Experimental and molecular pathology最新文献

{"title":"Hyperinsulinemic male LEW.1WR1 rats show early signs of impaired liver metabolism","authors":"Madushika Wimalarathne ,&nbsp;Bailey L. Bowser ,&nbsp;Albert B. Arul ,&nbsp;Quiana C. Wilkerson-Vidal ,&nbsp;Moses A. David ,&nbsp;Emily C. Hunt ,&nbsp;Helen Gibson ,&nbsp;Renã A.S. Robinson ,&nbsp;Sharifa T. Love-Rutledge","doi":"10.1016/j.yexmp.2025.104955","DOIUrl":"10.1016/j.yexmp.2025.104955","url":null,"abstract":"<div><div>Weanling LEW.1WR1 (1WR1) rats are susceptible to type 1 diabetes (T1D) and hyperinsulinemic. Similar to human patients with T1D, these animals are susceptible to developing fatty liver infiltrates. Insulin resistance-related steatosis can lead to the development of severe forms of nonalcoholic fatty liver disease (NAFLD). Previous work in 1WR1 rats suggests that in the absence of T1D, they have increased body mass that is not reconciled by measuring their abdominal fat pads; this suggests 1WR1 rats have an underlying predisposition to store fat in the liver unrelated to diabetes status. We hypothesized that 1WR1 rats show early signs of NAFLD development. We assessed proteomics changes in the livers of glucose intolerant and hyperinsulinemic young adult 1WR1 rats to identify early detectable characteristics of NAFLD development.</div><div>Our results show young adult 1WR1 rats have UBD/<em>FAT10</em> gene over expression in the liver. Additionally, they have decreased mitochondrial protein levels, which may lead to lipid accumulation in the liver. A quantitative proteomic analysis showed protein expression related to branch chain fatty acid metabolism, fatty acid beta-oxidation, and oxidative phosphorylation in the liver is significantly different in 1WR1 rats compared to control LEW/SsNHsd (SsNHsd) rats. In summary, our study shows that 1WR1 rats developed early characteristics of mitochondrial dysfunction and insulin resistance in the liver independent of T1D, which are commonly observed with NAFLD development.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"141 ","pages":"Article 104955"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic next-generation sequencing to detect MYD88 L265P in Lymphoplasmacytic lymphoma compared to ddPCR","authors":"Lauren M. Wainman,&nbsp;Guohong Huang,&nbsp;Donald C. Green,&nbsp;Gregory J. Tsongalis,&nbsp;Laura J. Tafe,&nbsp;Wahab A. Khan,&nbsp;Prabhjot Kaur,&nbsp;Parth S. Shah ,&nbsp;Jeremiah X. Karrs","doi":"10.1016/j.yexmp.2025.104956","DOIUrl":"10.1016/j.yexmp.2025.104956","url":null,"abstract":"<div><div>Lymphoplasmacytic lymphoma (LPL) is a B-cell lymphoproliferative disorder typically involving the bone marrow with infiltration by small lymphocytes and plasma cells. Studies have identified MYD88 L265P mutation as a diagnostic marker to distinguish LPL from other small B-cell lymphomas. Detection rates for this mutation have varied depending on the analytic methodology, with previous data suggesting that routine next-generation sequencing (NGS) does not demonstrate the required sensitivity to reliably detect MYD88 L265P. NGS has become part of routine clinical testing because it allows detection of variants across multiple genes. To study the utility of NGS in the detection of MYD88 L265P, we performed droplet digital PCR (ddPCR) and routine NGS on a cohort of 34 cases of lymphoid neoplasms (22 LPL, 4 CLL, 1 MCL, 1 MGUS, 2 plasma cell myeloma, and 4 negative bone marrow cases). We utilized manual review and BAMtools to assess MYD88 L265P in NGS cases. Limit of detection for ddPCR was determined to be 0.4 % variant allele frequency (VAF) with 10 ng DNA input. MYD88 L265P VAF detection by NGS and ddPCR was comparable down to 0.5 % VAF (R² = 0.968). Setting an appropriate threshold for detection based on ddPCR results resulted in zero NGS false positives. We found that low tumor content did not impact the detection of MYD88 L265P by NGS. This study demonstrates that NGS can be a sensitive and reliable method for detection of MYD88 L265P with adequate coverage and specific assessment parameters.