authors. Am J Pathol 1994, 145:237e238 12. Cohen S, Furie MB: Artificial intelligence and pathobiology join forces in The American Journal of Pathology. Am J Pathol 2019, 189:4e5 Sobel and Furie 4 ajp.amjpathol.org - The American Journal of Pathology
CENTENNIAL GUEST EDITORIAL Highlights of the First 100 Years of Publications on Kidney Disease in The American Journal of Pathology Michael S. Goligorsky From the Renal Research Institute and Departments of Medicine, Pharmacology and Physiology, New York Medical College at the Touro University, Valhalla, New York; and Technion Medical School, Haifa, Israel For this Centennial Issue, my editorial assignment has been to showcase the most forward-looking and time-tested publications on kidney disease in the history of The American Journal of Pathology (AJP). Admittedly, deciding on the cornerstone articles published by AJPin the span of 100 years is not an enviable and unavoidably subjective task. With those constraints in mind, I would venture to suggest the following investigators and studies that shaped the evolving pathophysiological concepts, thus contributing significantly to the practice of nephrology. Piercing through time layers of publications dedicated to kidney disease, one cannot help but notice the paucity of such studies, predominantly descriptive, during the first quarter century of AJP. Nonetheless, the classic description of diabetic Kimmelstiel-Wilson nodules in diabetic nephropathy1 belongs to that period. Those early studies were joined in the 1950s by a few publications introducing immunohistochemical staining of the kidney and generation of animal models of glomerular diseases, followed by studies of kidney regeneration and cell proliferation using incorporation of tritiated thymidine, and, most importantly, the advent of electron microscopy (EM) imaging of the kidney.2 Accrued developments of a safe needle biopsy and successful kidney transplantation then spurred on scientific interest in the new discipline around the world and resulted in seminal publications in AJP. In the 1950s, D.B. Jones, a professor of pathology at the State University of New York Upstate Medical Center, published a series of studies dedicated to different aspects of glomerular scarring, inflammation, and repair, the nature of scar tissue, and nephrotic glomerulonephritis. He pioneered the use of ultrathin sections, periodic acideSchiff stain, gold toning, and EM, revealing a penetrating insight into the disease and its healing.3e8 This oeuvre places Jones among the vanguard of pathologists loyal to studies of kidney disease and their publication in AJP. By analogy with the American Society of Investigative Pathology awarding a Gold-Headed Cane for the most outstanding work, Jones deserves a similar prize in the field of nephrology for his influential accomplishments. In the case of AJP publications, the prize could be named a Gold Pencil. In the 1960s and 1970s, this prize also could have been awarded to R. Heptinstall, professor of pathology at the Johns Hopkins University Medical School, who unveiled a series of studies on radiation-induced and other forms of interstitial nephritis9 and effects of pharmaceuticals on the ischemic kidney, as examined using microradiography and microdissection,10 and in hypertensive rats treated with heparin.11,12 In the field of kidney transplantation, research from Boston, Massachusetts, and Denver, Colorado, prevailed in morphologic studies on transplant rejection in rats and humans,13e15 and graft rejection in rats.16,17 A. Morrison’s laboratory combined stereologic, functional, and ultrastructural techniques in describing glomerular hypertrophy in the subtotally nephrectomized rat, a model to remain popular for decades.18,19 C. Tisher’s group provided hallmarks of and arguments for an independent entitydIgA nephropathy.20 Accepted for publication November 4, 2024. This Guest Editorial is part of The American Journal of Pathology’s (AJP’s) Centennial Celebration, a collection of pieces that highlight notable publications that have appeared inAJPand the lasting impact that they have had on the shape of the discipline. Address correspondence to Michael S. Goligorsky, M.D., Ph.D., Renal Research Institute and Departments of Medicine, Pharmacology and Physiology, New York Medical College at the Touro University, Valhalla, NY. E-mail: michael_goligorsky@nymc.edu. Copyright ª2025 American Society for Investigative Pathology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies. https://doi.org/10.1016/j.ajpath.2024.11.001 ajp.amjpathol.org Reprinted from: The American Journal of Pathology, Vol. 195, No. 2, February 2025
