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Development of a Caco-2-based intestinal mucosal model to study intestinal barrier properties and bacteria-mucus interactions.
IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-23 DOI: 10.1080/19490976.2024.2434685
Evelien Floor, Jinyi Su, Maitrayee Chatterjee, Elise S Kuipers, Noortje IJssennagger, Faranak Heidari, Laura Giordano, Richard W Wubbolts, Silvia M Mihăilă, Daphne A C Stapels, Yvonne Vercoulen, Karin Strijbis

The intestinal mucosal barrier is a dynamic system that allows nutrient uptake, stimulates healthy microbe-host interactions, and prevents invasion by pathogens. The mucosa consists of epithelial cells connected by cellular junctions that regulate the passage of nutrients covered by a mucus layer that plays an important role in host-microbiome interactions. Mimicking the intestinal mucosa for in vitro assays, particularly the generation of a mucus layer, has proven to be challenging. The intestinal cell-line Caco-2 is widely used in academic and industrial laboratories due to its capacity to polarize, form an apical brush border, and reproducibly grow into confluent cell layers in different culture systems. However, under normal culture conditions, Caco-2 cultures lack a mucus layer. Here, we demonstrate for the first time that Caco-2 cultures can form a robust mucus layer when cultured under air-liquid interface (ALI) conditions on Transwell inserts with addition of vasointestinal peptide (VIP) in the basolateral compartment. We demonstrate that unique gene clusters are regulated in response to ALI and VIP single stimuli, but the ALI-VIP combination treatment resulted in a significant upregulation of multiple mucin genes and proteins, including secreted MUC2 and transmembrane mucins MUC13 and MUC17. Expression of tight junction proteins was significantly altered in the ALI-VIP condition, leading to increased permeability to small molecules. Commensal Lactiplantibacillus plantarum bacteria closely associated with the Caco-2 mucus layer and differentially colonized the surface of the ALI cultures. Pathogenic Salmonella enterica were capable of invading beyond the mucus layer and brush border. In conclusion, Caco-2 ALI-VIP cultures provide an accessible and straightforward way to culture an in vitro intestinal mucosal model with improved biomimetic features. This novel in vitro intestinal model can facilitate studies into mucus and epithelial barrier functions and in-depth molecular characterization of pathogenic and commensal microbe-mucus interactions.

{"title":"Development of a Caco-2-based intestinal mucosal model to study intestinal barrier properties and bacteria-mucus interactions.","authors":"Evelien Floor, Jinyi Su, Maitrayee Chatterjee, Elise S Kuipers, Noortje IJssennagger, Faranak Heidari, Laura Giordano, Richard W Wubbolts, Silvia M Mihăilă, Daphne A C Stapels, Yvonne Vercoulen, Karin Strijbis","doi":"10.1080/19490976.2024.2434685","DOIUrl":"https://doi.org/10.1080/19490976.2024.2434685","url":null,"abstract":"<p><p>The intestinal mucosal barrier is a dynamic system that allows nutrient uptake, stimulates healthy microbe-host interactions, and prevents invasion by pathogens. The mucosa consists of epithelial cells connected by cellular junctions that regulate the passage of nutrients covered by a mucus layer that plays an important role in host-microbiome interactions. Mimicking the intestinal mucosa for <i>in vitro</i> assays, particularly the generation of a mucus layer, has proven to be challenging. The intestinal cell-line Caco-2 is widely used in academic and industrial laboratories due to its capacity to polarize, form an apical brush border, and reproducibly grow into confluent cell layers in different culture systems. However, under normal culture conditions, Caco-2 cultures lack a mucus layer. Here, we demonstrate for the first time that Caco-2 cultures can form a robust mucus layer when cultured under air-liquid interface (ALI) conditions on Transwell inserts with addition of vasointestinal peptide (VIP) in the basolateral compartment. We demonstrate that unique gene clusters are regulated in response to ALI and VIP single stimuli, but the ALI-VIP combination treatment resulted in a significant upregulation of multiple mucin genes and proteins, including secreted MUC2 and transmembrane mucins MUC13 and MUC17. Expression of tight junction proteins was significantly altered in the ALI-VIP condition, leading to increased permeability to small molecules. Commensal <i>Lactiplantibacillus plantarum</i> bacteria closely associated with the Caco-2 mucus layer and differentially colonized the surface of the ALI cultures. Pathogenic <i>Salmonella enterica</i> were capable of invading beyond the mucus layer and brush border. In conclusion, Caco-2 ALI-VIP cultures provide an accessible and straightforward way to culture an <i>in vitro</i> intestinal mucosal model with improved biomimetic features. This novel <i>in vitro</i> intestinal model can facilitate studies into mucus and epithelial barrier functions and in-depth molecular characterization of pathogenic and commensal microbe-mucus interactions.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2434685"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Impact of liquid-liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH2.
IF 2 4区 医学 Q3 HEMATOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-23 DOI: 10.1080/16078454.2024.2445403
Fengming Wang, Chuyun Shen

Objective: Liquid-liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and to confirm their effects on tumor progression.

