In patients with chronic kidney disease (CKD), skeletal muscle mass and function are known to occasionally decline. However, the muscle regeneration and differentiation process in uremia has not been extensively studied. In mice with CKD induced by adenine-containing diet, the tibialis anterior muscle injured using a barium chloride injection method recovered poorly as compared to control mice. In the cultured murine skeletal myocytes, stimulation with indoxyl sulfate (IS), a representative uremic toxin, morphologically jeopardized the differentiation, which was counteracted by L-ascorbic acid (L-AsA) treatment. Transcriptome analysis of cultured myocytes identified a set of genes whose expression was down-regulated by IS stimulation but up-regulated by L-AsA treatment. Gene silencing of myomixer, one of the genes in the set, impaired myocyte fusion during differentiation. By contrast, lentiviral overexpression of myomixer compensated for a hypomorphic phenotype caused by IS treatment. The split-luciferase technique demonstrated that IS stimulation negatively affected early myofusion activity that was rescued by L-AsA treatment. Lastly, in mice with CKD compared with control mice, myomixer expression in the muscle tissue in addition to the muscle weight after the injury was reduced, both of which were restored with L-AsA treatment. Collectively, data showed that the uremic milieu impairs the expression of myomixer and impedes the myofusion process. Considering frequent musculoskeletal injuries in uremic patients, defective myocyte fusion followed by delayed muscle damage recovery could underlie their muscle loss and weakness.
众所周知,慢性肾脏病(CKD)患者的骨骼肌质量和功能偶尔会下降。然而,尿毒症患者的肌肉再生和分化过程尚未得到广泛研究。在用含腺嘌呤饮食诱导的 CKD 小鼠中,与对照组小鼠相比,用氯化钡注射法损伤的胫骨前肌恢复较差。在培养的小鼠骨骼肌细胞中,具有代表性的尿毒症毒素--硫酸吲哚酯(IS)的刺激会从形态上破坏其分化,而 L-抗坏血酸(L-AsA)处理则可抵消这种破坏。对培养的肌细胞进行转录组分析发现了一组基因,它们的表达在 IS 刺激下下调,但在 L-AsA 处理下上调。基因沉默myomixer是这组基因中的一个,它阻碍了分化过程中的肌细胞融合。相比之下,慢病毒过表达 myomixer 可补偿 IS 处理导致的低畸形表型。分裂荧光素酶技术表明,IS 刺激对早期肌融合活性产生了负面影响,而 L-AsA 处理则可挽救这种影响。最后,与对照组小鼠相比,CKD 小鼠在损伤后肌肉组织中的 myomixer 表达量和肌肉重量都有所减少,而 L-AsA 治疗可恢复这两种表达量。总之,这些数据表明,尿毒症环境会损害肌融合器的表达,阻碍肌融合过程。考虑到尿毒症患者经常出现肌肉骨骼损伤,肌细胞融合缺陷和肌肉损伤恢复延迟可能是他们肌肉损失和无力的原因。
{"title":"Uremia Impedes Skeletal Myocyte Myomixer Expression and Fusogenic Activity","authors":"Takaaki Higashihara , Motoki Odawara , Hiroshi Nishi , Takehito Sugasawa , Yumika Suzuki , Satoshi Kametaka , Reiko Inagi , Masaomi Nangaku","doi":"10.1016/j.ajpath.2024.01.005","DOIUrl":"https://doi.org/10.1016/j.ajpath.2024.01.005","url":null,"abstract":"<div><p>In patients with chronic kidney disease (CKD), skeletal muscle mass and function are known to occasionally decline. However, the muscle regeneration and differentiation process in uremia has not been extensively studied. In mice with CKD induced by adenine-containing diet, the tibialis anterior muscle injured using a barium chloride injection method recovered poorly as compared to control mice. In the cultured murine skeletal myocytes, stimulation with indoxyl sulfate (IS), a representative uremic toxin, morphologically jeopardized the differentiation, which was counteracted by L-ascorbic acid (L-AsA) treatment. Transcriptome analysis of cultured myocytes identified a set of genes whose expression was down-regulated by IS stimulation but up-regulated by L-AsA treatment. Gene silencing of myomixer, one of the genes in the set, impaired myocyte fusion during differentiation. By contrast, lentiviral overexpression of myomixer compensated for a hypomorphic phenotype caused by IS treatment. The split-luciferase technique demonstrated that IS stimulation negatively affected early myofusion activity that was rescued by L-AsA treatment. Lastly, in mice with CKD compared with control mice, myomixer expression in the muscle tissue in addition to the muscle weight after the injury was reduced, both of which were restored with L-AsA treatment. Collectively, data showed that the uremic milieu impairs the expression of myomixer and impedes the myofusion process. Considering frequent musculoskeletal injuries in uremic patients, defective myocyte fusion followed by delayed muscle damage recovery could underlie their muscle loss and weakness.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140558215","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}
Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure in vivo during serial orthotopic passages of mouse KrasLSL-G12D/+;Trp53flox/flox;Pdx1-Cre (KPC) cancer cells in the tumor and in migrating through the size-restricted 3-μm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)–overexpressing cancer cells and derived subclusters with copy number amplifications in MYC-PTK2 (protein tyrosine kinase 2) locus and PIK3CA. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas–Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the KPC mice. Reduction of α-smooth muscle actin deposition in the CD248 knockout KPC mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of MYC-PTK2 locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.
