Pub Date : 2024-08-29DOI: 10.1016/j.xcrm.2024.101713
Tianyu Han, Laura Žigutytė, Luisa Huck, Marc Sebastian Huppertz, Robert Siepmann, Yossi Gandelsman, Christian Blüthgen, Firas Khader, Christiane Kuhl, Sven Nebelung, Jakob Nikolas Kather, Daniel Truhn
Reliably detecting potentially misleading patterns in automated diagnostic assistance systems, such as those powered by artificial intelligence (AI), is crucial for instilling user trust and ensuring reliability. Current techniques fall short in visualizing such confounding factors. We propose DiffChest, a self-conditioned diffusion model trained on 515,704 chest radiographs from 194,956 patients across the US and Europe. DiffChest provides patient-specific explanations and visualizes confounding factors that might mislead the model. The high inter-reader agreement, with Fleiss' kappa values of 0.8 or higher, validates its capability to identify treatment-related confounders. Confounders are accurately detected with 10%-100% prevalence rates. The pretraining process optimizes the model for relevant imaging information, resulting in excellent diagnostic accuracy for 11 chest conditions, including pleural effusion and heart insufficiency. Our findings highlight the potential of diffusion models in medical image classification, providing insights into confounding factors and enhancing model robustness and reliability.
{"title":"Reconstruction of patient-specific confounders in AI-based radiologic image interpretation using generative pretraining.","authors":"Tianyu Han, Laura Žigutytė, Luisa Huck, Marc Sebastian Huppertz, Robert Siepmann, Yossi Gandelsman, Christian Blüthgen, Firas Khader, Christiane Kuhl, Sven Nebelung, Jakob Nikolas Kather, Daniel Truhn","doi":"10.1016/j.xcrm.2024.101713","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101713","url":null,"abstract":"<p><p>Reliably detecting potentially misleading patterns in automated diagnostic assistance systems, such as those powered by artificial intelligence (AI), is crucial for instilling user trust and ensuring reliability. Current techniques fall short in visualizing such confounding factors. We propose DiffChest, a self-conditioned diffusion model trained on 515,704 chest radiographs from 194,956 patients across the US and Europe. DiffChest provides patient-specific explanations and visualizes confounding factors that might mislead the model. The high inter-reader agreement, with Fleiss' kappa values of 0.8 or higher, validates its capability to identify treatment-related confounders. Confounders are accurately detected with 10%-100% prevalence rates. The pretraining process optimizes the model for relevant imaging information, resulting in excellent diagnostic accuracy for 11 chest conditions, including pleural effusion and heart insufficiency. Our findings highlight the potential of diffusion models in medical image classification, providing insights into confounding factors and enhancing model robustness and reliability.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145221","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}
Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.
{"title":"Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.","authors":"Yaogang Zhong, Feng Geng, Logan Mazik, Xinmin Yin, Aline Paixao Becker, Shabber Mohammed, Huali Su, Enming Xing, Yongjun Kou, Cheng-Yao Chiang, Yunzhou Fan, Yongchen Guo, Qiang Wang, Pui-Kai Li, Xiaokui Mo, Etienne Lefai, Liqing He, Xiaolin Cheng, Xiang Zhang, Arnab Chakravarti, Deliang Guo","doi":"10.1016/j.xcrm.2024.101706","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101706","url":null,"abstract":"<p><p>Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis. These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo. Our findings underscore the promising therapeutic potential of effectively targeting GBM by combining glutamine metabolism inhibition with lysosome suppression.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139454","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}
Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor β1 (TGF-β1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.
