American Journal of Pathology最新文献

{"title":"Beyond Redox Regulation","authors":"Chuang Li ,&nbsp;Yili Fang ,&nbsp;Ying Maggie Chen","doi":"10.1016/j.ajpath.2024.12.011","DOIUrl":"10.1016/j.ajpath.2024.12.011","url":null,"abstract":"<div><div>Cellular stress, such as oxidative and endoplasmic reticulum (ER) stresses, contributes to the development of various kidney diseases. Oxidative stress is prompted by reactive oxygen species accumulation and delicately mitigated by glutathione and thioredoxin (Trx) antioxidant systems. Initially identified as a Trx-binding partner, Trx-interacting protein (TXNIP) is significantly up-regulated and activated by oxidative and ER stresses. The function of TXNIP is closely linked to its subcellular localizations. Under normal physiological conditions, TXNIP primarily localizes to the nucleus. When exposed to reactive oxygen species or ER stress, TXNIP relocates to mitochondria and binds to mitochondrial Trx2, which releases Trx-tethered apoptosis signal-regulating kinase 1 and activates apoptosis signal-regulating kinase 1–mediated apoptosis. Oxidative and ER stresses are also closely associated with autophagy. TXNIP can promote or inhibit autophagy depending on context. Although recent studies have highlighted the indispensable role of TXNIP in the etiology and progression of kidney disease, TXNIP-targeted therapy is still missing. This review focuses on the following: i) oxidative and ER stresses; ii) regulation and function of TXNIP during cellular stress; iii) TXNIP in stress-regulated autophagy; iv) TXNIP in kidney diseases (nephrotic syndrome, diabetic nephropathy and chronic kidney disease, acute kidney injury, and kidney aging); and v) novel treatment agents targeting TXNIP in kidney disease. Current advances in chemical compounds and RNA-based therapy suppressing TXNIP are also reviewed.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 615-625"},"PeriodicalIF":4.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cytotoxic T-Lymphocyte–Associated Protein 4 Fused to a Modified Fragment of IgG1 Reduces Muscle Fiber Damage in a Model of Duchenne Muscular Dystrophy by Attenuating Proinflammatory Gene Expression in Myeloid Lineage Cells","authors":"Michelle Wehling-Henricks ,&nbsp;Su-yin Kok ,&nbsp;Haley Gamboa ,&nbsp;Pranav Kannan ,&nbsp;Connor Thomas ,&nbsp;Ivan Flores ,&nbsp;Steven S. Welc ,&nbsp;James G. Tidball","doi":"10.1016/j.ajpath.2024.12.012","DOIUrl":"10.1016/j.ajpath.2024.12.012","url":null,"abstract":"<div><div>Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting, genetic disease that is greatly amplified by an immune response to the diseased muscles. The <em>mdx</em> mouse model of DMD was used to test whether the pathology can be reduced by treatment with a cytotoxic T-lymphocyte–associated protein 4 fused to a modified fragment of IgG1 (CTLA4-Ig) fusion protein that blocks costimulatory signals required for activation of T cells. CTLA4-Ig treatment reduced <em>mdx</em> sarcolemma lesions and reduced the numbers of activated T cells, macrophages, and antigen-presenting cells in <em>mdx</em> muscle and reduced macrophage invasion into muscle fibers. <em>In vitro</em> data showed that CTLA4-Ig acts directly on bone marrow cells and macrophages to modify their function and gene expression. CTLA4-Ig treatment of <em>mdx</em> bone marrow cells diminished their mobility and chemotactic response to chemokine ligand-2. Treating <em>mdx</em> macrophages with CTLA4-Ig reduced their cytolysis of muscle cells <em>in vitro</em>. RNA-sequencing analysis of <em>mdx</em> macrophages showed that CTLA4-Ig reduced expression of genes associated with leukocyte chemotaxis, migration, and extravasation; &gt;90% of those affected genes were tumor necrosis factor-α target genes. Comparison of <em>mdx</em> and wild-type macrophages by RNA sequencing showed that 46% of the genes down-regulated by CTLA4-Ig were genes up-regulated in macrophages by the presence of muscular dystrophy in mice. These findings show that CTLA4-Ig is a promising immunotherapeutic for DMD, and many of its beneficial effects may result from direct actions on macrophages that modify their expression of proinflammatory genes.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 717-740"},"PeriodicalIF":4.