MedComm最新文献

{"title":"Phase I clinical trial to assess safety and efficacy of Oraxol, a novel oral paclitaxel chemotherapy agent, in patients with previously treated metastatic breast cancer","authors":"Yunfang Yu,&nbsp;Ying Wang,&nbsp;Luhui Mao,&nbsp;Suiwen Ye,&nbsp;Xiuping Lai,&nbsp;Junyi Chen,&nbsp;Yiwen Zhang,&nbsp;Jieqiong Liu,&nbsp;Junyan Wu,&nbsp;Tao Qin,&nbsp;Herui Yao","doi":"10.1002/mco2.70097","DOIUrl":"https://doi.org/10.1002/mco2.70097","url":null,"abstract":"<p>Oraxol, a novel oral paclitaxel chemotherapy agent, has emerged as a potential alternative for treating metastatic breast cancer (MBC). However, its safety and efficacy remain uncertain due to insufficient evidence supporting it. This open-label, single-arm, phase I trial was designed to assess the pharmacokinetics, safety, and preliminary antitumor activity of Oraxol in previously treated MBC. The primary objective was to investigate the pharmacokinetics of Oraxol, while secondary endpoints included assessing safety, tolerability, and antitumor activity. Twenty-four patients (median age, 53 years) were enrolled, and pharmacokinetic analysis showed consistent and reproducible absorption of Oraxol. Note that 96% patients experienced treatment-related adverse events (TRAEs) and no deaths attributed to TRAEs. The overall response rate was 34.8%, including 34.8% achieving partial response and 56.5% having stable disease. The median follow-up was 45.7 months, with median progression-free survival (PFS) of 3.41 months and median overall survival of 17.80 months. Notably, among patients with triple-negative breast cancer, the disease control rate was 100%, and the median PFS was 8.90 months, which notably exceeded the outcomes observed in other subtypes. Oraxol significantly alters metabolism and correlates with response and survival. In conclusion, Oraxol exhibited promising antitumor efficacy and manageable safety profiles in MBC patients.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 3","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70097","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CDK4/6 suppresses colorectal cancer by destabilizing YAP1","authors":"Yalei Wen,&nbsp;Xiao Yang,&nbsp;Shengrong Li,&nbsp;Lei Huang,&nbsp;Jiayi Chen,&nbsp;Lirong Tan,&nbsp;Xiuqing Ma,&nbsp;Yingjie Zhu,&nbsp;Zhengqiu Li,&nbsp;Changliang Shan,&nbsp;Chunze Zhang,&nbsp;Qiushi Zhang,&nbsp;Mingchao Liang,&nbsp;Haoxing Zhang,&nbsp;Tongzheng Liu","doi":"10.1002/mco2.70103","DOIUrl":"https://doi.org/10.1002/mco2.70103","url":null,"abstract":"<p>Colorectal cancer (CRC) is among the most prevalent and deadly cancers worldwide. The Yes-associated protein 1 (YAP1) is frequently dysregulated in cancers, contributing to cancer stemness, chemoresistance, and cancer-related death. However, strategies directly targeting YAP1 have not yet been successful because of the lack of active binding pockets and unregulated toxicity. In this study, our Food and Drug Administration (FDA)-approved drug screening reveals that abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes the proteasome-dependent degradation of YAP1, thereby inhibiting tumor progression in CRC cells and patient-derived xenograft models. We further identify deubiquitinating enzyme 3 (DUB3) as the bona fide deubiquitinase of YAP1 in CRC. Mechanistically, CDK4/6 directly phosphorylates DUB3 at Ser41, activating DUB3 to deubiquitinate and stabilize YAP1. Conversely, loss of Ser41 phosphorylation by CDK4/6 inhibition or Ser41A mutation, promotes YAP1 degradation and suppresses YAP1-driven tumor progression. Histological analysis shows a positive correlation between DUB3 and YAP1 expression in CRC specimens. Collectively, our study uncovers a novel oncogenic role of the CDK4/6-DUB3 pathway, which promotes YAP1 stabilization and tumor-promoting function, highlighting that targeting CDK4/6 offers a potential therapeutic strategy for CRC with aberrantly upregulated DUB3 and YAP1.