Neoplasia最新文献

{"title":"A deep learning based holistic diagnosis system for immunohistochemistry interpretation and molecular subtyping","authors":"Lin Fan ,&nbsp;Jiahe Liu ,&nbsp;Baoyang Ju ,&nbsp;Doudou Lou ,&nbsp;Yushen Tian","doi":"10.1016/j.neo.2024.100976","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100976","url":null,"abstract":"<div><h3>Background</h3><p>Breast cancer in different molecular subtypes, which is determined by the overexpression rates of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), and Ki67, exhibit distinct symptom characteristics and sensitivity to different treatment. The immunohistochemical method, one of the most common detecting tools for tumour markers, is heavily relied on artificial judgment and in clinical practice, with an inherent limitation in interpreting stability and operating efficiency. Here, a holistic intelligent breast tumour diagnosis system has been developed for tumour-markeromic analysis, combining the automatic interpretation and clinical suggestion.</p></div><div><h3>Methods</h3><p>The holistic intelligent breast tumour diagnosis system included two main modules. The interpreting modules were constructed based on convolutional neural network, for comprehensively extracting and analyzing the multi-features of immunostaining. Referring to the clinical classification criteria, the interpreting results were encoded in a low-dimensional feature representation in the subtyping module, to efficiently output a holistic detecting result of the critical tumour-markeromic with diagnosis suggestions on molecular subtypes.</p></div><div><h3>Results</h3><p>The overexpression rates of HER2, ER, PR, and Ki67, as well as an effective determination of molecular subtypes were successfully obtained by this diagnosis system, with an average sensitivity of 97.6 % and an average specificity of 96.1 %, among those, the sensitivity and specificity for interpreting HER2 were up to 99.8 % and 96.9 %.</p></div><div><h3>Conclusion</h3><p>The holistic intelligent breast tumour diagnosis system shows improved performance in the interpretation of immunohistochemical images over pathologist-level, which can be expected to overcome the limitations of conventional manual interpretation in efficiency, precision, and repeatability.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100976"},"PeriodicalIF":4.8,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000137/pdfft?md5=a0bfe62e5827eebf3b9ba7233d057374&pid=1-s2.0-S1476558624000137-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corrigendum to “Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.” [Neoplasia Volume 23, Issue 9, September 2021, Pages 1002-1015]","authors":"Chinnadurai Mani ,&nbsp;Kaushlendra Tripathi ,&nbsp;Sandeep Chaudhary ,&nbsp;Ranganatha R. Somasagara ,&nbsp;Rodney P. Rocconi ,&nbsp;Chiquito Crasto ,&nbsp;Mark Reedy ,&nbsp;Mohammad Athar ,&nbsp;Komaraiah Palle","doi":"10.1016/j.neo.2024.100978","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100978","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100978"},"PeriodicalIF":4.8,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000150/pdfft?md5=fda44061fb5e63883f877199466ef9da&pid=1-s2.0-S1476558624000150-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139942062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Who benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-dimensional model for candidate selection","authors":"Meng-qi Jiang ,&nbsp;Li-qiang Qian ,&nbsp;Yu-jia Shen ,&nbsp;Yuan-yuan Fu ,&nbsp;Wen Feng ,&nbsp;Zheng-ping Ding ,&nbsp;Yu-chen Han ,&nbsp;Xiao-long Fu","doi":"10.1016/j.neo.2024.100979","DOIUrl":"10.1016/j.neo.2024.100979","url":null,"abstract":"<div><h3>Background</h3><p>Despite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy.</p></div><div><h3>Methods</h3><p>We retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3.</p></div><div><h3>Findings</h3><p>A total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p &lt; 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (<em>p</em> &lt; 0.001).