{"title":"Decoding the pathogenesis of spermatogenic failure in cryptorchidism through single-cell transcriptomic profiling.","authors":"Xiaoyan Wang, Qiang Liu, Ziyan Zhuang, Jianxing Cheng, Wenxiu Zhang, Qiaoling Jiang, Yifei Guo, Ran Li, Xiaojian Lu, Lina Cui, Jiaming Weng, Yanlin Tang, Jingwei Yue, Songzhan Gao, Kai Hong, Jie Qiao, Hui Jiang, Jingtao Guo, Zhe Zhang","doi":"10.1016/j.xcrm.2024.101709","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101709","url":null,"abstract":"<p><p>Cryptorchidism, commonly known as undescended testis, affects 1%-9% of male newborns, posing infertility and testis tumor risks. Despite its prevalence, the detailed pathophysiology underlying male infertility within cryptorchidism remains unclear. Here, we profile and analyze 46,644 single-cell transcriptomes from individual testicular cells obtained from adult males diagnosed with cryptorchidism and healthy controls. Spermatogenesis compromise in cryptorchidism links primarily to spermatogonium self-renewal and differentiation dysfunctions. We illuminate the involvement of testicular somatic cells, including immune cells, thereby unveiling the activation and degranulation of mast cells in cryptorchidism. Mast cells are identified as contributors to interstitial fibrosis via transforming growth factor β1 (TGF-β1) and cathepsin G secretion. Furthermore, significantly increased levels of secretory proteins indicate mast cell activation and testicular fibrosis in the seminal plasma of individuals with cryptorchidism compared to controls. These insights serve as valuable translational references, enriching our comprehension of testicular pathogenesis and informing more precise diagnosis and targeted therapeutic strategies for cryptorchidism.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124964","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}
This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).
{"title":"Phase 1a study of ESG401, a Trop2 antibody-drug conjugate, in patients with locally advanced/metastatic solid tumors.","authors":"Jiani Wang, Zhongsheng Tong, Yinuo Tan, Yehui Shi, Yun Wu, Qing Zhou, Xiaoyan Xing, Xiaomei Chen, Fuming Qiu, Fei Ma","doi":"10.1016/j.xcrm.2024.101707","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101707","url":null,"abstract":"<p><p>This phase 1a study assesses ESG401 in patients with heavily pretreated locally advanced or metastatic solid tumors, focusing on metastatic breast cancer. Forty patients are enrolled: three experience dose-limiting toxicities, establishing the maximum tolerated dose at 16 mg/kg on days 1, 8, and 15 of a 28-day cycle. The most common grade ≥3 treatment-related adverse events are neutropenia and leukopenia. Among 38 efficacy-evaluable patients, the objective response rate (ORR) is 34.2%, the disease control rate (DCR) is 65.8%, and the clinical benefit rate (CBR) is 50.0% (including stable disease for at least 6 months). The median progression-free survival is 5.1 months, and the median duration of response is 6.3 months. In patients receiving therapeutically relevant doses, the ORR, DCR, and CBR are 40.6%, 75.0%, and 56.3%, respectively. ESG401 demonstrates a favorable safety profile and promising antitumor activity in this heavily treated population. The trial is registered at ClinicalTrials.gov (NCT04892342).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104788","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}
Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).
{"title":"CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors.","authors":"Gang Xu, Wei Liu, Ying Wang, Xiaoli Wei, Furong Liu, Yanyun He, Libo Zhang, Qin Song, Zhiyao Li, Changyu Wang, Ruihua Xu, Bo Chen","doi":"10.1016/j.xcrm.2024.101710","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101710","url":null,"abstract":"<p><p>Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131952","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}
Pub Date : 2024-08-26DOI: 10.1016/j.xcrm.2024.101702
Magdalena Schwarzmüller, Cristina Lozano, Merle Schanz, Irene A Abela, Silvan Grosse-Holz, Selina Epp, Martina Curcio, Jule Greshake, Peter Rusert, Michael Huber, Roger D Kouyos, Huldrych F Günthard, Alexandra Trkola
The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies.
