Cell Reports Medicine最新文献_第3页

Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo. 通过同时表达 NF2 和 SuperHippo，在临床前模型中对弥漫性胸膜间皮瘤进行基因治疗。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 Epub Date: 2024-10-04 DOI: 10.1016/j.xcrm.2024.101763

Rui Zhu, Xincheng Liu, Xu Zhang, Zhenxing Zhong, Sixian Qi, Ruxin Jin, Yuan Gu, Yu Wang, Chen Ling, Kang Chen, Dan Ye, Fa-Xing Yu

{"title":"Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.","authors":"Rui Zhu, Xincheng Liu, Xu Zhang, Zhenxing Zhong, Sixian Qi, Ruxin Jin, Yuan Gu, Yu Wang, Chen Ling, Kang Chen, Dan Ye, Fa-Xing Yu","doi":"10.1016/j.xcrm.2024.101763","DOIUrl":"10.1016/j.xcrm.2024.101763","url":null,"abstract":"Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142379157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma. 吉西他滨联合托瑞帕利单抗治疗不符合顺铂治疗条件的复发性或转移性鼻咽癌患者的 2 期试验。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101779

Xiong Zou, Xi Ding, Zheng-Kai Feng, Yan-Feng Ouyang, Hui-Feng Li, Kai Wen, Zhi-Qiang Wang, You-Ping Liu, Yong-Long Liu, Wei-Jing Zhang, Qi Yang, Si-Yuan Chen, Yu-Long Xie, Ruo-Qi Xie, Chao Lin, Chen-Mei Gu, Pei-Yu Huang, Rui Sun, Yi-Jun Hua, Rui You, Ming-Yuan Chen

{"title":"A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma.","authors":"Xiong Zou, Xi Ding, Zheng-Kai Feng, Yan-Feng Ouyang, Hui-Feng Li, Kai Wen, Zhi-Qiang Wang, You-Ping Liu, Yong-Long Liu, Wei-Jing Zhang, Qi Yang, Si-Yuan Chen, Yu-Long Xie, Ruo-Qi Xie, Chao Lin, Chen-Mei Gu, Pei-Yu Huang, Rui Sun, Yi-Jun Hua, Rui You, Ming-Yuan Chen","doi":"10.1016/j.xcrm.2024.101779","DOIUrl":"10.1016/j.xcrm.2024.101779","url":null,"abstract":"Cisplatin is a cornerstone chemotherapy for nasopharyngeal carcinoma (NPC); however, certain patients are ineligible for cisplatin-based regimens. This phase 2 trial (NCT04405622) evaluated the efficacy and safety of gemcitabine and toripalimab in previously untreated patients with recurrent or metastatic NPC who were either ineligible for cisplatin or had experienced severe adverse events from prior cisplatin-based treatments. Patients received gemcitabine (1,000 mg/m2) and toripalimab (240 mg) every three weeks for six cycles, followed by toripalimab monotherapy for up to two years. The primary endpoint was the incidence of grade ≥3 adverse events, while secondary endpoints included objective response rate (ORR) and overall survival (OS). Of 30 screened patients, 21 were enrolled. No treatment-related fatalities occurred, with the most frequent adverse events being headache and nausea. The ORR was 61.9%, coupled with a disease control rate of 100%. Overall, gemcitabine plus toripalimab demonstrated low toxicity and promising efficacy for this specific patient cohort.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

An RNA damage response network mediates the lethality of 5-FU in colorectal cancer. RNA损伤应答网络介导了5-FU对结直肠癌的致死作用。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 Epub Date: 2024-10-07 DOI: 10.1016/j.xcrm.2024.101778

Jung-Kuei Chen, Karl A Merrick, Yi Wen Kong, Anita Izrael-Tomasevic, George Eng, Erika D Handly, Jesse C Patterson, Ian G Cannell, Lucia Suarez-Lopez, Aaron M Hosios, Anh Dinh, Donald S Kirkpatrick, Kebing Yu, Christopher M Rose, Jonathan M Hernandez, Haeun Hwangbo, Adam C Palmer, Matthew G Vander Heiden, Ömer H Yilmaz, Michael B Yaffe