</p></div><div><h3>Interpretation</h3><p>IASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100979"},"PeriodicalIF":4.8,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000162/pdfft?md5=bd2ae44ddcd51e1ee9c73cd124f793f8&pid=1-s2.0-S1476558624000162-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139918371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single cell analysis unveils the commonality and heterogeneity between nasopharyngeal and oropharyngeal carcinoma","authors":"Liping Wang ,&nbsp;Shuang Li ,&nbsp;Xinran Li ,&nbsp;Guangzheng Zhuo ,&nbsp;Qian Zhang ,&nbsp;Guohong Liu ,&nbsp;Yunbao Pan","doi":"10.1016/j.neo.2024.100980","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100980","url":null,"abstract":"<div><p>Nasopharyngeal carcinoma (NPC) and oropharyngeal carcinoma (OPC) are subtypes of head and neck cancer with different treatment effects due to the heterogeneity of tumor microenvironments. This study was to investigate the distinctive tumor microenvironments of NPC and OPC. Analyzing single-cell data from 10 cases of each subtype, we reveal significant differences in cellular composition, with NPC microenvironment dominated by T/NK and B cells, and OPC characterized by prevalent epithelial cells and fibroblasts. Dynamic transitions of CD8 T cells are observed in both tumor types, involving shifts from naivety to cytotoxicity, proliferation, and eventual exhaustion/exhausted states. Additionally, Tregs exhibit heightened proliferative abilities in later developmental stages, concomitant with exhaustion. These highly proliferative T cells and Tregs manifest elevated glycolysis and lactate metabolism activities. Furthermore, we explore intercellular communication between glycolytic malignant epithelial cells and these proliferative T cells. These findings offer comprehensive insights into the heterogeneity of tumor microenvironments and provide a solid foundation for future therapeutic strategies and targeted interventions.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100980"},"PeriodicalIF":4.8,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000174/pdfft?md5=59376fcd78eee7b7d5cd3a592ffd5d6c&pid=1-s2.0-S1476558624000174-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139908521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting myeloma metabolism: How abnormal metabolism contributes to multiple myeloma progression and resistance to proteasome inhibitors","authors":"Xiang Zhou ,&nbsp;Rui He ,&nbsp;Wei-Xin Hu,&nbsp;Saiqun Luo,&nbsp;Jingping Hu","doi":"10.1016/j.neo.2024.100974","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100974","url":null,"abstract":"<div><p>Multiple myeloma is a hematological malignancy that has evolved from antibody-secreting B lymphocytes. Like other types of cancers, myeloma cells have acquired functional capabilities which are referred to as “Hallmarks of Cancer”, and one of their most important features is the metabolic disorders. Due to the high secretory load of the MM cells, the first-line medicine proteasome inhibitors have found their pronounced effects in MM cells for blocking the degradation of misfolded proteins, leading to their accumulation in the ER and overwhelming ER stress. Moreover, proteasome inhibitors have been reported to be effective in myeloma by targeting glucose, lipid, amino acid metabolism of MM cells. In this review, we have described the abnormal metabolism of the three major nutrients, such as glucose, lipid and amino acids, which participate in the cellular functions. We have described their roles in myeloma progression, how they could be exploited for therapeutic purposes, and current therapeutic strategies targeting these metabolites, hoping to uncover potential novel therapeutic targets and promote the development of future therapeutic approaches.