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142998571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The KMeansGraphMIL Model","authors":"Linghao Chen ,&nbsp;Huiling Xiao ,&nbsp;Jiale Jiang ,&nbsp;Bing Li ,&nbsp;Weixiang Liu ,&nbsp;Wensheng Huang","doi":"10.1016/j.ajpath.2024.12.008","DOIUrl":"10.1016/j.ajpath.2024.12.008","url":null,"abstract":"<div><div>Colorectal cancer (CRC) is one of the top three most lethal malignancies worldwide, posing a significant threat to human health. Recently proposed immunotherapy checkpoint blockade treatments have proven effective for CRC, but their use depends on measuring specific biomarkers in patients. Among these biomarkers, tumor mutational burden (TMB) has emerged as a novel indicator, traditionally requiring next-generation sequencing for measurement, which is time-consuming, labor intensive, and costly. To provide an economical and rapid way to predict patients' TMB, the KMeansGraphMIL model was proposed based on weakly supervised multiple-instance learning. Compared with previous weakly supervised multiple-instance learning models, KMeansGraphMIL leveraged both the similarity of image patch feature vectors and the spatial relationships between patches. This approach improved the model's area under the receiver operating characteristic curve to 0.8334 and significantly increased the recall to 0.7556. Thus, this study presents an economical and rapid framework for predicting CRC TMB, offering the potential for physicians to quickly develop treatment plans and saving patients substantial time and money.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 671-679"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histopathologic Marks of Tongue in a Mouse Model of Oculopharyngeal Muscular Dystrophy Suggest Biomechanical Defects","authors":"Rebecca Kordikowski Boix ,&nbsp;Erik Bos ,&nbsp;Milad Shademan ,&nbsp;Sander Mallon ,&nbsp;Sofie van Zanen-Gerhardt ,&nbsp;Ngoc Lu-Nguyen ,&nbsp;Alberto Malerba ,&nbsp;Christina J.J. Coenen de Roo ,&nbsp;Vered Raz","doi":"10.1016/j.ajpath.2024.12.009","DOIUrl":"10.1016/j.ajpath.2024.12.009","url":null,"abstract":"<div><div>Difficulty swallowing (dysphagia) is common in the elderly population and in patients with adult-onset neuromuscular disease. In oculopharyngeal muscular dystrophy (OPMD), dysphagia is often the first symptom. OPMD is an autosomal-dominant myopathy caused by a trinucleotide-expansion mutation in the gene encoding poly(A) binding protein nuclear 1 (PABPN1). Expanded-mutant PABPN1 forms insoluble nuclear aggregates that reduce the levels of the soluble form. Clinical tongue involvement in OPMD has been documented but is poorly understood. Histopathologic analysis of the tongue in an OPMD mouse model was done by light and electron microscopy combined with RNA sequencing. PABPN1 nuclear aggregates were found at moderate levels, whereas deposition of insoluble PABPN1 in blood vessels was prominent already at 4 months of age. Muscle wasting of the tongue was age associated. RNA signatures of the OPMD tongue were enriched for mitochondrial and cytoskeletal genes. Electron microscopy revealed abnormalities in sarcomere and mitochondria organization in <em>A17</em>/+ mice, suggesting an energy and contractile deficit in OPMD tongue. This detailed analysis of the histopathology of the tongue in the <em>A17</em>/+ mouse model opens new avenues for understanding the mechanisms of dysphagia.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 741-753"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep Learning for Classification of Inflammatory Bowel Disease Activity in Whole Slide Images of Colonic Histopathology","authors":"Amit Das ,&nbsp;Tanmay Shukla ,&nbsp;Naofumi Tomita ,&nbsp;Ryland Richards ,&nbsp;Laura Vidis ,&nbsp;Bing Ren ,&nbsp;Saeed Hassanpour","doi":"10.1016/j.ajpath.2024.12.010","DOIUrl":"10.1016/j.ajpath.2024.12.010","url":null,"abstract":"<div><div>Grading activity of inflammatory bowel disease (IBD) using standardized histopathological scoring systems remains challenging due to limited availability of pathologists with IBD expertise and interobserver variability. In this study, a deep learning model was developed to classify activity grades in hematoxylin and eosin–stained whole slide images (WSIs) from patients with IBD, offering a robust approach for general pathologists. This study utilized 2077 WSIs from 636 patients who visited Dartmouth-Hitchcock Medical Center in 2018 and 2019, scanned at ×40 magnification (0.25 μm/pixel). Board-certified gastrointestinal pathologists categorized the WSIs into four activity classes: inactive, mildly active, moderately active, and severely active. A transformer-based model was developed and validated using five-fold cross-validation to classify IBD activity. Using HoVer-Net, neutrophil distribution across activity grades was examined. Attention maps from the model highlighted areas contributing to its prediction. The model classified IBD activity with weighted averages of 0.871 (95% CI, 0.860–0.883) for the area under the curve, 0.695 (95% CI, 0.674–0.715) for precision, 0.697 (95% CI, 0.678–0.716) for recall, and 0.695 (95% CI, 0.674–0.714) for F1 score. Neutrophil distribution was significantly different across activity classes. Qualitative evaluation of attention maps by a gastrointestinal pathologist suggested their potential for improved interpretability. The model demonstrates robust diagnostic performance and could enhance consistency and efficiency in IBD activity assessment.