{"title":"Stromal Rigidity Stress Accelerates Pancreatic Intraepithelial Neoplasia Progression and Chromosomal Instability via Nuclear Protein Tyrosine Kinase 2 Localization","authors":"Li-Yun Ding , Chia-Jung Chang , Szu-Ying Chen , Kuan-Lin Chen , Yueh-Shan Li , Yun-Chieh Wu , Ting-Yi Hsu , Hsin-Yu Ying , Hsin-Yi Wu , Michael W. Hughes , Chia-Yih Wang , Chih-Han Chang , Ming-Jer Tang , Woei-Jer Chuang , Yan-Shen Shan , Chia-Jung Chang , Po-Hsien Huang","doi":"10.1016/j.ajpath.2024.02.023","DOIUrl":"10.1016/j.ajpath.2024.02.023","url":null,"abstract":"<div><p>Because the mechanotransduction by stromal stiffness stimulates the rupture and repair of the nuclear envelope in pancreatic progenitor cells, accumulated genomic aberrations are under selection in the tumor microenvironment. Analysis of cell growth, micronuclei, and phosphorylated Ser-139 residue of the histone variant H2AX (γH2AX) foci linked to mechanotransduction pressure <em>in vivo</em> during serial orthotopic passages of mouse <em>Kras</em><sup><em>LSL-G12D/+</em></sup><em>;Trp53</em><sup><em>flox/flox</em></sup><em>;Pdx1-Cre</em> (<em>KPC</em>) cancer cells in the tumor and in migrating through the size-restricted 3-μm micropores. To search for pancreatic cancer cell-of-origin, analysis of single-cell data sets revealed that the extracellular matrix shaped an alternate route of acinar-ductal transdifferentiation of acinar cells into topoisomerase II α (TOP2A)–overexpressing cancer cells and derived subclusters with copy number amplifications in <em>MYC</em>-<em>PTK2</em> (protein tyrosine kinase 2) locus and <em>PIK3CA</em>. High-PTK2 expression is associated with 171 differentially methylated CpG loci, 319 differentially expressed genes, and poor overall survival in The Cancer Genome Atlas–Pancreatic Adenocarcinoma cohort. Abolished RGD-integrin signaling by disintegrin KG blocked the PTK2 phosphorylation, increased cancer apoptosis, decreased vav guanine nucleotide exchange factor 1 (VAV1) expression, and prolonged overall survival in the <em>KPC</em> mice. Reduction of α-smooth muscle actin deposition in the <em>CD248</em> knockout <em>KPC</em> mice remodeled the tissue stroma and down-regulated TOP2A expression in the epithelium. In summary, stromal stiffness induced the onset of cancer cells-of-origin by ectopic TOP2A expression, and the genomic amplification of <em>MYC</em>-<em>PTK2</em> locus via alternative transdifferentiation of pancreatic progenitor cells is the vulnerability useful for disintegrin KG treatment.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024001329/pdfft?md5=75b1ae0cec2837b760b61024332a46c1&pid=1-s2.0-S0002944024001329-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140791590","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}
Pub Date : 2024-04-09DOI: 10.1016/j.ajpath.2024.03.010
Xinying Li , Sicheng Fu , Hao Cheng , Min Ma , Zijian Song , Jun Li , Shuang Wu , Chong Zhang , Xiaoxia Wang , Maoyu Tang , Xuexue Pu , Qiang Ji , Jinquan Liang , Zhibin Zhao , Heinrich Körner , Bin Li , Min Shao , Hua Wang
Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and retinoic acid receptor–related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (LDHA) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase–LDHA signaling was required for retinoic acid receptor–related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase–LDHA signaling as a driving force in MAIT17 responses.