Methods: Based on public transcriptomic data, this study screened LLPS- and immune-related genes for MM-derived plasma cells. Subtypes were identified using consensus clustering, followed by comparisons using t-test and survival analysis. Least absolute shrinkage and selection operator was implemented to screen prognostic signatures, and Kaplan-Meier and receiver operator characteristic curves were plotted to assess their prognostic values. After transfected with sh-DDX21, CCK8, flow cytometry, and Transwells were used to observe MM cell proliferation, apoptosis, migration, and invasion.

Results: By overlapping LLPS- and immune-related genes, 103 genes were obtained to cluster MM samples into three subtypes, which had significant differences in survival and immune landscape. Cox regression analysis screened out EZH2 and DDX21 that significantly overexpressed in MM to construct a prognostic model, with superior performance in predicting MM prognostic risks. Notably, subtype2 with more adverse prognosis showed significantly elevated risk scores and was more distributed in groups with high prognostic risk. In vitro experiments confirmed that cell proliferation, invasion, and migration were significantly inhibited in MM.1S cells transfected with sh-DDX21.

Conclusion: LLPS-related EZH2 and DDX21 were novel markers to predict prognostic risk of MM. Among them, DDX21 was experimentally confirmed to promote MM cell proliferation, migration and invasion. These potential prognostic markers could be targeted in future personalized therapeutic strategies for MM, potentially improving patient outcomes.

{"title":"Impact of liquid-liquid phase separation- and immune-related gene signatures on multiple myeloma prognosis: focus on DDX21 and EZH2.","authors":"Fengming Wang, Chuyun Shen","doi":"10.1080/16078454.2024.2445403","DOIUrl":"https://doi.org/10.1080/16078454.2024.2445403","url":null,"abstract":"<p><strong>Objective: </strong>Liquid-liquid phase separation (LLPS) may affect the therapeutic sensitivity of multiple myeloma (MM). This study aimed to identify LLPS-related genes with MM prognostic values and to confirm their effects on tumor progression.</p><p><strong>Methods: </strong>Based on public transcriptomic data, this study screened LLPS- and immune-related genes for MM-derived plasma cells. Subtypes were identified using consensus clustering, followed by comparisons using <i>t</i>-test and survival analysis. Least absolute shrinkage and selection operator was implemented to screen prognostic signatures, and Kaplan-Meier and receiver operator characteristic curves were plotted to assess their prognostic values. After transfected with sh-DDX21, CCK8, flow cytometry, and Transwells were used to observe MM cell proliferation, apoptosis, migration, and invasion.</p><p><strong>Results: </strong>By overlapping LLPS- and immune-related genes, 103 genes were obtained to cluster MM samples into three subtypes, which had significant differences in survival and immune landscape. Cox regression analysis screened out <i>EZH2</i> and <i>DDX21</i> that significantly overexpressed in MM to construct a prognostic model, with superior performance in predicting MM prognostic risks. Notably, subtype2 with more adverse prognosis showed significantly elevated risk scores and was more distributed in groups with high prognostic risk. <i>In vitro</i> experiments confirmed that cell proliferation, invasion, and migration were significantly inhibited in MM.1S cells transfected with sh-DDX21.</p><p><strong>Conclusion: </strong>LLPS-related <i>EZH2</i> and <i>DDX21</i> were novel markers to predict prognostic risk of MM. Among them, <i>DDX21</i> was experimentally confirmed to promote MM cell proliferation, migration and invasion. These potential prognostic markers could be targeted in future personalized therapeutic strategies for MM, potentially improving patient outcomes.</p>","PeriodicalId":13161,"journal":{"name":"Hematology","volume":"30 1","pages":"2445403"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876379","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}
引用次数: 0
Clinical characteristics and prognostic analysis of CDKN2A/2B gene in pediatric acute lymphoblastic leukemia: a retrospective case-control study. 小儿急性淋巴细胞白血病 CDKN2A/2B 基因的临床特征和预后分析:一项回顾性病例对照研究。
IF 2 4区 医学 Q3 HEMATOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-15 DOI: 10.1080/16078454.2024.2439606
Shi-Mei Huang, Hui-Qin Chen, Li-Ting Liu, Ya-Ting Zhang, Jian Wang, Dun-Hua Zhou, Jian-Pei Fang, Lu-Hong Xu