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 3","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70103","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early-life antibiotic exposure aggravates hepatic steatosis through enhanced endotoxemia and lipotoxic effects driven by gut Parabacteroides","authors":"Xi Zhang,&nbsp;Darren Chak Lun Chan,&nbsp;Jie Zhu,&nbsp;Daniel Zhen Ye Sin,&nbsp;Ye Peng,&nbsp;Matthew Kwok Leong Wong,&nbsp;Wenyi Zhu,&nbsp;Yee Tsui,&nbsp;Andrea M. Haqq,&nbsp;Joseph Y. Ting,&nbsp;Anita Kozyrskyj,&nbsp;Francis Ka Leung Chan,&nbsp;Siew Chien Ng,&nbsp;Hein Min Tun","doi":"10.1002/mco2.70104","DOIUrl":"https://doi.org/10.1002/mco2.70104","url":null,"abstract":"<p>Compelling evidence supports a link between early-life gut microbiota and the metabolic outcomes in later life. Using an early-life antibiotic exposure model in BALB/c mice, we investigated the life-course impact of prenatal and/or postnatal antibiotic exposures on the gut microbiome of offspring and the development of metabolic dysfunction-associated steatotic liver disease (MASLD). Compared to prenatal antibiotic exposure alone, postnatal antibiotic exposure more profoundly affected gut microbiota development and succession, which led to aggravated endotoxemia and metabolic dysfunctions. This was primarily resulted from the overblooming of gut <i>Parabacteroides</i> and hepatic accumulation of cytotoxic lysophosphatidyl cholines (LPCs), which acted in conjunction with LPS derived from <i>Parabacteroides distasonis</i> (LPS_PA) to induce cholesterol metabolic dysregulations, endoplasmic reticulum (ER) stress and apoptosis. Integrated serum metabolomics, hepatic lipidomics and transcriptomics revealed enhanced glycerophospholipid hydrolysis and LPC production in association with the upregulation of PLA2G10, the gene controlling the expression of the group X secretory Phospholipase A2s (sPLA2-X). Taken together, our results show microbial modulations on the systemic MASLD pathogenesis and hepatocellular lipotoxicity pathways following early-life antibiotic exposure, hence help inform refined clinical practices to avoid any prolonged maternal antibiotic administration in early life and potential gut microbiota-targeted intervention strategies.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 3","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Contrast-enhanced ultrasound enables precision diagnosis of preoperative muscle invasion in bladder cancer: a prospective study","authors":"Qiyun Ou,&nbsp;Weibin Xie,&nbsp;Yunfang Yu,&nbsp;Bing Ou,&nbsp;Man Luo,&nbsp;Yongjian Chen,&nbsp;Weiwei Pan,&nbsp;Yiming Lai,&nbsp;Zhuohang Li,&nbsp;Jianqiu Kong,&nbsp;Zhuo Wu,&nbsp;Jingliang Ruan,&nbsp;Jingjing Han,&nbsp;Tianxin Lin,&nbsp;Baoming Luo","doi":"10.1002/mco2.70106","DOIUrl":"https://doi.org/10.1002/mco2.70106","url":null,"abstract":"<p>Bladder cancer's high mortality underscores the need for precise staging, especially to differentiate between nonmuscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) types. This prospective study evaluated the efficacy of contrast-enhanced ultrasound (CEUS) for preoperative staging, focusing on its ability to distinguish NMIBC from MIBC. Conducted from April 2020 to September 2021, the study involved 163 patients (median age: 64.0 years; 137 males, 26 females), with 133 NMIBC (81.6%) and 30 MIBC (18.4%). Each patient underwent CEUS followed by transurethral resection of bladder tumor or radical cystectomy. CEUS demonstrated high diagnostic accuracy in determining muscle invasion status (sensitivity 83.3%, specificity 92.5%, accuracy 90.8%, area under the receiver operating characteristic curve [AUC] 0.88). Comparative analyses against MRI (AUC 0.77) showed CEUS outperforming in muscle invasion detection. Combining CEUS with MRI improved diagnostic accuracy, particularly when MRI vesical imaging reporting and data system score was 3 points. The combined approach achieved an AUC of 0.73, with sensitivity, specificity, and accuracy of 76.2, 70.2, and 71.6%, respectively. Thus, CEUS emerges as a valuable diagnostic tool for preoperative staging of bladder cancer, particularly in its role in assessing muscle invasion status and thereby aiding in clinical decision-making and intervention outcomes.