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100974"},"PeriodicalIF":4.8,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000113/pdfft?md5=b46bea063ea215c71f9a03e0f51003ae&pid=1-s2.0-S1476558624000113-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139743879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor microenvironment(TME) and single-source dual-energy CT(ssDECT) on assessment of inconformity between RECIST1.1 and pathological remission in neoadjuvant immunotherapy of NSCLC","authors":"Chao Sun ,&nbsp;Xiaobo Ma ,&nbsp;Fanyang Meng ,&nbsp;Xi Chen ,&nbsp;Xu Wang ,&nbsp;Wenyu Sun ,&nbsp;Yinghui Xu ,&nbsp;Hua He ,&nbsp;Huimao Zhang ,&nbsp;Kewei Ma","doi":"10.1016/j.neo.2024.100977","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100977","url":null,"abstract":"<div><h3>Background</h3><p>The inconformity (IC) between pathological and imaging remissions after neoadjuvant immunotherapy in patients with NSCLC can affect the evaluation of curative effect of neoadjuvant therapy and the decision regarding the chance of surgery.</p></div><div><h3>Materials and methods</h3><p>Patients who achieved disease control(CR/PR/SD) after neoadjuvant chemoimmunotherapy from a clinical trial (NCT04326153) and after neoadjuvant chemotherapy during the same period were enrolled in this study. All patients underwent radical resection and systematic mediastinal lymphadenectomy after neoadjuvant treatments. The pathological remission, immunohistochemistry (CD4, CD8, CD20, CD56, FoxP3, CD68, CD163, CD11b tumor-infiltrating lymphocytes, or macrophages), and single-source dual-energy computed tomography (ssDECT) scans were assessed. The IC between imaging remission by CT and pathological remission was investigated. The underlying cause of IC, the correlation between IC and DFS, and prognostic biomarkers were explored.</p></div><div><h3>Results</h3><p>After neoadjuvant immunotherapy, enhanced immune killing and reduced immunosuppressive performance were observed. 70 % of neoadjuvant chemoimmunotherapy patients were in high/medium IC level. Massive necrosis and repair around and inside the cancer nest were the main pathological changes observed 30–45 days post-treatment with PD1/PD-L1 antibody and were the main causes of IC between the pathology and imaging responses after neoadjuvant immunotherapy. High IC and preoperative CD8 expression (H score ≥ 3) indicate a high pathological response rate and prolonged DFS. Iodine material density ssDECT images showed that the iodine content in the lesion causes hyperattenuation in post-neoadjuvant lesion in PCR patient.</p></div><div><h3>Conclusions</h3><p>Compared to chemotherapy and targeted therapy, the efficacy of neoadjuvant immunotherapy was underestimated based on the RECIST criteria due to the unique antitumor therapeutic mechanism. Preoperative CD8+ expression and ssDECT predict this IC and evaluate the residual tumor cells. This is of great significance for screening immune beneficiaries and making more accurate judgments about the timing of surgery.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"50 ","pages":"Article 100977"},"PeriodicalIF":4.8,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000149/pdfft?md5=5b73b126ae6603596dae7e21b11ea037&pid=1-s2.0-S1476558624000149-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139727030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A liquid biomarker signature of inflammatory proteins accurately predicts early pancreatic cancer progression during FOLFIRINOX chemotherapy","authors":"Casper W.F. van Eijck ,&nbsp;Sergio Sabroso-Lasa ,&nbsp;Gaby J. Strijk ,&nbsp;Dana A.M. Mustafa ,&nbsp;Amine Fellah ,&nbsp;Bas Groot Koerkamp ,&nbsp;Núria Malats ,&nbsp;Casper H.J. van Eijck","doi":"10.1016/j.neo.2024.100975","DOIUrl":"10.1016/j.neo.2024.100975","url":null,"abstract":"<div><h3>Background</h3><p>Pancreatic ductal adenocarcinoma (PDAC) is often treated with FOLFIRINOX, a chemotherapy associated with high toxicity rates and variable efficacy. Therefore, it is crucial to identify patients at risk of early progression during treatment. This study aims to explore the potential of a multi-omics biomarker for predicting early PDAC progression by employing an in-depth mathematical modeling approach.</p></div><div><h3>Methods</h3><p>Blood samples were collected from 58 PDAC patients undergoing FOLFIRINOX before and after the first cycle. These samples underwent gene (GEP) and inflammatory protein expression profiling (IPEP). We explored the predictive potential of exclusively IPEP through Stepwise (Backward) Multivariate Logistic Regression modeling. Additionally, we integrated GEP and IPEP using Bayesian Kernel Regression modeling, aiming to enhance predictive performance. Ultimately, the FOLFIRINOX IPEP (FFX-IPEP) signature was developed.