American Journal of Pathology最新文献

Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma: Current Progress, Mechanisms of Action, and Challenges. 开发用于治疗胆管癌的 CAR-T 疗法和个性化疫苗：当前进展、作用机制和挑战。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-13 DOI: 10.1016/j.ajpath.2024.10.021

Dan Li, Lalitya Andaloori, Matthew Crowe, Shaoli Lin, Jessica Hong, Neeha Zaidi, Mitchell Ho

{"title":"Development of CAR-T Therapies and Personalized Vaccines for the Treatment of Cholangiocarcinoma: Current Progress, Mechanisms of Action, and Challenges.","authors":"Dan Li, Lalitya Andaloori, Matthew Crowe, Shaoli Lin, Jessica Hong, Neeha Zaidi, Mitchell Ho","doi":"10.1016/j.ajpath.2024.10.021","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.10.021","url":null,"abstract":"Cholangiocarcinoma (CCA) is a highly lethal malignancy with rising incidence, high mortality, poor overall survival rates, and limited responsiveness to traditional chemo-radiotherapy. Targeted therapies addressing specific gene mutations have expanded treatment options for some patient populations. The introduction of chimeric antigen receptor-modified T cell (CAR-T) immunotherapy and personalized vaccines have opened up a new avenue for managing various cancers. Considerable efforts have been dedicated to preclinical research and ongoing clinical trials aimed at investigating immunotherapeutic approaches such as CAR-T therapy, vaccines, and antibody-based therapies such as antibody drug conjugates. However, the potential of CAR-T therapy and vaccines in treating advanced unresectable/metastatic CCA remains largely unexplored. This review offers an overview of the current landscape of antibody-based immunotherapy, particularly CAR-T therapy and vaccines in the context of CCA treatment. It outlines a framework for selecting CAR-T and vaccine targets and delves into the biology of promising targetable antigens, as well as potential future therapeutic targets.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827015","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}

引用次数: 0

Correction.

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-12-13 DOI: 10.1016/j.ajpath.2024.11.002

引用次数: 0

Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors. 调节肝移植中的脂肪连接蛋白和抵抗素可保护来自扩展标准捐献者的移植物。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.016

Araní Casillas-Ramírez, Cristina Maroto-Serrat, Francisco Sanus, Marc Micó-Carnero, Carlos Rojano-Alfonso, Margalida Cabrer, Carmen Peralta

{"title":"Regulation of Adiponectin and Resistin in Liver Transplantation Protects Grafts from Extended-Criteria Donors.","authors":"Araní Casillas-Ramírez, Cristina Maroto-Serrat, Francisco Sanus, Marc Micó-Carnero, Carlos Rojano-Alfonso, Margalida Cabrer, Carmen Peralta","doi":"10.1016/j.ajpath.2024.10.016","DOIUrl":"10.1016/j.ajpath.2024.10.016","url":null,"abstract":"The donor shortage increases liver transplantation (LT) waiting lists, making it crucial to consider extended-criteria donors, such as steatotic donors after brain death (DBDs) or cardiocirculatory death (DCDs). Nevertheless, steatosis, brain death, and cardiocirculatory death are key risk factors for poor LT outcomes. We investigated the role and therapeutic usefulness of several adipocytokines to protect such grafts from extended-criteria donors. Sprague rats with nutritionally induced steatosis were used in an experimental LT model with grafts from DBDs or DCDs. Adiponectin, resistin, and visfatin were measured and pharmacologically modulated, and effects on liver injury were assessed. Visfatin played no role under conditions of neither DBD nor DCD LT. Brain death increased adiponectin and reduced resistin. Adiponectin harmed steatotic and nonsteatotic DBD grafts, via a resistin-dependent mechanism; restraining adiponectin increased resistin, reducing damage. Resistin treatment protected both types of DBD grafts, whereas suppressing it increased damage. This adiponectin-resistin pathway was dependent on protein kinase C. In DCD LT, adiponectin and resistin were not modified in nonsteatotic grafts, but reduced in steatotic ones. Adiponectin or resistin treatments protected steatotic grafts: hepatic adiponectin activated AMPK; hepatic resistin increased phosphatidylinositol 3-kinase-Akt. Concomitant administration of both adipocytokines increased both signaling pathways, intensifying protection. Therefore, pharmacologic modulation of adiponectin and resistin resulted in therapies that potentially might be translated to clinical studies to improve surgical outcomes for LT from extended-criteria donors.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680658","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}

引用次数: 0

Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis. 基因缺失 HIF-Prolyl-Hydroxylase (PHD) 1（而非药物抑制）可减轻肝纤维化。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.018