{"title":"An RNA damage response network mediates the lethality of 5-FU in colorectal cancer.","authors":"Jung-Kuei Chen, Karl A Merrick, Yi Wen Kong, Anita Izrael-Tomasevic, George Eng, Erika D Handly, Jesse C Patterson, Ian G Cannell, Lucia Suarez-Lopez, Aaron M Hosios, Anh Dinh, Donald S Kirkpatrick, Kebing Yu, Christopher M Rose, Jonathan M Hernandez, Haeun Hwangbo, Adam C Palmer, Matthew G Vander Heiden, Ömer H Yilmaz, Michael B Yaffe","doi":"10.1016/j.xcrm.2024.101778","DOIUrl":"10.1016/j.xcrm.2024.101778","url":null,"abstract":"5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine triphosphate (dTTP), and causing DNA damage. Here, we show that clinical combinations of 5-FU with oxaliplatin or irinotecan show no synergy in human colorectal cancer (CRC) trials and sub-additive killing in CRC cell lines. Using selective 5-FU metabolites, phospho- and ubiquitin proteomics, and primary human CRC organoids, we demonstrate that 5-FU-mediated CRC cell killing primarily involves an RNA damage response during ribosome biogenesis, causing lysosomal degradation of damaged rRNAs and proteasomal degradation of ubiquitinated ribosomal proteins. Tumor types clinically responsive to 5-FU treatment show upregulated rRNA biogenesis while 5-FU clinically non-responsive tumor types do not, instead showing greater sensitivity to 5-FU's DNA damage effects. Finally, we show that treatments upregulating ribosome biogenesis, including KDM2A inhibition, promote RNA-dependent cell killing by 5-FU, demonstrating the potential for combinatorial targeting of this ribosomal RNA damage response for improved cancer therapy.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11514606/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Chronic pain management and sleep disorders. 慢性疼痛管理和睡眠障碍

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101761

Anja N Seiger, Thomas Penzel, Ingo Fietze

引用次数: 0

Closed-loop neural interfaces for pain: Where do we stand? 治疗疼痛的闭环神经接口：我们的现状如何？

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101662

Jing Wang, Zhe Sage Chen

引用次数: 0

Current developments in endometriosis-associated pain. 子宫内膜异位症相关疼痛的最新进展。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101769

Lydia Coxon, Lysia Demetriou, Katy Vincent

引用次数: 0

Targeting exosomal double-stranded RNA-TLR3 signaling pathway attenuates morphine tolerance and hyperalgesia. 靶向外泌体双链RNA-TLR3信号通路可减轻吗啡耐受性和痛觉减退。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101782

Bing Wang, Dong-Sheng Le, Li Liu, Xue-Xue Zhang, Fan Yang, Guo-Rong Lai, Chao Zhang, Mai-Lin Zhao, Yun-Peng Shen, Ping-Sheng Liao, Tong Liu, Ying-Ping Liang

{"title":"Targeting exosomal double-stranded RNA-TLR3 signaling pathway attenuates morphine tolerance and hyperalgesia.","authors":"Bing Wang, Dong-Sheng Le, Li Liu, Xue-Xue Zhang, Fan Yang, Guo-Rong Lai, Chao Zhang, Mai-Lin Zhao, Yun-Peng Shen, Ping-Sheng Liao, Tong Liu, Ying-Ping Liang","doi":"10.1016/j.xcrm.2024.101782","DOIUrl":"10.1016/j.xcrm.2024.101782","url":null,"abstract":"Long-term morphine use leads to tolerance and hyperalgesia in patients with chronic pain, with neuroinflammation playing a key role, but its underlying mechanisms remain elusive. This study determines that repeated intrathecal morphine injections increase double-stranded RNA (dsRNA) production in spinal neurons, due to downregulated adenosine deaminase RNA specific 1 (ADAR1) expression. Lentivirus-induced ADAR1 elevation decreases the high levels of intracellular dsRNA and attenuates morphine tolerance and hyperalgesia. dsRNA is released into cerebrospinal fluid via exosomes (Exos) after repeated morphine injections and is taken up by microglia for TLR3-TRIF-IL-6 signaling activation. Blocking Exos release with GW4869 or inhibition of TLR3 signaling mitigates neuroinflammation, preventing the development of morphine tolerance and hyperalgesia. Intrathecal injection of TLR3 inhibitor alone shows analgesic effects in neuropathic pain, and co-administration with morphine amplifies the analgesic efficacy of morphine. These findings demonstrate that targeting dsRNA-TLR3 signaling to mitigate neuroinflammation could be a promising treatment for morphine tolerance.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Development and validation of a machine learning model to predict myocardial blood flow and clinical outcomes from patients' electrocardiograms. 开发和验证机器学习模型，根据患者心电图预测心肌血流量和临床疗效。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 Epub Date: 2024-09-25 DOI: 10.1016/j.xcrm.2024.101746

Fares Alahdab, Maliazurina Binti Saad, Ahmed Ibrahim Ahmed, Qasem Al Tashi, Muhammad Aminu, Yushui Han, Jonathan B Moody, Venkatesh L Murthy, Jia Wu, Mouaz H Al-Mallah