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"141 ","pages":"Article 104956"},"PeriodicalIF":2.8,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of concern: “1,25-Dihydroxyvitamin D3 enhances neural stem cell proliferation and oligodendrocyte differentiation” [Experimental and Molecular Pathology 98 (2015) 240–245]","authors":"","doi":"","DOIUrl":"","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"144 ","pages":"Article 104985"},"PeriodicalIF":3.7,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145747072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico analysis unveils rs2109069 of DPP9 as a potential catalyst for COVID-19 severity and risk of inflammatory symptoms","authors":"Chi-Ying Lee ,&nbsp;Zih-Yin Lai ,&nbsp;Yung-Jen Chuang","doi":"10.1016/j.yexmp.2024.104946","DOIUrl":"10.1016/j.yexmp.2024.104946","url":null,"abstract":"<div><h3>Background</h3><div>During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits.</div></div><div><h3>Methods</h3><div>We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (<em>DPP9</em>), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the <em>DPP9</em> expression patterns in selected organs, including the lungs, blood vessels, and skin.</div></div><div><h3>Results</h3><div><em>In silico</em> analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients.</div></div><div><h3>Conclusions</h3><div>Our <em>in silico</em> findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104946"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142744210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic criteria and therapeutic implications of rapid-onset demyelinating polyneuropathies","authors":"Wiktoria Rałowska-Gmoch ,&nbsp;Magdalena Koszewicz ,&nbsp;Beata Łabuz-Roszak ,&nbsp;Sławomir Budrewicz ,&nbsp;Edyta Dziadkowiak","doi":"10.1016/j.yexmp.2024.104942","DOIUrl":"10.1016/j.yexmp.2024.104942","url":null,"abstract":"<div><div>Guillain-Barré syndrome (GBS) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are the most common autoimmune polyneuropathies. Their aetiology is unclear. The pathomechanism includes damage mainly to the myelin sheath and, in the long-term process, secondary axonal loss. Both inflammatory polyneuropathies involve different combinations of motor, sensory and autonomic fibres in the peripheral nerves. The differential diagnosis should be based on clinical and neurophysiological features, and laboratory tests. Numerous studies aim to demonstrate the most common errors in the diagnosis of Guillain-Barré syndrome and acute-onset CIDP. Misdiagnosis can result in the wrong treatment. We still do not have reliable markers to help diagnose the disease or to monitor the effectiveness of the therapy.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104942"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142579061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired immunoproteasomal function exacerbates renal ischemia-reperfusion injury","authors":"Yasushi Ishii ,&nbsp;Aya Fukui-Miyazaki ,&nbsp;Sari Iwasaki ,&nbsp;Takahiro Tsuji ,&nbsp;Kiyohiko Hotta ,&nbsp;Hajime Sasaki ,&nbsp;Shimpei Nakagawa ,&nbsp;Takuma Yoshida ,&nbsp;Eri Murata ,&nbsp;Koji Taniguchi ,&nbsp;Nobuo Shinohara ,&nbsp;Akihiro Ishizu ,&nbsp;Masanori Kasahara ,&nbsp;Utano Tomaru","doi":"10.1016/j.yexmp.2024.104939","DOIUrl":"10.1016/j.yexmp.2024.104939","url":null,"abstract":"<div><div>Oxidative stress caused by reactive oxygen species (ROS) is involved in the pathogenesis of renal ischemia-reperfusion injury (I/R injury), a major cause of acute kidney injury and delayed graft function (DGF). DGF is an early transplant complication that worsens graft prognosis and patient survival, but the underlying molecular changes are unclear. The proteasome is a multicatalytic enzyme complex that degrades both normal and damaged proteins, and recent studies have revealed that the immunoproteasome, a specific proteasome isoform whose proteolytic activity enhances the generation of antigenic peptides, plays critical roles in the cellular response against oxidative stress. In this study, we demonstrate