Christopher Tuffs, Mareen Dupovac, Katrin Richter, Sophia Holten, Thomas Schaschinger, Oliver Marg, Adisa Poljo, Ayse Nur Tasdemir, Jonathan M Harnoss, Adrian Billeter, Martin Schneider, Moritz J Strowitzki

{"title":"Genetic Loss of HIF-Prolyl-Hydroxylase 1, but Not Pharmacological Inhibition, Mitigates Hepatic Fibrosis.","authors":"Christopher Tuffs, Mareen Dupovac, Katrin Richter, Sophia Holten, Thomas Schaschinger, Oliver Marg, Adisa Poljo, Ayse Nur Tasdemir, Jonathan M Harnoss, Adrian Billeter, Martin Schneider, Moritz J Strowitzki","doi":"10.1016/j.ajpath.2024.10.018","DOIUrl":"10.1016/j.ajpath.2024.10.018","url":null,"abstract":"Liver fibrosis is characterized by excessive deposition of extracellular matrix due to chronic inflammation of the liver. Hepatic stellate cells (HSCs) become activated and produce excessive amounts of extracellular matrix. It was previously shown that loss of HIF-prolyl-hydroxylase 1 (PHD1) attenuates HSC activation and fibrotic tissue remodeling in a murine model of biliary liver fibrosis. Thus, the protective effect of PHD1 deficiency (PHD1-/-) in an additional (toxic) model of liver fibrosis was validated and the effect of dimethyloxalylglycine (DMOG), a pan-HIF-prolyl-hydroxylase inhibitor, on the development of liver fibrosis, was evaluated. Liver fibrosis was induced utilizing carbon tetrachloride in wild-type (WT), PHD1-/-, vehicle-treated, and DMOG-treated mice. Livers were further analyzed by Sirius red staining and gene expression analysis of profibrotic genes to assess fibrosis development. When compared with WT mice, PHD1-/- mice developed less-severe liver fibrosis. By contrast, DMOG treatment did not prevent liver fibrosis. PHD1-/- mice showed fewer α-SMA+ cells and less macrophage infiltration compared with WT mice. Gene expression of profibrogenic and proinflammatory genes was reduced in livers from carbon tetrachloride-exposed PHD1-/- mice. In vitro analyses of PHD1-deficient human HSCs revealed attenuated mRNA levels of profibrotic genes, as well as impaired migration and invasion. Although PHD1 deficiency attenuates activation of HSCs, pharmacologic PHD inhibition does not ameliorate fibrosis development. Selective PHD1 inhibitors could prove effective in preventing and treating liver fibrosis.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680656","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}

引用次数: 0

Evidence and Mechanism of Bile Acid-Mediated Gut-Brain Axis in Anxiety and Depression. 胆汁酸介导的肠脑轴在焦虑和抑郁中的作用证据和机制

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.019

Sydney O Idahosa, Rokia Diarra, Hernoor K Ranu, Raidah H Nasiri, Sei Higuchi

{"title":"Evidence and Mechanism of Bile Acid-Mediated Gut-Brain Axis in Anxiety and Depression.","authors":"Sydney O Idahosa, Rokia Diarra, Hernoor K Ranu, Raidah H Nasiri, Sei Higuchi","doi":"10.1016/j.ajpath.2024.10.019","DOIUrl":"10.1016/j.ajpath.2024.10.019","url":null,"abstract":"Bidirectional communication between the brain and gastrointestinal tract, called the gut-brain axis, is linked with our emotions. Intestinal lipids, hormones, and molecules, such as bile acids (BAs), have been known to impact our mood, motivation, and emotions via the gut-brain axis. BAs are synthesized from cholesterol in the liver and serve as a regulator of lipid metabolism and hormonal secretion in the intestine. Human studies have indicated that the alteration of plasma BA levels is associated with depression and anxiety. Several possible mechanisms, such as BA receptor-dependent and receptor-independent mechanisms, have been reported for emotional control. Animal studies have indicated that the deletion of BA receptors shows behavioral abnormalities. BAs regulate gut hormones, glucagon-like peptide-1 secretion, bioactive lipids, oleoylethanolamide, and the immune system function, which influences neural activities. Thus, BAs are considered to act as an emotional regulator. This review aims to summarize the following: clinical evidence of BA concentration linked to mental disorders, including depression and anxiety; and animal studies of BA-related signaling correlated with its neurobehavioral effect supporting its mechanism. In this review, we will discuss future research required for further neurobehavioral treatment.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680643","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}