{"title":"Differentiation of Type 17 Mucosal-Associated Invariant T Cells in Circulation Contributes to the Severity of Sepsis","authors":"Xinying Li , Sicheng Fu , Hao Cheng , Min Ma , Zijian Song , Jun Li , Shuang Wu , Chong Zhang , Xiaoxia Wang , Maoyu Tang , Xuexue Pu , Qiang Ji , Jinquan Liang , Zhibin Zhao , Heinrich Körner , Bin Li , Min Shao , Hua Wang","doi":"10.1016/j.ajpath.2024.03.010","DOIUrl":"10.1016/j.ajpath.2024.03.010","url":null,"abstract":"<div><p>Mucosal-associated invariant T (MAIT) cells are essential in defending against infection. Sepsis is a systemic inflammatory response to infection and a leading cause of death. The relationship between the overall competency of the host immune response and disease severity is not fully elucidated. This study identified a higher proportion of circulating MAIT17 with expression of IL-17A and retinoic acid receptor–related orphan receptor γt in patients with sepsis. The proportion of MAIT17 was correlated with the severity of sepsis. Single-cell RNA-sequencing analysis revealed an enhanced expression of lactate dehydrogenase A (<em>LDHA</em>) in MAIT17 in patients with sepsis. Cell-culture experiments demonstrated that phosphoinositide 3-kinase–LDHA signaling was required for retinoic acid receptor–related orphan receptor γt expression in MAIT17. Finally, the elevated levels of plasma IL-18 promoted the differentiation of circulating MAIT17 cells in sepsis. In summary, this study reveals a new role of circulating MAIT17 in promoting sepsis severity and suggests the phosphoinositide 3-kinase–LDHA signaling as a driving force in MAIT17 responses.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611404","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}
Pub Date : 2024-04-08DOI: 10.1016/j.ajpath.2024.04.001
{"title":"This Month in AJP","authors":"","doi":"10.1016/j.ajpath.2024.04.001","DOIUrl":"10.1016/j.ajpath.2024.04.001","url":null,"abstract":"","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024001263/pdfft?md5=07019add06ac748ee2a7febcd4e502ec&pid=1-s2.0-S0002944024001263-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140773451","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}
Pub Date : 2024-04-06DOI: 10.1016/j.ajpath.2024.03.008
Manasi Kotulkar, Julia Barbee, Diego Paine-Cabrera, Dakota Robarts, Maura O’Neil, Udayan Apte
Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role during liver regeneration. This study investigated the role of the HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. Wild-type (WT), hepatocyte-specific HNF4α-knockout (KO), cMyc-KO, and HNF4α-cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, normal chow diet was fed for 1 week after CDE diet. WT mice exhibited significant liver injury and decreased HNF4α mRNA and protein expression after CDE diet. HNF4α deletion resulted in significantly higher injury with increased inflammation, fibrosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet but indicated similar recovery. Deletion of cMyc lowered liver injury with activation of inflammatory genes compared with WT and HNF4α-KO mice after CDE diet. DKO mice had a phenotype comparable to that of the HNF4α-KO mice after CDE diet and a complete recovery. DKO mice exhibited a significant increase in hepatic progenitor cell markers both after injury and recovery phase. Taken together, these data show that HNF4α protects against inflammatory and fibrotic changes after CDE diet–induced injury, which is driven by cMyc.