the impact of the immunoproteasome in human DGF and in a mouse model of I/R injury. In patients with DGF, the expression of β5i, a specific immunoproteasome subunit, was decreased in vascular endothelial cells. In a mouse model, β5i knockout (KO) exacerbated renal I/R injury. KO mice showed greater inflammation, oxidative stress, and endothelial damage compared with wild-type mice. Impaired immunoproteasomal activity also caused increased cell death, ROS production, and expression of inflammatory factors in mouse renal vascular endothelial cells under conditions of hypoxia and reoxygenation. In conclusion, reduced expression of the immunoproteasomal catalytic subunit β5i exacerbates renal I/R injury in vivo, potentially increasing the risk of DGF. Further research targeting β5i expression in DGF could lead to the development of novel therapeutic strategies and biomarkers.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104939"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142461419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A weighted and cumulative point system for accurate scoring of intestinal pathology in a piglet model of necrotizing enterocolitis","authors":"Simone Margaard Offersen,&nbsp;Nicole Lind Henriksen,&nbsp;Anders Brunse","doi":"10.1016/j.yexmp.2024.104936","DOIUrl":"10.1016/j.yexmp.2024.104936","url":null,"abstract":"<div><div>Necrotizing enterocolitis (NEC) is a serious condition in premature infants, in which a portion of the intestine undergoes inflammation and necrosis. The preterm pig develops NEC spontaneously, making it a suitable model for exploring novel NEC treatments. We aimed to revise the intestinal scoring system to more accurately describe the diversity of NEC lesions in the preterm piglet model. We included 333 preterm piglets from four experiments, each delivered via cesarean section. The piglets were fed either a gently processed (GP) or harshly processed (HP) milk formula for 96 h before euthanasia. At necropsy, the gastrointestinal tract was assessed with 1) an established 6-grade score and 2) a descriptive approach focusing on the distribution and severity of hyperemia, hemorrhage, pneumatosis intestinalis (intramural gas), and necrosis. Subsequently, the descriptive registrations were converted into a weighted and cumulative point (WCP) score. Compared to the 6-grade score, the WCP score enabled a greater segregation of severity levels, especially among organs with more prominent NEC lesions. IL-1β in small intestinal lesions and both IL-8 and IL-1β in colon lesions correlated positively with the WCP scale. A histopathological grade system (0–8) was established and revealed mucosal pathology in lesion biopsies, which were not recognized macroscopically. Finally, the WCP score showed a higher NEC-promoting effect of the HP formula compared to the GP formula. The descriptive registrations and extended score range of this revised intestinal scoring system enhance the accuracy of describing NEC lesions in preterm pigs. This approach may increase the efficiency of preclinical NEC experiments.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104936"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Facilitating cholangiocarcinoma inhibition by targeting CD47","authors":"Kulthida Vaeteewoottacharn ,&nbsp;Sakda Waraasawapati ,&nbsp;Phattarin Pothipan ,&nbsp;Ryusho Kariya ,&nbsp;Saowaluk Saisomboon ,&nbsp;Supawadee Bunthot ,&nbsp;Chawalit Pairojkul ,&nbsp;Kanlayanee Sawanyawisuth ,&nbsp;Kazuhiko Kuwahara ,&nbsp;Sopit Wongkham ,&nbsp;Seiji Okada","doi":"10.1016/j.yexmp.2024.104935","DOIUrl":"10.1016/j.yexmp.2024.104935","url":null,"abstract":"<div><div>Immune evasion is one of the mechanisms by which cancer cells acquire immunity during cancer development and progression. One of these is the increased expression of cluster of differentiation 47 (CD47), a transmembrane glycoprotein that protects cells from phagocytic elimination. The interaction between CD47 and signal regulatory protein alpha (SIRPα) on macrophages alleviates the phagocytic signal. The present group previously