引用次数: 0

CDR1as Deficiency Prevents Photoreceptor Degeneration by Regulating miR-7a-5p/α-syn/Parthanatos Pathway in Retinal Detachment. CDR1as 缺陷通过调节视网膜脱离中的 miR-7a-5p/α-syn/Parthanatos 通路防止感光细胞退化

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.015

Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong

{"title":"CDR1as Deficiency Prevents Photoreceptor Degeneration by Regulating miR-7a-5p/α-syn/Parthanatos Pathway in Retinal Detachment.","authors":"Feiyu Jin, Yuanye Yan, Ziyang Ye, Lisong Wang, Can Deng, Jiazhen Jiang, Kai Dong","doi":"10.1016/j.ajpath.2024.10.015","DOIUrl":"10.1016/j.ajpath.2024.10.015","url":null,"abstract":"Retinal detachment (RD) is the separation of the neural retina from the retinal pigment epithelium, with photoreceptor degeneration being a major cause of irreversible vision loss. Ischemia and hypoxia after RD decreased the level of miR-7a-5p (miR-7) and promoted the expression of its main target, α-synuclein (α-syn), which activated the parthanatos pathway and led to photoreceptor damage. Circular RNA CDR1as, which is an antisense transcript of cerebellar degeneration-related protein 1, functions as a \"sponge\" for miR-7, thereby regulating its abundance and activity. In this study, we first reported that CDR1as expression is elevated after RD. Adeno-associated virus serotype 9 vector containing the shRNA-CDR1as sequence was used to inhibit CDR1as expression via subretinal injection. Hematoxylin and eosin staining and transmission electron microscopy revealed that the morphology and outer nuclear layer thickness of the retina were preserved and photoreceptor cell death was decreased after experimental RD in mice. Mechanistically, CDR1as deficiency significantly increased the expression of miR-7, then decreased the expression of α-syn, poly (ADP-ribose) polymerase 1, apoptosis-inducing factor, and migration inhibitory factor. Furthermore, visual function was improved as shown by Morris water maze experiments in the mouse model of RD. Our findings suggest a surprisingly neuroprotective role for CDR1as deficiency, which is probably mediated by enhancing miR-7 activity and inhibiting α-syn/poly (ADP-ribose) polymerase 1/apoptosis-inducing factor pathway, thereby preventing photoreceptor degeneration.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680641","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}

引用次数: 0

A Core of Keratocan-Negative Cells Survives in Old Corneal Scars. 陈旧角膜疤痕中存活着角膜阴性细胞的核心。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-19 DOI: 10.1016/j.ajpath.2024.10.017

Hadi Joud, Meisam Asgari, Victoria Emerick, Mei Sun, Marcel Y Avila, Curtis E Margo, Edgar M Espana

{"title":"A Core of Keratocan-Negative Cells Survives in Old Corneal Scars.","authors":"Hadi Joud, Meisam Asgari, Victoria Emerick, Mei Sun, Marcel Y Avila, Curtis E Margo, Edgar M Espana","doi":"10.1016/j.ajpath.2024.10.017","DOIUrl":"10.1016/j.ajpath.2024.10.017","url":null,"abstract":"Corneal scars originate from keratocyte-derived fibroblasts and myofibroblasts that are ultimately cleared through apoptosis or revert to keratocytes. A mouse model expressing the keratocyte lineage-specific reporter KeraRT/tetO-Cre/mTmG (I-KeramTmG) was interrogated to elucidate cell phenotype dynamics during scar maturation. This model expresses tdTomato (red) in all keratocan-negative cells, while enhanced green fluorescent protein (green) is expressed only by keratocytes. A 1-mm full-thickness keratotomy was generated in adult I-KeramTmG mice. The presence of keratocytes was determined at 3, 6, and 10 months after injury. At 3 and 6 months, few green cells were visualized at the scar borders, while few or no green cells were seen in the central (core) scar. At 10 months, green cells were seen throughout the scar, but most cells were red. Proliferation of stromal cells after injury was studied by 5-ethynyl-2'-deoxyuridine labeling and Ki-67 staining; both assays showed proliferation only during the first 2 weeks after injury. Second harmonic generation microscopy showed thickened and irregularly arranged collagen fibers in scars, suggesting that neither extracellular matrix organization nor cell phenotype had changed significantly at 10 months after injury. Findings from in vivo experiments suggest that in old corneal scars, a nonkeratocyte phenotype persists in an abnormal matrix with unique characteristics that probably prevent the regression of fibroblasts and myofibroblasts to keratocytes or invasion of surrounding keratocytes.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680639","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}