{"title":"Role of HNF4α-cMyc Interaction in CDE Diet–Induced Liver Injury and Regeneration","authors":"Manasi Kotulkar, Julia Barbee, Diego Paine-Cabrera, Dakota Robarts, Maura O’Neil, Udayan Apte","doi":"10.1016/j.ajpath.2024.03.008","DOIUrl":"10.1016/j.ajpath.2024.03.008","url":null,"abstract":"<div><p>Hepatocyte nuclear factor 4 alpha (HNF4α) is a nuclear factor essential for liver function that regulates the expression of cMyc and plays an important role during liver regeneration. This study investigated the role of the HNF4α-cMyc interaction in regulating liver injury and regeneration using the choline-deficient and ethionine-supplemented (CDE) diet model. Wild-type (WT), hepatocyte-specific HNF4α-knockout (KO), cMyc-KO, and HNF4α-cMyc double KO (DKO) mice were fed a CDE diet for 1 week to induce subacute liver injury. To study regeneration, normal chow diet was fed for 1 week after CDE diet. WT mice exhibited significant liver injury and decreased HNF4α mRNA and protein expression after CDE diet. HNF4α deletion resulted in significantly higher injury with increased inflammation, fibrosis, proliferation, and hepatic progenitor cell activation compared with WT mice after CDE diet but indicated similar recovery. Deletion of cMyc lowered liver injury with activation of inflammatory genes compared with WT and HNF4α-KO mice after CDE diet. DKO mice had a phenotype comparable to that of the HNF4α-KO mice after CDE diet and a complete recovery. DKO mice exhibited a significant increase in hepatic progenitor cell markers both after injury and recovery phase. Taken together, these data show that HNF4α protects against inflammatory and fibrotic changes after CDE diet–induced injury, which is driven by cMyc.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0002944024001238/pdfft?md5=a21507aac0f2c55c561b5e4c27d767d3&pid=1-s2.0-S0002944024001238-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611400","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}
Pub Date : 2024-04-06DOI: 10.1016/j.ajpath.2024.02.022
Chungsu Hwang , Yun Kyung Kang , Ji Yun Kim , So Hyun Shin , Joon Young Park , Ji Sun Song , So Young Kim , Se Jin Jung , Jung Hee Lee , Ju-Young Na , Dong Hoon Shin , Jee Yeon Kim , Sung Woo Park , Hyun Jung Lee
The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.
{"title":"TFE3/PI3K/Akt/mTOR Axis in Renal Cell Carcinoma Affects Tumor Microenvironment","authors":"Chungsu Hwang , Yun Kyung Kang , Ji Yun Kim , So Hyun Shin , Joon Young Park , Ji Sun Song , So Young Kim , Se Jin Jung , Jung Hee Lee , Ju-Young Na , Dong Hoon Shin , Jee Yeon Kim , Sung Woo Park , Hyun Jung Lee","doi":"10.1016/j.ajpath.2024.02.022","DOIUrl":"10.1016/j.ajpath.2024.02.022","url":null,"abstract":"<div><p>The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611291","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}
Pub Date : 2024-04-06DOI: 10.1016/j.ajpath.2024.03.009
Rushin H. Gindra , Yi Zheng , Emily J. Green , Mary E. Reid , Sarah A. Mazzilli , Daniel T. Merrick , Eric J. Burks , Vijaya B. Kolachalama , Jennifer E. Beane
Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous cell carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. This study followed a novel computational approach, the Graph Perceiver Network, leveraging hematoxylin and eosin–stained whole slide images to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues. The Graph Perceiver Network outperformed existing frameworks in classification accuracy predicting LUSC, lung adenocarcinoma, and nontumor lung tissue on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium datasets containing lung resection tissues while efficiently generating pathologist-aligned, class-specific heatmaps. The network was further tested using endobronchial biopsies from two data cohorts, containing normal to carcinoma in situ histology. It demonstrated a unique capability to differentiate carcinoma in situ lung squamous PMLs based on their progression status to invasive carcinoma. The network may have utility in stratifying PMLs for chemoprevention trials or more aggressive follow-up.