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 3","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70106","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Once-weekly glucagon-like peptide receptor agonist polyethylene glycol loxenatide protects against major adverse cardiovascular events in patients with type 2 diabetes: a multicenter ambispective cohort study (FLYING trial)","authors":"Jilin Li,&nbsp;Yu Tian,&nbsp;Liping Li,&nbsp;Yanyan Zhao,&nbsp;Shuhui Yang,&nbsp;Wencan Xu,&nbsp;Dan Zhu,&nbsp;Junjun Ye,&nbsp;Jingxian Chen,&nbsp;Weiting Liu,&nbsp;Haibo Xue,&nbsp;Wei Wu,&nbsp;Feiying Deng,&nbsp;Yale Duan,&nbsp;Zhizhen Hu,&nbsp;Bin Xie,&nbsp;Zhe-Sheng Chen,&nbsp;Kaijian Hou","doi":"10.1002/mco2.70094","DOIUrl":"https://doi.org/10.1002/mco2.70094","url":null,"abstract":"<p>This study aimed to determine the effects of polyethylene glycol loxenatide (PEG-Loxe), a glucagon-like peptide-1 receptor agonist, on a three-point major adverse cardiovascular event (3P-MACE) in patients with type 2 diabetes mellitus (T2DM). The study was conducted in six tertiary hospitals in three cities in China. Large language models were used to retrospectively screen and include 12,341 patients with T2DM who had either cardiovascular disease or cardiovascular risk factors. The patients were divided into the PEG-Loxe cohort (treated with PEG-Loxe, <i>n</i> = 1282) and the control cohort (treated with incretin glucose-lowering agents, <i>n</i> = 11,059). After a median follow-up of 4.0 years, 3P-MACE occurred in 51 (4.0%) and 1263 (11.4%) patients in PEG-Loxe and control cohorts, respectively (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49–0.94; <i>p </i>= 0.019). In the PEG-Loxe versus control cohorts, 21 (1.6%) versus 476 (4.3%) patients experienced nonfatal stroke (HR 0.63; <i>p </i>= 0.041), whereas 22 (1.7%) versus 545 (4.9%) experienced nonfatal myocardial infarction (HR 0.66; <i>p </i>= 0.058), and the incidence of cardiovascular death was 8 (0.6%) versus 240 (2.2%), respectively (HR 0.56; <i>p </i>= 0.118). We found a significantly lower incidence of first nonfatal myocardial infarction, nonfatal stroke, or cardiovascular deaths in the PEG-Loxe cohort than the control cohort.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbiota-derived 3-Methyl-L-histidine mediates the proatherogenic effect of high chicken protein diet","authors":"Shanshan Zhu,&nbsp;Ludi Liu,&nbsp;Yawen Zhao,&nbsp;Bingqi Ye,&nbsp;Jialin He,&nbsp;Wenkang Li,&nbsp;Yingxi Xu,&nbsp;Jiangyuan Zhu,&nbsp;Min Xia,&nbsp;Yan Liu","doi":"10.1002/mco2.70090","DOIUrl":"https://doi.org/10.1002/mco2.70090","url":null,"abstract":"<p>Diet rich in chicken protein has gained a widespread popularity for its profound effect on weight loss and glycemic control; however, its long-term effect on cardiovascular health and the underlying mechanisms remains obscure. Here, we demonstrated that higher intake of chicken protein was an independent risk factor for sub-clinical atherosclerosis. Adherence to high chicken protein diet (HCD) alleviated excessive weight gain and glycemic control regardless of the presence of gut microbiota in apolipoprotein E–deficient mice. In contrast, long-term HCD administration enhanced intestinal cholesterol absorption and accelerated atherosclerotic plaque formation in a gut microbiota-dependent manner. Integrative analysis of 16S rDNA sequencing and metabolomics profiling identified 3-Methyl-L-histidine (3-MH), resulting from an enrichment of <i>Lachnospiraceae</i>, as the key microbial effector to the atherogenic effect of HCD. Mechanistically, 3-MH facilitated the binding of hepatocyte nuclear factor 1A (HNF1A) to the promoter of NPC1-like intracellular cholesterol transporter 1 (NPC1L1), whereas inhibition of HNF1A–NPC1L1 axis abolished the atherogenic effect of 3-MH. Our findings uncovered a novel link between microbiota-derived 3-MH and disturbed cholesterol homeostasis, which ultimately accelerated atherosclerosis, and argued against the recommendation of HCD as weight loss regimens considering its adverse role in vascular health.