引用次数: 0

Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon. 小鼠回肠和结肠中结肠炎和适应性免疫系统对肠蠕动的节段性调控

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-17 DOI: 10.1016/j.ajpath.2024.10.020

Raquel Gomez-Bris, Pilar Rodríguez-Rodríguez, Marina Ortega-Zapero, Santiago Ruvira, Raquel Castillo-González, María Jesús Fernández-Aceñero, Aránzazu Cruz-Adalia, Angela Saez, Silvia-Magdalena Arribas, Jose-Maria Gonzalez-Granado

{"title":"Segmental Regulation of Intestinal Motility by Colitis and the Adaptive Immune System in the Mouse Ileum and Colon.","authors":"Raquel Gomez-Bris, Pilar Rodríguez-Rodríguez, Marina Ortega-Zapero, Santiago Ruvira, Raquel Castillo-González, María Jesús Fernández-Aceñero, Aránzazu Cruz-Adalia, Angela Saez, Silvia-Magdalena Arribas, Jose-Maria Gonzalez-Granado","doi":"10.1016/j.ajpath.2024.10.020","DOIUrl":"10.1016/j.ajpath.2024.10.020","url":null,"abstract":"Gastrointestinal motility disturbances are a hallmark of inflammatory bowel disease (IBD); however, their mechanisms remain unclear. This study used a dextran sulfate sodium-induced colitis mouse model, deficient in mature B and T lymphocytes, to assess intestinal motility and the role of the adaptive immune system in health and IBD. In healthy mice, the absence of adaptive lymphocytes reduced acetylcholine (ACh) sensitivity in the ileum. During colitis, it decreases motility by reducing the intensity and frequency of spontaneous contractions while increasing cholinergic responsiveness. In the proximal colon, adaptive immunity deficiency led to increased contractility and reduced ACh sensitivity in homeostasis, whereas colitis reduced contractile capacity. In the mid colon, immune-deficient mice have reduced ACh sensitivity in homeostasis and exacerbated contractile responses during colitis. In the distal colon, adaptive immunity loss reduced contractility in health and cholinergic responsiveness during colitis. These motility alterations were associated with altered acetylcholinesterase and M2/M3 muscarinic receptor expression. Notably, adaptive lymphocyte deficiency resulted in reduced tissue damage and lower tumor necrosis factor-α expression in the colon during colitis, paralleling intestinal motility changes. Overall, the adaptive immune system critically regulates motility and inflammation across different intestinal segments in IBD.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674902","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}

引用次数: 0

The Amyloid Cascade Hypothesis: A Conclusion in Search of Support. 淀粉样蛋白级联假说：寻找支持的结论

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.014

Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry

{"title":"The Amyloid Cascade Hypothesis: A Conclusion in Search of Support.","authors":"Rudy J Castellani, Pouya Jamshidi, Germán Plascencia-Villa, George Perry","doi":"10.1016/j.ajpath.2024.10.014","DOIUrl":"10.1016/j.ajpath.2024.10.014","url":null,"abstract":"The amyloid cascade hypothesis as the etiological underpinning of Alzheimer disease (AD) is supported by a large body of literature, the most influential of which are genetic studies of the 1980s and 1990s. Other evidence includes the neuropathology of Down syndrome, apparent toxicity of oligomeric amyloid-β (Aβ), interactions with apolipoprotein E, and the analogy of cardiac amyloidosis. On the other hand, there is considerable phenotypic heterogeneity among the rare familial AD kindreds, which tempers extrapolation to sporadic AD. Oligomer biology is still in the theoretical realm, with no clinical validation. Apolipoprotein E support for the amyloid cascade and other inferences from the literature are somewhat circular in their logic. Analogy with amyloidoses might also consider secondary amyloidosis, driven by systemic inflammation and treated by treating the underlying etiology. Much of the remaining literature supporting the amyloid cascade is dominated by hypothesis-generating studies. Importantly, we now have a developing evidence base from controlled clinical trials that can potentially inform the issue of Aβ as a cause or driver of disease in sporadic AD. Emerging data provide clear evidence of target engagement. Clinical outcome, however, has been either marginally positive or similar to placebo. Assuming these findings hold, it appears that Aβ neither drives nor mitigates the disease process.","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142611812","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}

引用次数: 0

This Month in AJP. 本月 AJP。

IF 4.7 2区医学

American Journal of Pathology Pub Date : 2024-11-10 DOI: 10.1016/j.ajpath.2024.10.012

引用次数: 0