{"title":"Graph Perceiver Network for Lung Tumor and Bronchial Premalignant Lesion Stratification from Histopathology","authors":"Rushin H. Gindra , Yi Zheng , Emily J. Green , Mary E. Reid , Sarah A. Mazzilli , Daniel T. Merrick , Eric J. Burks , Vijaya B. Kolachalama , Jennifer E. Beane","doi":"10.1016/j.ajpath.2024.03.009","DOIUrl":"10.1016/j.ajpath.2024.03.009","url":null,"abstract":"<div><p>Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous cell carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. This study followed a novel computational approach, the Graph Perceiver Network, leveraging hematoxylin and eosin–stained whole slide images to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues. The Graph Perceiver Network outperformed existing frameworks in classification accuracy predicting LUSC, lung adenocarcinoma, and nontumor lung tissue on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium datasets containing lung resection tissues while efficiently generating pathologist-aligned, class-specific heatmaps. The network was further tested using endobronchial biopsies from two data cohorts, containing normal to carcinoma <em>in situ</em> histology. It demonstrated a unique capability to differentiate carcinoma <em>in situ</em> lung squamous PMLs based on their progression status to invasive carcinoma. The network may have utility in stratifying PMLs for chemoprevention trials or more aggressive follow-up.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140611294","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}
Pub Date : 2024-03-26DOI: 10.1016/j.ajpath.2024.03.003
Jiehong Li , Yijian Li , Guanjin Chen , Yan Liang , Jianpeng Xie , Shuiying Zhang , Kai Zhong , Tong Jiang , Haisu Yi , Haixiong Tang , Xin Chen
Acute lung injury (ALI) is a devastating clinical syndrome caused by different factors, with high morbidity and mortality. Lung injury and inflammation caused by lipopolysaccharide (LPS) can be modulated by NLRP3 inflammasome activation, yet its exact function within the airway epithelium is still unknown. Meanwhile, glucose transporter protein 1 (GLUT1) contributes to a number of inflammatory illnesses, including ALI. The present study aimed to assess GLUT1's function in NLRP3 inflammasome activation of airway epithelium in LPS-induced acute lung injury. BALB/c mice and BEAS-2B cells were exposed to LPS (5 mg/kg and 200 μg/mL, respectively), with or without GLUT1 antagonists (WZB117 or BAY876). LPS up-regulated pulmonary expression of NLRP3 and GLUT1 in mice, which could be blocked by WZB117 or BAY876. Pharmacological inhibition of GLUT1 in vivo significantly attenuated lung tissue damage, neutrophil accumulation, and proinflammatory factors release (TNF-α, IL-6, and IL-1β) in LPS-exposed mice. Meanwhile, the activation markers of NLRP3 inflammasome (ASC, caspase-1, IL-1β, and IL-18) induced by LPS were also suppressed. In cultured BEAS-2B cells, LPS induced an increase in GLUT1 expression and triggered activation of the NLRP3 inflammasome, both of which were inhibited by GLUT1 antagonists. These results illustrate that GLUT1 participates in LPS-induced ALI and promotes the activation of the NLRP3 inflammasome in airway epithelial cells.
{"title":"GLUT1 Promotes NLRP3 Inflammasome Activation of Airway Epithelium in Lipopolysaccharide-Induced Acute Lung Injury","authors":"Jiehong Li , Yijian Li , Guanjin Chen , Yan Liang , Jianpeng Xie , Shuiying Zhang , Kai Zhong , Tong Jiang , Haisu Yi , Haixiong Tang , Xin Chen","doi":"10.1016/j.ajpath.2024.03.003","DOIUrl":"10.1016/j.ajpath.2024.03.003","url":null,"abstract":"<div><p>Acute lung injury (ALI) is a devastating clinical syndrome caused by different factors, with high morbidity and mortality. Lung injury and inflammation caused by lipopolysaccharide (LPS) can be modulated by NLRP3 inflammasome activation, yet its exact function within the airway epithelium is still unknown. Meanwhile, glucose transporter protein 1 (GLUT1) contributes to a number of inflammatory illnesses, including ALI. The present study aimed to assess GLUT1's function in NLRP3 inflammasome activation of airway epithelium in LPS-induced acute lung injury. BALB/c mice and BEAS-2B cells were exposed to LPS (5 mg/kg and 200 μg/mL, respectively), with or without GLUT1 antagonists (WZB117 or BAY876). LPS up-regulated pulmonary expression of NLRP3 and GLUT1 in mice, which could be blocked by WZB117 or BAY876. Pharmacological inhibition of GLUT1 <em>in vivo</em> significantly attenuated lung tissue damage, neutrophil accumulation, and proinflammatory factors release (TNF-α, IL-6, and IL-1β) in LPS-exposed mice. Meanwhile, the activation markers of NLRP3 inflammasome (ASC, caspase-1, IL-1β, and IL-18) induced by LPS were also suppressed. In cultured BEAS-2B cells, LPS induced an increase in GLUT1 expression and triggered activation of the NLRP3 inflammasome, both of which were inhibited by GLUT1 antagonists. These results illustrate that GLUT1 participates in LPS-induced ALI and promotes the activation of the NLRP3 inflammasome in airway epithelial cells.</p></div>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317578","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}