The decade of the 1980s opened with the presentation of the American Society of Investigative Pathology RousWhipple Award to M. Karnovsky,21 one of a few renal pathologists so honored (with R. Cotran, M. Farquhar, and F. Dixon being recipients of the Gold-Headed Cane award). Two remarkable published studies identified the contribution of glomerular epithelial cells and anionic charges to proteinuria in a rat model of aminonucleoside nephrosis. Kerjaschki et al22 provided strong evidence to support the idea that impaired sialylation of podocalyxin is associated with proteinuria in this rat model of nephrotic syndrome, work that forecasted the advent of molecular pathology. In parallel, Fishman and Karnovsky23 demonstrated reduced incorporation of 14C-glucosamine and 35S-sulfate into the neuraminidase-removable fraction of cultured glomerular epithelial cells subjected to puromycin, consistent with the defect in sialic acid and heparan sulfate moieties responsible for the distribution of negative charges in the glomerular filtration barrier. Bonsib 24 devised a strategy to remove podocytes from the renal biopsy of a patient with focal segmental necrotizing glomerulonephritis and subjecting it to scanning EM. His approach allowed direct visualization of the glomerular basement membrane, revealing its disruption and unimpeded communication between blood and ultrafiltrate. During this decade of the recognition of HIV/AIDS-associated kidney diseases, Chander et al25 showed that renal involvement manifested in mesangial hypocellularity, tubular degeneration, and presence of multiple complex nuclear and cytoplasmic inclusions. At the close of the decade, Jenette et al26 published a large study of antineutrophil cytoplasmic antibodyeassociated glomerulonephritis and vasculitis, concluding that these antibodies may not only serve as diagnostic markers but also be involved in the pathogenesis of the disease. The 1990s witnessed the burgeoning emergence of several topics most relevant to renal pathology today. In a valiant effort, Farquhar’s laboratory raised monoclonal IgG antibodies against detergent-soluble glomerular membrane proteins; 13 antibodies recognized diverse epitopes within glomeruli.27 The same group attempted to identify the membrane partners of some antibodies using immunoEM.28 With this strategy, they were able to identify antibodies against podocalyxin, proteins of the apical and basal membranes of podocytes, and slit diaphragms, some forming subepithelial deposits. Kerjaschki and Farquhar continued mapping of glomerular filtration slits in intact and polycation-damaged rat glomeruli.29 Using immuno-EM, they identified zonula occludens-1 localized at the base of podocytes and along the cytoplasmic surfaces of slit diaphragms of intact glomeruli. However, in glomeruli of nephrosis rats, zonula occludens-1 was found along the newly formed occluding junctions and remaining slit diaphragms. The investigators predicted that the ultrastructure of the glomerular filtration barrier may regulate glomerular hydraulic conductivity through focal tight junction assembly. On the strength of these discoveries published in the Journal, Dr. Farquhar deserves to be paid homage through an AJP Gold Pencil award. The work on mapping the landscape of podocyte membrane proteins, specifically the nephritogenic antigen of monoclonal antibody 5-1-6, continued with studies from D. Salant’s group. 30 H. Holthofer’s and D. Kerjaschki’s laboratory performed immuno-EM and elucidated localization of nephrin to filtration slits of podocytes, 31 whereas investigators from Helsinki, Finland, and Stockholm, Sweden, supplied evidence that nephrin is essential for formation of junctional complexes with ladder-like structures and slit diaphragms.32 Accolades, such as the AJPGold Pencil, for this decade also could be given to Kerjaschki, who continued screening of molecules governing glomerular filtration. Also in the 1990s, a megalin knockout mouse was generated and showed defects in reclaiming low-molecularweight plasma proteins from the ultrafiltrate, resulting in deficiency of lipophilic vitamins. 