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70090","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic and predictive effects of new steatotic liver disease nomenclatures: a large population-based study","authors":"Huixian Zeng,&nbsp;Letian Fang,&nbsp;Zhiyu Yang,&nbsp;Xinyu Zhao,&nbsp;Hongsen Chen,&nbsp;Puyi Xing,&nbsp;Zheyun Niu,&nbsp;Zheng Li,&nbsp;Zishuai Li,&nbsp;Jiayi Zhao,&nbsp;Wenbin Liu,&nbsp;Chunxia Jing,&nbsp;Hong You,&nbsp;Guangwen Cao","doi":"10.1002/mco2.70087","DOIUrl":"https://doi.org/10.1002/mco2.70087","url":null,"abstract":"<p>We aimed to compare the association of metabolic dysfunction-associated fatty liver disease (MAFLD), metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), metabolic dysfunction and ALD (MetALD), and MASLD with viral hepatitis (MASLD-Viral) with risks of cirrhosis, liver cancer, and mortality. The data of 464,556 adults from the UK Biobank (UKB), 13,526 adults from the National Health and Nutrition Examination Survey (NHANES), and 2554 adults from BeijngFH Health Cohort Study (FHCS) were included. Adjusted hazard ratios (aHR) and odds ratios were calculated using Cox and Logistic regression models, respectively. Compared with non-SLD, the risk of liver cancer increased from MetALD (aHR 1.70 [95% CI 1.37, 2.09]), MASLD (1.91 [1.66, 2.21]), MAFLD (2.01 [1.76, 2.29]), ALD (3.16 [2.54, 3.93]), to MASLD-Viral (22.0 [10.8, 44.4]) in a stepwise manner in the UKB; the risk of all-cause mortality increased from MetALD, MASLD, MAFLD, ALD, to MASLD-Viral in the NHANES. The odds ratio of liver fibrosis increased from MASLD, MAFLD, to MASLD-Viral in the FHCS. In patients with diabetes, metformin plus other drugs were associated with higher risks of cirrhosis, liver cancer, and all-cause mortality in MASLD or MAFLD. Prevention rather than antiglycemic treatment is important for patients with diabetic MASLD or MAFLD.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SHCBP1 is a novel regulator of PLK1 phosphorylation and promotes prostate cancer bone metastasis","authors":"Chen Tang,&nbsp;Shengmeng Peng,&nbsp;Yongming Chen,&nbsp;Bisheng Cheng,&nbsp;Shurui Li,&nbsp;Jie Zhou,&nbsp;Yongxin Wu,&nbsp;Lingfeng Li,&nbsp;Haitao Zhong,&nbsp;Zhenghui Guo,&nbsp;Yiming Lai,&nbsp;Hai Huang","doi":"10.1002/mco2.70082","DOIUrl":"https://doi.org/10.1002/mco2.70082","url":null,"abstract":"<p>Prostate cancer is a common male genitourinary malignancy with bone metastasis posing challenges for prognosis and treatment. This study aimed to investigate the role of SHC protein SH2 structural domain binding protein 1 (SHCBP1) in prostate cancer bone metastasis. Whole transcriptome sequencing of prostate cancer samples was conducted to identify oncogene expression, specifically focusing on SHCBP1. In vivo and in vitro models were used to study SHCBP1's impact on bone metastasis. Through co-immunoprecipitation, mass spectrometry, and Western blot assays, the interaction between SHCBP1 and cell cycle-related proteins was elucidated, along with analysis of downstream protein partners. SHCBP1 was found to enhance prostate cancer cell development, metastasis, and mitosis, with the SHCBP1—polo-like kinase 1 (PLK1)—CDC25C axis playing a key role in promoting tumorigenesis. Therapeutic inhibition of SHCBP1 increased docetaxel sensitivity. Clinical data showed elevated SHCBP1 expression in advanced prostate cancer stages. These findings offer insights into potential therapeutic strategies for prostate cancer bone metastasis and highlight the significance of the SHCBP1-PLK1-CDC25C axis in docetaxel sensitivity.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cannabidiol restores hematopoietic stem cell stemness in mouse through Atf2–Lrp6 axis after acute irradiation","authors":"Zhijie Bai,&nbsp;Congshu Huang,&nbsp;Huanhua Xu,&nbsp;Yuxin Wang,&nbsp;Zebin Liao,&nbsp;Pan Shen,&nbsp;Zhexin Ni,&nbsp;Chaoji Huangfu,&nbsp;Dezhi Sun,&nbsp;Yangyi Hu,&nbsp;Ningning Wang,&nbsp;Pengfei Zhang,&nbsp;Lei Zhou,&nbsp;Wei Zhou,&nbsp;Yue Gao","doi":"10.1002/mco2.70092","DOIUrl":"https://doi.org/10.1002/mco2.70092","url":null,"abstract":"<p>Bone marrow serves as the residence of hematopoietic stem cells and is recognized as one of the most radiosensitive tissues. Exposure to acute radiation leads to severe damage to bone marrow hematopoiesis which can be fatal, while few clinically applicable medication or specific therapeutic targets have been discovered. In this study, we found that the administration of cannabidiol significantly enhanced individual survival and restored the reconstitution capacity of bone marrow hematopoietic stem cells within 14 days after irradiation. Single-cell RNA sequencing analysis demonstrated that the expression levels of genes associated with stemness along with Wnt and BMP signaling pathways were restored by the cannabidiol treatment through the upregulation of <i>Atf2</i>, a transcription factor possessing multifunctional properties. <i>Atf2</i> upregulation induced by cannabidiol treatment potentially upregulated the expression of <i>Lrp6</i> to improve the stemness of hematopoietic stem cells. Further functional experiments validated the crucial role of <i>Atf2</i> in regulating multilineage differentiation potential of bone marrow hematopoietic stem and progenitor cells. Overall, our findings provide evidence for a promising radioprotective function of cannabidiol and <i>Atf2</i> as a candidate therapeutic target for acute radiation-induced hematopoietic injury, thereby paving the way for future research in the field.