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 4","pages":"Pages 680-689"},"PeriodicalIF":4.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemokine (C-C Motif) Ligand 2/CCR2/Extracellular Signal-Regulated Kinase Signal Induced through Cancer Cell–Macrophage Interaction Contributes to Hepatocellular Carcinoma Progression","authors":"Nobuaki Ishihara ,&nbsp;Yu-ichiro Koma ,&nbsp;Masaki Omori ,&nbsp;Shohei Komatsu ,&nbsp;Rikuya Torigoe ,&nbsp;Hiroki Yokoo ,&nbsp;Takashi Nakanishi ,&nbsp;Keitaro Yamanaka ,&nbsp;Yuki Azumi ,&nbsp;Shuichi Tsukamoto ,&nbsp;Takayuki Kodama ,&nbsp;Mari Nishio ,&nbsp;Manabu Shigeoka ,&nbsp;Hiroshi Yokozaki ,&nbsp;Takumi Fukumoto","doi":"10.1016/j.ajpath.2024.12.007","DOIUrl":"10.1016/j.ajpath.2024.12.007","url":null,"abstract":"<div><div>Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Herein, immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood–derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 3","pages":"Pages 589-608"},"PeriodicalIF":4.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Transcriptomics","authors":"Pierre Isnard ,&nbsp;Benjamin D. Humphreys","doi":"10.1016/j.ajpath.2024.06.012","DOIUrl":"10.1016/j.ajpath.2024.06.012","url":null,"abstract":"<div><div>The recent arrival of high-resolution spatial transcriptomics (ST) technologies is generating a veritable revolution in life sciences, enabling biomolecules to be measured in their native spatial context. By integrating morphology and molecular biology, ST technologies offer the potential of improving the understanding of tissue biology and disease and may also provide meaningful clinical insights. This review describes the main ST technologies currently available and the computational analysis for data interpretation and visualization, and illustrate their scientific and potential medical interest in the context of kidney disease. Finally, we discuss the perspectives and challenges of these booming new technologies.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 1","pages":"Pages 23-39"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Kidney Precision Medicine Project and Single-Cell Biology of the Injured Proximal Tubule","authors":"Danielle Janosevic,&nbsp;Thomas De Luca,&nbsp;Kidney Precision Medicine Project,&nbsp;Michael T. Eadon","doi":"10.1016/j.ajpath.2024.09.006","DOIUrl":"10.1016/j.ajpath.2024.09.006","url":null,"abstract":"<div><div>Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 1","pages":"Pages 7-22"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Kir5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats","authors":"Biyang Xu ,&nbsp;Vladislav Levchenko ,&nbsp;Adrian Zietara ,&nbsp;Sarah Fan ,&nbsp;Christine A. Klemens ,&nbsp;Alexander Staruschenko","doi":"10.1016/j.ajpath.2024.09.005","DOIUrl":"10.1016/j.ajpath.2024.09.005","url":null,"abstract":"<div><div>Maintaining acid–base homeostasis is critical for normal physiological function. The kidneys are essential for regulating acid–base homeostasis through maintaining systemic bicarbonate concentration. Chronic metabolic acidosis is an independent risk factor for chronic kidney diseases. Renal inwardly rectifying potassium channel K_ir5.1 plays an essential role in maintaining resting membrane potential. Patients with loss-of-function mutations in the <em>KCNJ16</em> gene, which encodes K_ir5.1, may have tubulopathy with hypokalemia, salt wasting, and hearing loss. Importantly, these mutations also disrupt acid–base balance, particularly causing metabolic acidosis. This study aimed to use Dahl salt-sensitive rats with a knockout of the <em>Kcnj16</em> gene (<em>SS</em>^{<em>Kcnj16−/−</em>}) to investigate how the deletion of K_ir5.1 affects the regulation of acid–base balance in salt-sensitive hypertension. <em>SS</em>^{<em>Kcnj16−/−</em>} rats displayed metabolic acidosis under a normal salt diet. Further analysis using RNA sequencing and Western blot analyses showed unchanged expression of proteins responsible for ammonia metabolism in the kidney of <em>SS</em>^{<em>Kcnj16−/−</em>} rats despite observed acidosis. However, there was a significant increase in the expression of bicarbonate transporter NBCe1, where there was a significant decrease in pendrin. In conclusion, the current study demonstrated that the loss of K_ir5.1 impairs the sensitivity of ammonia metabolism in the kidney in response to metabolic acidosis, which provides mechanistic insights into developing potential therapeutics for conditions involving hypokalemia and acid–base abnormalities.</div></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 1","pages":"Pages 115-125"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"This Month in AJP","authors":"","doi":"10.1016/j.ajpath.2024.10.012","DOIUrl":"10.1016/j.ajpath.2024.10.012","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":"195 1","pages":"Page 1"},"PeriodicalIF":4.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}