In this retrospective case-control study involving 424 pediatric patients diagnosed with Pediatric Acute Lymphoblastic Leukemia (ALL), the investigation focused on analyzing the clinical characteristics and prognosis associated with the Cyclin-dependent kinase inhibitor 2A/2B (CDKN2A/2B) gene. Treatment and evaluation followed the South China Children's Leukemia Group-ALL-2016 protocol (SCCLG-ALL-2016). Among the cohort, 92 patients (21.7%) exhibited CDKN2A/2B gene deletions, with 11.1% homozygous and 10.6% heterozygous deletions. Notably, ALL patients that do have CDKN2A/2B gene deletions tended to present at an older age (P = 0.001), demonstrate hepatosplenomegaly on palpation (P < 0.001), and exhibit a higher incidence of Central nervous system leukemia (CNSL) (P = 0.037) and T-ALL (P = 0.007). A significant correlation was observed between ALL that does have CDKN2A/2B gene deletions and ETV6::RUNX1-positive (8.7% vs. 19.3%, P = 0.017) and IKZF1 gene deletions (20.7% vs. 8.4%, P = 0.001). Survival analysis of 392 patients revealed no significant differences in 5-year relapse, Overall survival (OS), or Event-free survival (EFS) between ALL that does/ does not have CDKN2A/2B gene deletions. Subgroup analysis highlighted poorer prognosis among hepatosplenomegaly patients in the CDKN2A/2B gene deletion group, with a 5-year EFS of 81.8%, 95%CI (0.695-0.963), P = 0.05. Hepatosplenomegaly emerged as the most significant prognostic factor for EFS [HR = 2.306, 95%CI (1.192-4.461), P = 0.013]. Cox regression analyses identified covariates influencing prognosis, ALL with the CDKN2A/2B gene showing no significant impact on outcomes. In conclusion, while ALL that does have CDKN2A/2B gene deletions is associated with certain clinical characteristics and genetic aberrations, they did not significantly impact OS or EFS. Furthermore, subgroup analysis revealed a potential prognostic role of ALL that does have CDKN2A/2B deletions presenting with hepatosplenomegaly on palpation, emphasizing the importance of comprehensive risk stratification in treatment decision-making for this subgroup.

在这项涉及424名确诊为小儿急性淋巴细胞白血病(ALL)的儿童患者的回顾性病例对照研究中,调查的重点是分析与细胞周期蛋白依赖性激酶抑制剂2A/2B(CDKN2A/2B)基因相关的临床特征和预后。治疗和评估遵循华南儿童白血病组-ALL-2016方案(SCCLG-ALL-2016)。组群中有92名患者(21.7%)出现CDKN2A/2B基因缺失,其中11.1%为同源缺失,10.6%为杂合缺失。值得注意的是,CDKN2A/2B基因缺失的ALL患者往往发病年龄较大(P = 0.001),触诊时表现为肝脾肿大(P P = 0.037)和T-ALL(P = 0.007)。CDKN2A/2B基因缺失的ALL与ETV6::RUNX1阳性(8.7% vs. 19.3%,P = 0.017)和IKZF1基因缺失(20.7% vs. 8.4%,P = 0.001)之间存在明显相关性。对392名患者进行的生存分析表明,有/无CDKN2A/2B基因缺失的ALL患者在5年复发率、总生存率(OS)或无事件生存率(EFS)方面无明显差异。亚组分析显示,CDKN2A/2B基因缺失组肝脾肿大患者的预后较差,5年无事件生存率为81.8%,95%CI (0.695-0.963),P = 0.05。肝脾肿大是影响 EFS 的最重要预后因素[HR = 2.306,95%CI (1.192-4.461),P = 0.013]。Cox回归分析确定了影响预后的协变量,带有CDKN2A/2B基因的ALL对预后无显著影响。总之,虽然CDKN2A/2B基因缺失的ALL与某些临床特征和遗传畸变有关,但它们对OS或EFS没有显著影响。此外,亚组分析表明,CDKN2A/2B基因缺失的ALL患者在触诊时出现肝脾肿大可能对预后有影响,这强调了在对这一亚组患者进行治疗决策时进行全面风险分层的重要性。
{"title":"Clinical characteristics and prognostic analysis of <i>CDKN2A/2B</i> gene in pediatric acute lymphoblastic leukemia: a retrospective case-control study.","authors":"Shi-Mei Huang, Hui-Qin Chen, Li-Ting Liu, Ya-Ting Zhang, Jian Wang, Dun-Hua Zhou, Jian-Pei Fang, Lu-Hong Xu","doi":"10.1080/16078454.2024.2439606","DOIUrl":"https://doi.org/10.1080/16078454.2024.2439606","url":null,"abstract":"<p><p>In this retrospective case-control study involving 424 pediatric patients diagnosed with Pediatric Acute Lymphoblastic Leukemia (ALL), the investigation focused on analyzing the clinical characteristics and prognosis associated with the Cyclin-dependent kinase inhibitor 2A/2B (<i>CDKN2A/2B</i>) gene. Treatment and evaluation followed the South China Children's Leukemia Group-ALL-2016 protocol (SCCLG-ALL-2016). Among the cohort, 92 patients (21.7%) exhibited <i>CDKN2A/2B</i> gene deletions, with 11.1% homozygous and 10.6% heterozygous deletions. Notably, ALL patients that do have <i>CDKN2A/2B</i> gene deletions tended to present at an older age (<i>P </i>= 0.001), demonstrate hepatosplenomegaly on palpation (<i>P </i>< 0.001), and exhibit a higher incidence of Central nervous system leukemia (CNSL) (<i>P </i>= 0.037) and T-ALL (<i>P </i>= 0.007). A significant correlation was observed between ALL that does have <i>CDKN2A/2B</i> gene deletions and <i>ETV6::RUNX1-positive</i> (8.7% vs. 19.3%, <i>P </i>= 0.017) and <i>IKZF1</i> gene deletions (20.7% vs. 8.4%, <i>P </i>= 0.001). Survival analysis of 392 patients revealed no significant differences in 5-year relapse, Overall survival (OS), or Event-free survival (EFS) between ALL that does/ does not have <i>CDKN2A/2B</i> gene deletions. Subgroup analysis highlighted poorer prognosis among hepatosplenomegaly patients in the <i>CDKN2A/2B</i> gene deletion group, with a 5-year EFS of 81.8%, 95%CI (0.695-0.963), <i>P </i>= 0.05. Hepatosplenomegaly emerged as the most significant prognostic factor for EFS [HR = 2.306, 95%CI (1.192-4.461), <i>P </i>= 0.013]. Cox regression analyses identified covariates influencing prognosis, ALL with the <i>CDKN2A/2B</i> gene showing no significant impact on outcomes. In conclusion, while ALL that does have <i>CDKN2A/2B</i> gene deletions is associated with certain clinical characteristics and genetic aberrations, they did not significantly impact OS or EFS. Furthermore, subgroup analysis revealed a potential prognostic role of ALL that does have <i>CDKN2A/2B</i> deletions presenting with hepatosplenomegaly on palpation, emphasizing the importance of comprehensive risk stratification in treatment decision-making for this subgroup.</p>","PeriodicalId":13161,"journal":{"name":"Hematology","volume":"30 1","pages":"2439606"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828387","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}
引用次数: 0
Causal associations of metabolic dysfunction-associated steatotic liver disease with gestational hypertension and preeclampsia: a two-sample Mendelian randomization study.
IF 1.5 4区 医学 Q3 OBSTETRICS & GYNECOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-20 DOI: 10.1080/10641955.2024.2441862
Lu Zhang, Liang Fang, Jiahua Zou, Dong Zhou, Haonan Xie, Aihua Chen, Qingming Wu