</p>","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70092","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397030","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining DNA cleavage in type I CRISPR systems with the HNH domain","authors":"Senfeng Zhang,&nbsp;Yao Liu,&nbsp;Chunyi Hu","doi":"10.1002/mco2.70060","DOIUrl":"https://doi.org/10.1002/mco2.70060","url":null,"abstract":"&lt;p&gt;Two recent cryo-electron microscopy (cryo-EM) studies have captured the HNH domain's ability to replace Cas3 within the Cascade complex (CRISPR-associated complex for antiviral defense) in both type I-E and type I-F CRISPR-Cas systems.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; These findings reveal that Cas3 is not required and the HNH domain forms a ring-like structure with Cascade, enabling precise DNA cleavage and providing a new avenue for understanding bacterial CRISPR-Cas immune responses.&lt;/p&gt;&lt;p&gt;CRISPR-Cas systems, which stand for Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated genes, are adaptive immunity mechanisms in bacteria and archaea, designed responsible for protecting against viral invasion. The immune response typically involves three stages: adaptation, expression, and interference. Based on the Cas effectors used during CRISPR interference, these systems are categorized into two classes and seven types. Class 1, including types I, III, IV, and VII, comprises multi-subunit Cas protein effector complexes, whereas Class 2, which includes types II, V, and VI, is composed of single-subunit Cas protein effectors.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In canonical type I systems, multiple Cas proteins assemble into a crRNA-containing Cascade complex, which stands for CRISPR-associated complex for antiviral defense, with the exclusion of Cas3. When the target DNA is recognized and full R-loop formation, Cas 3 is recruited as the catalytic module responsible for mediating target DNA cleavage.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, recent studies have identified two novel variant type I systems. In one variant, the type I-E system, the C-terminus of Cas5 is fused with an HNH domain, and in another variant, the type I-F system, the HNH domain is inserted into the C-terminus of Cas8 (Figure 1A). Despite lacking the Cas3 nuclease, the HNH-Cascade can still cleave target DNA. This is especially intriguing, as in type II CRISPR-Cas systems, the HNH nuclease domain is responsible for cleaving the DNA target strand in Cas9. Consequently, understanding the processes behind PAM recognition, crRNA guidance, and precise DNA cleavage in HNH-mediated immunity within type I-E and type I-F systems has emerged as a critical area of research.&lt;/p&gt;&lt;p&gt;The two papers published by Hirano et al. and Zhang et al. report cryo-EM studies in the 3.0–3.48 Å range, capturing distinct states of the target-free HNH-Cascade and target-bound HNH-Cascade complexes in the type I-F (&lt;i&gt;Selenomonas sp&lt;/i&gt;) and type I-E (&lt;i&gt;Candidatus Cloacimonetes&lt;/i&gt;) systems, respectively. These studies reveal that both the type I-F HNH-Cascade complex and the type I-E HNH-Cascade complex adopt a ring-like architecture that provides a clear view of how these systems achieve precise DNA cleavage (Figure 1B).&lt;/p&gt;&lt;p&gt;In the type I-F HNH-Cascade complex, the structure is organized into head, backbone, and tail regions, resembling the subunit arrangement of type I-F Cascade complexes","PeriodicalId":94133,"journal":{"name":"MedComm","volume":"6 2","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mco2.70060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}