reported high CD47 expression in cholangiocarcinoma (CCA), a major health problem in Thailand and East Asia, and that blocking CD47 using anti-CD47 antibodies promoted the removal of CCA. However, the mechanism through which CD47 inhibition attenuates CCA growth remains unclear. This study explored the clinical significance of targeting CD47 in CCA. Expression levels of CD47 and the macrophage marker CD68 were determined in CCA tissues by immunohistochemistry and correlated with clinical parameters. The role of CD47 in CCA cells was established using CD47-deficient KKU-213A CCA clones <em>in vitro</em> and <em>in vivo</em>. The results showed that CD47 was highly expressed in CCA tissues and significantly correlated with lymph node metastasis (<em>P</em> = 0.038). Moderate-to-dense CD68-positive infiltrating cells in CCA tissues were significantly associated with shorter survival of patients (<em>P</em> = 0.019) and were an independent prognostic factor of CCA patients as determined by the Cox proportional hazard model (hazard ratio, 2.040; 95 % confidence interval, 1.109–3.752; <em>P</em> = 0.022). Three CD47-deficient KKU-213A clones (#19, #23, and #28) were generated. The elimination of CD47 did not affect cell proliferation but increased monocyte-derived macrophage-mediated phagocytosis <em>in vitro</em>. Decreased tumor weights and volumes were observed in mice injected with CD47-deficient CCA clones. This revealed a significant role for CD47 in CCA, with a focus on protecting cancer cells from macrophage phagocytosis.</div></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104935"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of different hypoxia exposure on myeloid-derived suppressor cells in mice","authors":"Qiying Xu ,&nbsp;Huifang Liu ,&nbsp;Yi Ye ,&nbsp;Tana Wuren ,&nbsp;Ri-li Ge","doi":"10.1016/j.yexmp.2024.104932","DOIUrl":"10.1016/j.yexmp.2024.104932","url":null,"abstract":"<div><p>For many people living at high altitudes for long or short periods of time, hypoxia is a challenge affecting many aspects of the body, including the immune system. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population that plays an important role in several pathological conditions. However, to the best of our knowledge, there are no data regarding the behavior of MDSCs under hypoxic conditions. Therefore, the aim of this study is to investigate the monocytic type (M)- and polymorphonuclear type (PMN)-MDSC ratios in different hypoxic conditions to reveal the relationship between MDSCs and high-altitude hypoxia, as well as to determine whether MDSCs are involved in the regulation of the immune balance under hypoxic conditions as immunosuppressive factors. For the first time, we showed that MDSC abundance varies under different lengths of hypoxic exposure. We found that acute normobaric hypoxia led to an initial increase in the number of M-MDSCs, which decreased within 30 d. Both M- and PMN-MDSC ratios initially decreased under hypobaric hypoxia conditions within 30 d, but after 6 months in the real high altitude environment, M-MDSC ratio increased significantly. In summary, our data suggest that different hypoxic conditions influence MDSCs in mice, thereby contributing to a better understanding of the process of hypoxia adaptation and the occurrence and development of high-altitude disease.</p></div>","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104932"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0014480024000510/pdfft?md5=c5e549c6d163acc2324d446f43910611&pid=1-s2.0-S0014480024000510-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Irisin and neuroinflammation: Challenges and opportunities” [Experimental and Molecular Pathology 140 (2024) 104941]","authors":"Erika Yolanda Hernández Sandoval,&nbsp;Zulma Dueñas","doi":"10.1016/j.yexmp.2024.104943","DOIUrl":"10.1016/j.yexmp.2024.104943","url":null,"abstract":"","PeriodicalId":12176,"journal":{"name":"Experimental and molecular pathology","volume":"140 ","pages":"Article 104943"},"PeriodicalIF":2.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}