</p></div><div><h3>Results</h3><p>Our findings revealed that proteins exhibited superior predictive accuracy than genes. Consequently, the FFX-IPEP signature consisted of six proteins: AMN, BANK1, IL1RL2, ITGB6, MYO9B, and PRSS8. The signature effectively identified patients transitioning from disease control to progression early during FOLFIRINOX, achieving remarkable predictive accuracy with an AUC of 0.89 in an independent test set. Importantly, the FFX-IPEP signature outperformed the conventional CA19-9 tumor marker.</p></div><div><h3>Conclusions</h3><p>Our six-protein FFX-IPEP signature holds solid potential as a liquid biomarker for the early prediction of PDAC progression during toxic FOLFIRINOX chemotherapy. Further validation in an external cohort is crucial to confirm the utility of the FFX-IPEP signature. Future studies should expand to predict progression under different chemotherapies to enhance the guidance of personalized treatment selection in PDAC.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"49 ","pages":"Article 100975"},"PeriodicalIF":4.8,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000125/pdfft?md5=0c207c5a52ef469c43f36332d18b03c0&pid=1-s2.0-S1476558624000125-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139713242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular heterogeneity in histomorphologic subtypes of lung adeno carcinoma represents a challenge for treatment decision","authors":"Tobias Kolb,&nbsp;Sarah Müller,&nbsp;Peter Möller,&nbsp;Thomas F.E. Barth,&nbsp;Ralf Marienfeld","doi":"10.1016/j.neo.2023.100955","DOIUrl":"https://doi.org/10.1016/j.neo.2023.100955","url":null,"abstract":"<div><p>Lung cancer is the leading cause in cancer related death, with non-small cell lung cancer (NSCLC) being the most frequent subtype. The importance of NSCLC is reflected by the various targeted therapy options especially for NSCLC adenocarcinomas (lung adeno carcinoma (LUAD)) as well as a set of options for immune therapies. However, despite these therapy advances, the majority of patients do not show a long-term response to either targeted therapy or immune checkpoint inhibition. One reason for treatment failure appears to be the NSCLC tumor heterogeneity. NSCLC heterogeneity might lead to an insufficient molecular characterization of a given sample due to the limited tumor material used for pathological assessment as the majority of analyses is performed on small biopsies. To get a more detailed insight into the tumor heterogeneity of NSCLC LUAD, especially in the light of its different histomorphological growth patterns, we analysed isolated NSCLC growth pattern areas and the corresponding entire tumor samples of a cohort of 31 NSLCS LUAD patients and compared their mutational landscape and their expression profiles. While significant differences of complex biomarkers, like tumor mutational burden (TMB) or microsatellite instability (MSI), were not detected between the five growth patterns -lepidic, papillary, micropapillary, acinar, and solid- we observed various subclonal mutations and copy number variants. Moreover, RNASeq analysis revealed growth pattern specific expression profiles affecting cellular processes like apoptosis, metastasis and proliferation. Taken together, our data provide novel insights into the tumor heterogeneity of LUAD required to overcome tumor heterogeneity related therapy resistance.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"49 ","pages":"Article 100955"},"PeriodicalIF":4.8,"publicationDate":"2024-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558623000787/pdfft?md5=a6e654e3ba3f9ad4fea8e2d4b78acb20&pid=1-s2.0-S1476558623000787-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139674449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reciprocal regulation of lncRNA MEF and c-Myc drives colorectal cancer tumorigenesis","authors":"Shuang Wu ,&nbsp;Xiangyu Dai ,&nbsp;Zhipu Zhu ,&nbsp;Dianhui Fan ,&nbsp;Su Jiang ,&nbsp;Yi Dong ,&nbsp;Bing Chen ,&nbsp;Qi Xie ,&nbsp;Zhihui Yao ,&nbsp;Qun Li ,&nbsp;Rick Francis Thorne ,&nbsp;Yao Lu ,&nbsp;Hao Gu ,&nbsp;Wanglai