33 This protein (gp330) and some of its fragments were identified as inducers of Heymann nephritis.34 Another major development was the recognition of transforming growth factor-b as a causative factor in fibrosis of antieglomerular basement membrane disease.35 Platelet-derived growth factor was discovered as a culprit of antieThy-1 nephritis, which was ameliorated by platelet depletion.36 Kriz et al37 meticulously described ultrastructural organization of contractile proteins in rat glomerular mesangial cells, thus initiating an early mechanostructural approach to glomerular mesangium participation in regulation of the blood flow. Discovery of induction of procoagulant plasminogen activator inhibitor-1 and tissue factor molecules and suppression of fibrinolytic tissue plasminogen activator and urokinase in lupus glomerulonephritis shed light on the development of microthrombi in progression of disease.38 Following the discovery of genes for autosomal dominant polycystic kidney disease, A. Ong in P. Harris’s laboratory 39 tracked the expression of polycystin-2 and polycystin-1 in normal and cystic human kidneys. This decade further witnessed proliferation of studies elucidating identities of mediators of kidney injury. R. Johnson’s and C. Alpers’ laboratories described increased osteopontin expression at the sites of tubulointerstital injury in three models of glomerulonephritis.40 Their groups also detected reparative responses of glomerular capillary endothelial cells, capable of healing microaneurysms, driven by basic fibroblast growth factor and vascular endothelial growth factor/vascular permeability factor.41 Glomerular endothelium also attracted the attention of McGregor et al,42 who observed up-regulation of von Willebrand factor and intercellular adhesion molecule-1 staining in capillary endothelia colocalizing with the enhanced expression of thrombospondin in the interstitiumda proposed association between inflammation and early fibrosis. Remodeling of the extracellular matrix was found in experimental glomerulonephritis by V. Nickeleit in R. Colvin’s laboratory, 43 who demonstrated accumulation of oncofetal forms of fibronectin 100 Years of Kidney Disease Publications The American Journal of Pathology - ajp.amjpathol.org 159
in cellular crescents. The de novo expression of extradomain A fibronectin was discovered by Abrass et al 44 in aged rat kidneys at sites of interstitial fibrosis with enhanced deposition of collagen types I and III. Techniques of in situ hybridization found an important application in chronological analysis of tumor necrosis factor a mRNA expression in endotoxin-induced septic kidneys, performed by E. Noiri in K. Kurokawa’s laboratory. 45 Overall, it appears that the closing decade of the 20th century provided a nutrient-rich broth for the Petri dish of kidney studies’ growth. In the first decade of the 21st century, rivulets of emerging research started to coalesce, forming mainstream waterways of today’s kidney pathology. Computational biology entered the fray with analysis of expression patterns of 7075 genes in kidney tumors to provide distinct expression patterns and derive novel molecular markers of renal epithelial neoplasms.46 Investigations of nephrin redistribution on podocytes in patients with nephrotic syndrome47 suggested the cytoskeleton-dependent shedding of nephrin from the plasma membrane to the extracellular milieu. K. Tryggvason’s laboratory persevered to find homophilic interactions of nephrin molecules that promote cell-cell adhesion.48 Perhaps, the discovery of nephrin that ignited follow-up investigations and the search for additional molecular fingerprints deserves recognition of Tryggvason with the AJP Gold Pencil award. Mapping of podocyte proteins continued with the demonstration of podocin acting as an anchoring component of other slit diaphragm proteins to the cytoskeleton of podocytes.49 Moreover, Sanders’s laboratory pursued previous studies of multiple myeloma cast nephropathy to identify the binding domain of immunoglobulin light chains for Tamm-Horsfall protein in the thick ascending limb of the loop of Henle.50 During this decade, a substantial cluster of publications was dedicated to the role of angiotensin II in pathogenesis of kidney disease. Benigni et al51 demonstrated that angiotensin-converting enzyme inhibition prevented hypertension, proteinuria, tubular atrophy, and broadening of the interstitium in rats with passive Heymann nephritis. An additional target for angiotensin-converting enzyme inhibition was described in interstitial fibroblast-like cells expressing components of the renin-angiotensin system in fibrotic areas. 