{"title":"Development and validation of a machine learning model to predict myocardial blood flow and clinical outcomes from patients' electrocardiograms.","authors":"Fares Alahdab, Maliazurina Binti Saad, Ahmed Ibrahim Ahmed, Qasem Al Tashi, Muhammad Aminu, Yushui Han, Jonathan B Moody, Venkatesh L Murthy, Jia Wu, Mouaz H Al-Mallah","doi":"10.1016/j.xcrm.2024.101746","DOIUrl":"10.1016/j.xcrm.2024.101746","url":null,"abstract":"We develop a machine learning (ML) model using electrocardiography (ECG) to predict myocardial blood flow reserve (MFR) and assess its prognostic value for major adverse cardiovascular events (MACEs). Using 3,639 ECG-positron emission tomography (PET) and 17,649 ECG-single-photon emission computed tomography (SPECT) data pairs, the ML model is trained with a swarm intelligence approach and support vector regression (SVR). The model achieves a receiver-operator curve (ROC) area under the curve (AUC) of 0.83, with a sensitivity and specificity of 0.75. An ECG-MFR value below 2 is significantly associated with MACE, with hazard ratios (HRs) of 3.85 and 3.70 in the discovery and validation phases, respectively. The model's C-statistic is 0.76, with a net reclassification improvement (NRI) of 0.35. Validated in an independent cohort, the ML model using ECG data offers superior MACE prediction compared to baseline clinical models, highlighting its potential for risk stratification in patients with coronary artery disease (CAD) using the accessible 12-lead ECG.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

The evolving landscape of neuromodulation for pain care. 用于疼痛治疗的神经调控技术不断发展。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 DOI: 10.1016/j.xcrm.2024.101787

Jean-Pascal Lefaucheur, Yinghui Fan, Bifa Fan, Perianen Ramasawmy, Andrea Antal, Dimos D Mitsikostas, Cecile De Vos

引用次数: 0

A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics. 克罗恩病患者的活体类器官生物库揭示了个性化疗法的分子亚型。

IF 11.7 1区医学

Cell Reports Medicine Pub Date : 2024-10-15 Epub Date: 2024-09-26 DOI: 10.1016/j.xcrm.2024.101748

Courtney Tindle, Ayden G Fonseca, Sahar Taheri, Gajanan D Katkar, Jasper Lee, Priti Maity, Ibrahim M Sayed, Stella-Rita Ibeawuchi, Eleadah Vidales, Rama F Pranadinata, Mackenzie Fuller, Dominik L Stec, Mahitha Shree Anandachar, Kevin Perry, Helen N Le, Jason Ear, Brigid S Boland, William J Sandborn, Debashis Sahoo, Soumita Das, Pradipta Ghosh

{"title":"A living organoid biobank of patients with Crohn's disease reveals molecular subtypes for personalized therapeutics.","authors":"Courtney Tindle, Ayden G Fonseca, Sahar Taheri, Gajanan D Katkar, Jasper Lee, Priti Maity, Ibrahim M Sayed, Stella-Rita Ibeawuchi, Eleadah Vidales, Rama F Pranadinata, Mackenzie Fuller, Dominik L Stec, Mahitha Shree Anandachar, Kevin Perry, Helen N Le, Jason Ear, Brigid S Boland, William J Sandborn, Debashis Sahoo, Soumita Das, Pradipta Ghosh","doi":"10.1016/j.xcrm.2024.101748","DOIUrl":"10.1016/j.xcrm.2024.101748","url":null,"abstract":"Crohn's disease (CD) is a complex and heterogeneous condition with no perfect preclinical model or cure. To address this, we explore adult stem cell-derived organoids that retain their tissue identity and disease-driving traits. We prospectively create a biobank of CD patient-derived organoid cultures (PDOs) from colonic biopsies of 53 subjects across all clinical subtypes and healthy subjects. Gene expression analyses enabled benchmarking of PDOs as tools for modeling the colonic epithelium in active disease and identified two major molecular subtypes: immune-deficient infectious CD (IDICD) and stress and senescence-induced fibrostenotic CD (S2FCD). Each subtype shows internal consistency in the transcriptome, genome, and phenome. The spectrum of morphometric, phenotypic, and functional changes within the \"living biobank\" reveals distinct differences between the molecular subtypes. Drug screens reverse subtype-specific phenotypes, suggesting phenotyped-genotyped CD PDOs can bridge basic biology and patient trials by enabling preclinical phase \"0\" human trials for personalized therapeutics.","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11513829/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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