Hu","doi":"10.1016/j.neo.2024.100971","DOIUrl":"https://doi.org/10.1016/j.neo.2024.100971","url":null,"abstract":"<div><p>More than half of all cancers demonstrate aberrant c-Myc expression, making this arguably the most important human oncogene. Deregulated long non-coding RNAs (lncRNAs) are also commonly implicated in tumorigenesis, and some limited examples have been established where lncRNAs act as biological tuners of c-Myc expression and activity. Here, we demonstrate that the lncRNA denoted c-Myc Enhancing Factor (MEF) enjoys a cooperative relationship with c-Myc, both as a transcriptional target and driver of c-Myc expression. Mechanistically, MEF functions by binding to and stabilizing the expression of hnRNPK in colorectal cancer cells. The MEF-hnRNPK interaction serves to disrupt binding between hnRNPK and the E3 ubiquitin ligase TRIM25, which attenuates TRIM25-dependent hnRNPK ubiquitination and proteasomal destruction. In turn, the stabilization of hnRNPK through MEF enhances c-Myc expression by augmenting the translation c-Myc. Moreover, modulating the expression of MEF in shRNA-mediated knockdown and overexpression studies revealed that MEF expression is essential for colorectal cancer cell proliferation and survival, both in vitro and in vivo. From the clinical perspective, we show that MEF expression is differentially increased in colorectal cancer tissues compared to normal adjacent tissues. Further, correlations exist between MEF, c-Myc, and hnRNPK suggesting the MEF-c-Myc positive feedback loop is active in patients. Together these data demonstrate that MEF is a pivotal partner of the c-Myc network and propose MEF as a valuable therapeutic target for colorectal cancer.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"49 ","pages":"Article 100971"},"PeriodicalIF":4.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000083/pdfft?md5=1889e62be21c43ba26a09b22058a81f1&pid=1-s2.0-S1476558624000083-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139652882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer","authors":"Mudasir Rashid ,&nbsp;Rumaisa Rashid ,&nbsp;Nikhil Gadewal ,&nbsp;John M. Carethers ,&nbsp;Minoru Koi ,&nbsp;Hassan Brim ,&nbsp;Hassan Ashktorab","doi":"10.1016/j.neo.2024.100970","DOIUrl":"10.1016/j.neo.2024.100970","url":null,"abstract":"<div><p>The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., <em>MLH1</em> and <em>MSH2</em>) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic <em>MSH3</em> alterations have been linked to a specific form of MSI called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that is associated with patient poor prognosis and elevated among African American (AA) rectal cancer patients. Genetic variants of <em>MSH3</em> and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of <em>MSH3</em> among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified <em>MSH3</em> variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (<em>p.</em>E413K; <em>p.</em>S466N; <em>p.</em>S920F; <em>p.</em>E976K; <em>p.</em>H1010Y; <em>p.</em>E1081K). All identified <em>MSH3</em> variants were non-synonymous, novel, pathogenic, and show loss or gain of hydrogen bonding, ionic bonding, hydrophobic bonding, and disulfide bonding and have a deleterious effect on the structure of MSH3 protein. Some variants were located within the ATPase site of MSH3, affecting ATP hydrolysis that is critical for MSH3′s function. Other variants were in the MSH3-MSH2 interacting domain, important for MSH3’s binding to MSH2. Overall, our data suggest that these variants among AA CRC patients affect the function of MSH3 making them pathogenic and likely contributing to the development or advancement of CRC among AA. Further clarifying functional studies will be necessary to fully understand the impact of these variants on MSH3 function and CRC development in AA patients.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"49 ","pages":"Article 100970"},"PeriodicalIF":4.8,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000071/pdfft?md5=cab8958f4c72a1490aa1f60da31e9c51&pid=1-s2.0-S1476558624000071-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570365","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}