Background: Hypertensive disorders of pregnancy (HDPs), which include gestational hypertension (GH) and preeclampsia (PE), are the primary causes of maternal morbidity and mortality worldwide. Recent studies have found a correlation between metabolic dysfunction-associated steatotic liver disease (MASLD) and HDPs, but the causality of this association remains to be identified. Therefore, this study aims to evaluate the causal relationship between MASLD and HDPs through Mendelian randomization (MR) analysis.

Methods: The summary statistics from genome-wide association studies were employed to conduct a two-sample MR analysis. Five complementary MR methods, including inverse variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode were performed to assess the causality of MASLD on GH and PE. Furthermore, we conducted various sensitivity analyses to ensure the stability and reliability of the results.

Results: Genetically predicted MASLD significantly increased the risk of GH (IVW: OR = 1.138, 95% CI: 1.062-1.220, p < 0.001), while there was little evidence of a causal relationship between MASLD and PE (IVW: OR = 0.980, 95% CI: 0.910-1.056, p = 0.594). The sensitivity analyses indicated no presence of heterogeneity and horizontal pleiotropy.

Conclusion: This MR study provided evidence supporting the causal effect of MASLD on GH. Our findings underscore the significance of providing more intensive prenatal care and early intervention for pregnant women with MASLD to prevent potential adverse obstetric outcomes.

{"title":"Causal associations of metabolic dysfunction-associated steatotic liver disease with gestational hypertension and preeclampsia: a two-sample Mendelian randomization study.","authors":"Lu Zhang, Liang Fang, Jiahua Zou, Dong Zhou, Haonan Xie, Aihua Chen, Qingming Wu","doi":"10.1080/10641955.2024.2441862","DOIUrl":"https://doi.org/10.1080/10641955.2024.2441862","url":null,"abstract":"<p><strong>Background: </strong>Hypertensive disorders of pregnancy (HDPs), which include gestational hypertension (GH) and preeclampsia (PE), are the primary causes of maternal morbidity and mortality worldwide. Recent studies have found a correlation between metabolic dysfunction-associated steatotic liver disease (MASLD) and HDPs, but the causality of this association remains to be identified. Therefore, this study aims to evaluate the causal relationship between MASLD and HDPs through Mendelian randomization (MR) analysis.</p><p><strong>Methods: </strong>The summary statistics from genome-wide association studies were employed to conduct a two-sample MR analysis. Five complementary MR methods, including inverse variance weighting (IVW), MR-Egger, weighted median, simple mode and weighted mode were performed to assess the causality of MASLD on GH and PE. Furthermore, we conducted various sensitivity analyses to ensure the stability and reliability of the results.</p><p><strong>Results: </strong>Genetically predicted MASLD significantly increased the risk of GH (IVW: OR = 1.138, 95% CI: 1.062-1.220, <i>p</i> < 0.001), while there was little evidence of a causal relationship between MASLD and PE (IVW: OR = 0.980, 95% CI: 0.910-1.056, <i>p</i> = 0.594). The sensitivity analyses indicated no presence of heterogeneity and horizontal pleiotropy.</p><p><strong>Conclusion: </strong>This MR study provided evidence supporting the causal effect of MASLD on GH. Our findings underscore the significance of providing more intensive prenatal care and early intervention for pregnant women with MASLD to prevent potential adverse obstetric outcomes.</p>","PeriodicalId":13054,"journal":{"name":"Hypertension in Pregnancy","volume":"44 1","pages":"2441862"},"PeriodicalIF":1.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142864080","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}
引用次数: 0
Desulfovibrio vulgaris flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway.
IF 12.2 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-24 DOI: 10.1080/19490976.2024.2446376
Yue Dong, Fanyi Meng, Jingyi Wang, Jingge Wei, Kexin Zhang, Siqi Qin, Mengfan Li, Fucheng Wang, Bangmao Wang, Tianyu Liu, Weilong Zhong, Hailong Cao