52 Another target of angiotensin IIepromoted fibrogenesis was identified by J. Egido’s laboratory as induction of connective tissue growth factor in rats with immune complex nephritis.53 One more cluster of studies nested around the structural markers and criteria of therapeutic interventions. An intriguing line of studies was published by Kanellis et al,54 who detected the decrease in glomerular expression of an anti-inflammatory and anti-chemotactic protein, Slit-2, with systemic administration of Slit-2 to rats with crescentic glomerulonephritis improving the disease morphologically and functionally. Direct blockade of the chemokine receptor CCR2 in mice with unilateral ureteral obstruction decreased inflammatory infiltrate and ameliorated progression of fibrosis. 55 In other studies, lipoxin A4 was found to modulate and ameliorate the expression of platelet-derived growth factoreinduced genes, like transforming growth factor-b, fibronectin, thrombospondin, and several collagens, all of which are involved in progression of kidney disease.56 13-Cis-retinoic acid was deployed to successfully provide immunosuppressive and anti-fibrotic effects in the model of chronic allograft nephropathy in rats.57 Yet another strategy to counteract profibrotic effects of transforming growth factor-b in rat remnant kidney was introduced by Hou et al,58 who used ultrasound microbubblemediated gene transfer of Smad7 to silence fibrogenic signaling. Inhibition of transforming growth factorbeinduced kidney fibrosis also was accomplished by antisense oligonucleotides against thrombospondin-1.59 These pharmacomorphologic studies were supplemented by early attempts at using stem cells for therapy. Bussolati et al60 isolated human CD133þ kidney-derived multipotent stem cells with potential to differentiate toward epithelial or endothelial lineages and showed that these cells were able to home into the glycerol-injured kidney and participate in kidney repair. In a rat model of allogenic bone marrow transplant, Rookmaaker et al61 identified a small number of chimeric donor cells in intact glomeruli, but numbers of bone marrowederived cells dramatically increased after induction of Thy-1.1 glomerulonephritis. The end of this decade witnessed the emergence of thorough investigations of the extracellular matrix components in kidney disease progression, like decorin,62 and ingenious therapeutic strategies, like the use of microbial IgA protease to remove IgA immune complexes from mouse glomeruli in vivo.63 Multiplexed analysis of large numbers of variables64 was already on the horizon to explode in the past decade with transcriptome and spatial transcriptome, genome, epigenome, proteome, and metabolome studies of diverse morbid conditions of the kidney. This brave new world has brought about myriads of data left for analysis fit only for computer mining. The harvest from these searches is forthcoming. Those zeitgeist investigations infuse today’s tapestry of kidney pathology with viable themes. The past decade of studies, too near us and leaving insufficient exposure time to judge their endurance and utility, will have to be left for future reflection. Acknowledgments I express my deep gratitude to Surya V. Seshan, M.D., Professor of Pathology, Weill-Cornell Medical School, New York, for careful reading of the draft of the manuscript and providing me with invaluable insights; and to Karl Skorecki, M.D., Professor of Medicine, Technion Medical School, for suggestions and encouraging support. Regrettably, the required format precludes mentioning review articles and several seminal noneThe American Journal of Pathology Goligorsky 160 ajp.amjpathol.org - The American Journal of Pathology
publications, like immunologic studies by Dixon and Wilson, renal hypertension study by Goldblatt, and nephron microdissection study by Oliver, among many others. Any other omissions are my responsibility. Disclosure Statement None declared. References 1. Kimmelstiel P, Wilson C: Intercapillary lesions in the glomeruli of the kidney. Am J Pathol 1936, 12:83e98 2. Farquhar M, Hooper J, Moon H: Diabetic glomerulosclerosis; electron and light microscopic studies. Am J Pathol 1959, 35:721e753 3. Jones DB: The nature of scar tissue in glomerulonephritis. Am J Pathol 1963, 42:185e199 4. Jones DB: Inflammation and repair of the glomerulus. Am J Pathol 1951, 27:991e1009 5. Jones DB, Loring W: Glomerular thrombosis. Am J Pathol 1951, 27: 841e855 6. Jones DB: Nephrosclerosis and the glomerulus. Am J Pathol 1953, 29:619e631 7. Jones DB: Nephrotic glomerulonephritis. Am J Pathol 1957, 33: 313e329 8. Jones DB: Glomerulonephritis. Am J Pathol 1953, 29:33e51 9. 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