The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. Desulfovibrio vulgaris (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found Desulfovibrio was abundant in high-fat diet-induced Apcmin/+ mice, and DSV, a member of Desulfovibrio, triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that D. vulgaris flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.

{"title":"<i>Desulfovibrio vulgaris</i> flagellin exacerbates colorectal cancer through activating LRRC19/TRAF6/TAK1 pathway.","authors":"Yue Dong, Fanyi Meng, Jingyi Wang, Jingge Wei, Kexin Zhang, Siqi Qin, Mengfan Li, Fucheng Wang, Bangmao Wang, Tianyu Liu, Weilong Zhong, Hailong Cao","doi":"10.1080/19490976.2024.2446376","DOIUrl":"https://doi.org/10.1080/19490976.2024.2446376","url":null,"abstract":"<p><p>The initiation and progression of colorectal cancer (CRC) are intimately associated with genetic, environmental and biological factors. <i>Desulfovibrio vulgaris</i> (DSV), a sulfate-reducing bacterium, has been found excessive growth in CRC patients, suggesting a potential role in carcinogenesis. However, the precise mechanisms underlying this association remain incompletely understood. We have found <i>Desulfovibrio</i> was abundant in high-fat diet-induced <i>Apc</i><sup><i>min/+</i></sup> mice, and DSV, a member of <i>Desulfovibrio</i>, triggered colonocyte proliferation of germ-free mice. Furthermore, the level of DSV progressively rose from healthy individuals to CRC patients. Flagella are important accessory structures of bacteria, which can help them colonize and enhance their invasive ability. We found that <i>D. vulgaris</i> flagellin (DVF) drove the proliferation, migration, and invasion of CRC cells and fostered the growth of CRC xenografts. DVF enriched the epithelial-mesenchymal transition (EMT)-associated genes and characterized the facilitation of DVF on EMT. Mechanistically, DVF induced EMT through a functional transmembrane receptor called leucine-rich repeat containing 19 (LRRC19). DVF interacted with LRRC19 to modulate the ubiquitination of tumor necrosis factor receptor-associated factor (TRAF)6, rather than TRAF2. This interaction drove the ubiquitination of pivotal molecule TAK1, further enhancing its autophosphorylation and ultimately contributing to EMT. Collectively, DVF interacts with LRRC19 to activate the TRAF6/TAK1 signaling pathway, thereby promoting the EMT of CRC. These data shed new light on the role of gut microbiota in CRC and establish a potential clinical therapeutic target.</p>","PeriodicalId":12909,"journal":{"name":"Gut Microbes","volume":"17 1","pages":"2446376"},"PeriodicalIF":12.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142881946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 immune checkpoint LAG-3 is expressed by melanoma cells and correlates with clinical progression of the melanoma.
IF 6.5 2区 医学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-24 DOI: 10.1080/2162402X.2024.2430066
Melanie Wiecken, Devayani Machiraju, Shounak Chakraborty, Eva-Maria Mayr, Bénédicte Lenoir, Rosa Eurich, Jasmin Richter, Nicole Pfarr, Niels Halama, Jessica C Hassel

Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage (p < 0.001) and previous exposure to immune checkpoint inhibitors (p = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival (p = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival (p = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.

{"title":"The immune checkpoint LAG-3 is expressed by melanoma cells and correlates with clinical progression of the melanoma.","authors":"Melanie Wiecken, Devayani Machiraju, Shounak Chakraborty, Eva-Maria Mayr, Bénédicte Lenoir, Rosa Eurich, Jasmin Richter, Nicole Pfarr, Niels Halama, Jessica C Hassel","doi":"10.1080/2162402X.2024.2430066","DOIUrl":"https://doi.org/10.1080/2162402X.2024.2430066","url":null,"abstract":"<p><p>Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage (<i>p</i> < 0.001) and previous exposure to immune checkpoint inhibitors (<i>p</i> = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival (<i>p</i> = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival (<i>p</i> = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"14 1","pages":"2430066"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142883141","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 westward spread dynamics of cholera from the eastern endemic Democratic Republic of the Congo.
IF 8.4 2区 医学 Q1 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-09 DOI: 10.1080/22221751.2024.2437245
Harry César Ntumba Kayembe, Nadège Makuntima Taty, Hippolyte Nani-Tuma Situakibanza
{"title":"The westward spread dynamics of cholera from the eastern endemic Democratic Republic of the Congo.","authors":"Harry César Ntumba Kayembe, Nadège Makuntima Taty, Hippolyte Nani-Tuma Situakibanza","doi":"10.1080/22221751.2024.2437245","DOIUrl":"10.1080/22221751.2024.2437245","url":null,"abstract":"","PeriodicalId":11602,"journal":{"name":"Emerging Microbes & Infections","volume":" ","pages":"2437245"},"PeriodicalIF":8.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11632934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142767276","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}
引用次数: 0
Mode of birth in nulliparous term singleton pregnancies in vertex presentation before and after implementation of an evidence-based intervention: quality-improvement study.
IF 1.7 4区 医学 Q3 OBSTETRICS & GYNECOLOGY Pub Date : 2025-12-01 Epub Date: 2025-01-02 DOI: 10.1080/14767058.2024.2443968
Petra Psenkova, M Veliskova, D Dzubinska, I Waczulikova, M Tedla, P Peskovicova, J Zahumensky

Purpose: The main objective of this study was to assess the impact of a composite quality improvement intervention on mode of birth in nullipara term singleton vertex (NTSVs).

Material and methods: This was an ambidirectional study following the implementation of the intervention to reduce cesarean section rate in NSTV by comparing two birth cohorts, pre-composite quality improvement intervention cohort (January 2013-December 2015) and post-composite quality improvement intervention cohort (January 2018-December 2020).

Results: In the studied periods, there was a total of 7713 NTSV births. Compared to pre-composite quality improvement intervention, there was a post-composite quality improvement intervention reduction in NTSV cesarean section rate from 30.89% to 13.31% (p < 0.0001). Obstetric and non-obstetric indications for elective cesarean sections decreased from 5.52% to 1.04% (p < 0.0001) and from 4.82% to 0.52% (p < 0.0001), respectively. The frequency of emergency cesarean sections in this group decreased from 20.56% to 11.75% (p < 0.0001), especially those performed for failure to progress in labor (from 13.69% to 7.30%; p < 0.0001). There has been a rising trend with regards to maternal age. However, the proportion of mothers aged 35 years and more giving birth by cesarean section reduced from 46.94% to 20.28%. These reductions in cesarean section rates occurred without any negative impact on core fetal outcomes.

Conclusions: This quality improvement study demonstrates that it is feasible to significantly reduce cesarean section rate in NTSV by adopting specific composite measures. However, this requires the understanding of the inherent problems and barriers within the unit and the involvement of all stake holders.

{"title":"Mode of birth in nulliparous term singleton pregnancies in vertex presentation before and after implementation of an evidence-based intervention: quality-improvement study.","authors":"Petra Psenkova, M Veliskova, D Dzubinska, I Waczulikova, M Tedla, P Peskovicova, J Zahumensky","doi":"10.1080/14767058.2024.2443968","DOIUrl":"https://doi.org/10.1080/14767058.2024.2443968","url":null,"abstract":"<p><strong>Purpose: </strong>The main objective of this study was to assess the impact of a composite quality improvement intervention on mode of birth in nullipara term singleton vertex (NTSVs).</p><p><strong>Material and methods: </strong>This was an ambidirectional study following the implementation of the intervention to reduce cesarean section rate in NSTV by comparing two birth cohorts, pre-composite quality improvement intervention cohort (January 2013-December 2015) and post-composite quality improvement intervention cohort (January 2018-December 2020).</p><p><strong>Results: </strong>In the studied periods, there was a total of 7713 NTSV births. Compared to pre-composite quality improvement intervention, there was a post-composite quality improvement intervention reduction in NTSV cesarean section rate from 30.89% to 13.31% (<i>p</i> < 0.0001). Obstetric and non-obstetric indications for elective cesarean sections decreased from 5.52% to 1.04% (<i>p</i> < 0.0001) and from 4.82% to 0.52% (<i>p</i> < 0.0001), respectively. The frequency of emergency cesarean sections in this group decreased from 20.56% to 11.75% (<i>p</i> < 0.0001), especially those performed for failure to progress in labor (from 13.69% to 7.30%; <i>p</i> < 0.0001). There has been a rising trend with regards to maternal age. However, the proportion of mothers aged 35 years and more giving birth by cesarean section reduced from 46.94% to 20.28%. These reductions in cesarean section rates occurred without any negative impact on core fetal outcomes.</p><p><strong>Conclusions: </strong>This quality improvement study demonstrates that it is feasible to significantly reduce cesarean section rate in NTSV by adopting specific composite measures. However, this requires the understanding of the inherent problems and barriers within the unit and the involvement of all stake holders.</p>","PeriodicalId":50146,"journal":{"name":"Journal of Maternal-Fetal & Neonatal Medicine","volume":"38 1","pages":"2443968"},"PeriodicalIF":1.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923472","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}
引用次数: 0
Time to progression predicts outcome of patients with multiple myeloma that can be influenced by autologous hematopoietic stem cell transplantation.
IF 2 4区 医学 Q3 HEMATOLOGY Pub Date : 2025-12-01 Epub Date: 2025-01-03 DOI: 10.1080/16078454.2024.2448024
Yanhua Yue, Yingjie Miao, Yifang Zhou, Yangling Shen, Luo Lu, Fei Wang, Yang Cao, Bai He, Weiying Gu

Objectives: Currently, there is limited understanding regarding the prognostic significance of time to progression (TTP) after first remission in multiple myeloma (MM).

Methods: We conducted a retrospective analysis of clinical data from 209 patients with MM. These patients were categorized into ≤ 6 months, ≤ 12 months, ≤ 24 months, > 24 months, 6-12 months, and 12-24 months subgroups based on TTP.

Results: Patients in ≤ 12 months group exhibited shorter median overall survival (OS) and OS-1 compared to those in ≤ 24 months group (61.73 vs 96.10 months, P = 0.02; 54.00 vs 74.17 months, P = 0.048). ≤ 6 months group exhibited shorter median OS and OS-1 compared to 6-12 months group (33.63 vs 79.60 months, P = 0.022; 19.93 vs 65.17 months, P = 0.015). Patients in 6-12 months group had shorter median OS and OS-1 compared to those in 12-24 months group (79.60 vs 100.43 months, P < 0.001; 65.17 vs 77.17 months, P = 0.012).No significant difference in OS was observed between patients in 12-24 months and > 24 months groups. For patients who experienced progression within 12 or 24 months after remission, undergoing autologous hematopoietic stem cell transplantation (ASCT) after progression conferred a median OS and OS-2 advantage over receiving post-progression chemotherapy. Multivariable analysis confirmed that TTP was an independent predictor for OS in patients with MM.

Conclusion: Patients with MM who experience earlier disease progression within 12 months after remission have a worse prognosis, and post-progression ASCT can improve their survival outcomes.

{"title":"Time to progression predicts outcome of patients with multiple myeloma that can be influenced by autologous hematopoietic stem cell transplantation.","authors":"Yanhua Yue, Yingjie Miao, Yifang Zhou, Yangling Shen, Luo Lu, Fei Wang, Yang Cao, Bai He, Weiying Gu","doi":"10.1080/16078454.2024.2448024","DOIUrl":"https://doi.org/10.1080/16078454.2024.2448024","url":null,"abstract":"<p><strong>Objectives: </strong>Currently, there is limited understanding regarding the prognostic significance of time to progression (TTP) after first remission in multiple myeloma (MM).</p><p><strong>Methods: </strong>We conducted a retrospective analysis of clinical data from 209 patients with MM. These patients were categorized into ≤ 6 months, ≤ 12 months, ≤ 24 months, > 24 months, 6-12 months, and 12-24 months subgroups based on TTP.</p><p><strong>Results: </strong>Patients in ≤ 12 months group exhibited shorter median overall survival (OS) and OS-1 compared to those in ≤ 24 months group (61.73 vs 96.10 months, <i>P</i> = 0.02; 54.00 vs 74.17 months, <i>P</i> = 0.048). ≤ 6 months group exhibited shorter median OS and OS-1 compared to 6-12 months group (33.63 vs 79.60 months, <i>P</i> = 0.022; 19.93 vs 65.17 months, <i>P</i> = 0.015). Patients in 6-12 months group had shorter median OS and OS-1 compared to those in 12-24 months group (79.60 vs 100.43 months, <i>P</i> < 0.001; 65.17 vs 77.17 months, <i>P</i> = 0.012).No significant difference in OS was observed between patients in 12-24 months and > 24 months groups. For patients who experienced progression within 12 or 24 months after remission, undergoing autologous hematopoietic stem cell transplantation (ASCT) after progression conferred a median OS and OS-2 advantage over receiving post-progression chemotherapy. Multivariable analysis confirmed that TTP was an independent predictor for OS in patients with MM.</p><p><strong>Conclusion: </strong>Patients with MM who experience earlier disease progression within 12 months after remission have a worse prognosis, and post-progression ASCT can improve their survival outcomes.</p>","PeriodicalId":13161,"journal":{"name":"Hematology","volume":"30 1","pages":"2448024"},"PeriodicalIF":2.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142921541","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}
引用次数: 0
Deciphering distinct pathogenic mechanisms of ankylosing spondylitis and systemic sclerosis via shared biomarkers ZSWIM6 and CCL3L3: Insights from an integrative bioinformatics approach.
IF 3.3 4区 医学 Q3 IMMUNOLOGY Pub Date : 2025-12-01 Epub Date: 2024-12-27 DOI: 10.1080/08916934.2024.2445557
Liangyu Huang, Jiarui Chen, Renbang Yang, Jianjun Shi, Chenxing Zhou, Tianyou Chen, Sitan Feng, Chengqian Huang, Jieping Huang, Jiang Xue, Zhongxian Zhou, Jichong Zhu, Shaofeng Wu, Xinli Zhan, Chong Liu

Ankylosing Spondylitis (AS) and Systemic Sclerosis (SSc) are both autoimmune diseases, albeit with distinct anatomical targets. AS primarily affects the spine and sacroiliac joints, triggering inflammation and eventual fusion of the vertebrae. SSc predominantly impacts the skin and connective tissues, leading to skin fibrosis, thickening, and potential damage to vital organs such as the lungs, heart, and kidneys. Despite their differing anatomical manifestations, inflammation serves as a pivotal factor in both conditions. Exploring the causes of the different pathogenesis of inflammation in AS and SSc could provide new insights into their treatment. We selected RNA-seq profiles of peripheral blood mononuclear cells (PBMCs) from the GEO datasets GSE73754 and GSE19617. DEGs were identified using the Limma R package with an adjusted p-value cutoff of < 0.05. Gene Ontology pathway analysis, SVM recursive feature elimination, and Gene Set Enrichment Analysis (GSEA) were conducted to analyze the DEGs. CIBERSORT was applied to estimate immune cell composition and its correlation with hub genes. Single-cell RNA sequencing data from peripheral blood mononuclear cells in the GSE194315 dataset were included to support differential expression analysis and biomarker identification. Additionally, single-cell RNA sequencing data from bone marrow blood samples were utilized to further validate these findings, offering complementary insights into biomarker expression across distinct sample types. A total of 762 DEGs were identified between AS patients and controls, and 441 DEGs between SSc patients and controls. Both conditions showed enrichment in the Natural killer cell mediated cytotoxicity pathway. ZSWIM6 and CCL3L3 were identified as potential biomarkers in AS and SSc, with significant diagnostic capabilities demonstrated by ROC analysis. Correlation analysis revealed associations between these biomarkers and specific immune cell types. The study utilizing ZSWIM6 and CCL3L3 as potential biomarkers provides deep insights into the distinct molecular mechanisms of SSc and AS. These findings lay the foundation for future research on targeted therapies and enhance our understanding of immune cell interactions in these autoimmune diseases.

{"title":"Deciphering distinct pathogenic mechanisms of ankylosing spondylitis and systemic sclerosis via shared biomarkers ZSWIM6 and CCL3L3: Insights from an integrative bioinformatics approach.","authors":"Liangyu Huang, Jiarui Chen, Renbang Yang, Jianjun Shi, Chenxing Zhou, Tianyou Chen, Sitan Feng, Chengqian Huang, Jieping Huang, Jiang Xue, Zhongxian Zhou, Jichong Zhu, Shaofeng Wu, Xinli Zhan, Chong Liu","doi":"10.1080/08916934.2024.2445557","DOIUrl":"https://doi.org/10.1080/08916934.2024.2445557","url":null,"abstract":"<p><p>Ankylosing Spondylitis (AS) and Systemic Sclerosis (SSc) are both autoimmune diseases, albeit with distinct anatomical targets. AS primarily affects the spine and sacroiliac joints, triggering inflammation and eventual fusion of the vertebrae. SSc predominantly impacts the skin and connective tissues, leading to skin fibrosis, thickening, and potential damage to vital organs such as the lungs, heart, and kidneys. Despite their differing anatomical manifestations, inflammation serves as a pivotal factor in both conditions. Exploring the causes of the different pathogenesis of inflammation in AS and SSc could provide new insights into their treatment. We selected RNA-seq profiles of peripheral blood mononuclear cells (PBMCs) from the GEO datasets GSE73754 and GSE19617. DEGs were identified using the Limma R package with an adjusted <i>p</i>-value cutoff of < 0.05. Gene Ontology pathway analysis, SVM recursive feature elimination, and Gene Set Enrichment Analysis (GSEA) were conducted to analyze the DEGs. CIBERSORT was applied to estimate immune cell composition and its correlation with hub genes. Single-cell RNA sequencing data from peripheral blood mononuclear cells in the GSE194315 dataset were included to support differential expression analysis and biomarker identification. Additionally, single-cell RNA sequencing data from bone marrow blood samples were utilized to further validate these findings, offering complementary insights into biomarker expression across distinct sample types. A total of 762 DEGs were identified between AS patients and controls, and 441 DEGs between SSc patients and controls. Both conditions showed enrichment in the Natural killer cell mediated cytotoxicity pathway. ZSWIM6 and CCL3L3 were identified as potential biomarkers in AS and SSc, with significant diagnostic capabilities demonstrated by ROC analysis. Correlation analysis revealed associations between these biomarkers and specific immune cell types. The study utilizing ZSWIM6 and CCL3L3 as potential biomarkers provides deep insights into the distinct molecular mechanisms of SSc and AS. These findings lay the foundation for future research on targeted therapies and enhance our understanding of immune cell interactions in these autoimmune diseases.</p>","PeriodicalId":8688,"journal":{"name":"Autoimmunity","volume":"58 1","pages":"2445557"},"PeriodicalIF":3.3,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142891604","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}
引用次数: 0
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