{"title":"Decoupling HIV-1 antiretroviral drug inhibition from plasma antibody activity to evaluate broadly neutralizing antibody therapeutics and vaccines.","authors":"Magdalena Schwarzmüller, Cristina Lozano, Merle Schanz, Irene A Abela, Silvan Grosse-Holz, Selina Epp, Martina Curcio, Jule Greshake, Peter Rusert, Michael Huber, Roger D Kouyos, Huldrych F Günthard, Alexandra Trkola","doi":"10.1016/j.xcrm.2024.101702","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101702","url":null,"abstract":"<p><p>The development of broadly neutralizing antibody (bnAb)-based therapeutic HIV-1 vaccines and cure concepts depends on monitoring bnAb plasma activity in people with HIV (PWH) on suppressive antiretroviral therapy (ART). To enable this, analytical strategies must be defined to reliably distinguish antibody-based neutralization from drug inhibition. Here, we explore strategies that either utilize drug-resistant viruses or remove drugs from plasma. We develop ART-DEX (ART dissociation and size exclusion), an approach which quantitatively separates drugs from plasma proteins following pH-triggered release allowing accurate definition of antibody-based neutralization. We demonstrate that ART-DEX, alone or combined with ART-resistant viruses, provides a highly effective and scalable means of assessing antibody neutralization during ART. Implementation of ART-DEX in standard neutralization protocols should be considered to enhance the analytical capabilities of studies evaluating bnAb therapeutics and therapeutic vaccines, furthering the development of advanced ART and HIV-1 cure strategies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104784","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}
Pub Date : 2024-08-23DOI: 10.1016/j.xcrm.2024.101701
Qian Wang, Ian A Mellis, Yicheng Guo, Carmen Gherasim, Riccardo Valdez, Aubree Gordon, David D Ho, Lihong Liu
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies are substantially expanded 1 month after a shot of XBB.1.5 monovalent mRNA vaccine (XBB.1.5 MV) booster, but the durability of this response remains unknown. Here, we address this question by performing neutralization assays on four viral variants (D614G, BA.5, XBB.1.5, and JN.1) using sera from participants obtained at ∼1 month, ∼3 months, and ∼6 months post an XBB.1.5 MV booster. Our findings indicate that the resulting neutralizing antibody titers are robust and generally remain at stable levels for the study period, similar to those following XBB infection. Importantly, this durability of neutralizing antibody titers contrasts with the decline observed after a booster of the original monovalent or BA.5 bivalent mRNA vaccine. Our results are in line with the recent national data from the Centers for Disease Control and Prevention, showing that the efficacy against symptomatic SARS-CoV-2 infection is sustained for up to 4 months after an XBB.1.5 MV booster.
{"title":"Robust SARS-CoV-2-neutralizing antibodies sustained through 6 months post XBB.1.5 mRNA vaccine booster.","authors":"Qian Wang, Ian A Mellis, Yicheng Guo, Carmen Gherasim, Riccardo Valdez, Aubree Gordon, David D Ho, Lihong Liu","doi":"10.1016/j.xcrm.2024.101701","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101701","url":null,"abstract":"<p><p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies are substantially expanded 1 month after a shot of XBB.1.5 monovalent mRNA vaccine (XBB.1.5 MV) booster, but the durability of this response remains unknown. Here, we address this question by performing neutralization assays on four viral variants (D614G, BA.5, XBB.1.5, and JN.1) using sera from participants obtained at ∼1 month, ∼3 months, and ∼6 months post an XBB.1.5 MV booster. Our findings indicate that the resulting neutralizing antibody titers are robust and generally remain at stable levels for the study period, similar to those following XBB infection. Importantly, this durability of neutralizing antibody titers contrasts with the decline observed after a booster of the original monovalent or BA.5 bivalent mRNA vaccine. Our results are in line with the recent national data from the Centers for Disease Control and Prevention, showing that the efficacy against symptomatic SARS-CoV-2 infection is sustained for up to 4 months after an XBB.1.5 MV booster.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104790","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}
Pub Date : 2024-08-23DOI: 10.1016/j.xcrm.2024.101708
Andrea C Masi, Lauren C Beck, John D Perry, Claire L Granger, Alice Hiorns, Gregory R Young, Lars Bode, Nicholas D Embleton, Janet E Berrington, Christopher J Stewart
Necrotizing enterocolitis (NEC) is a severe intestinal disease of very preterm infants with mother's own milk (MOM) providing protection, but the contribution of the MOM microbiota to NEC risk has not been explored. Here, we analyze MOM of 110 preterm infants (48 NEC, 62 control) in a cross-sectional study. Breast milk contains viable bacteria, but there is no significant difference in MOM microbiota between NEC and controls. Integrative analysis between MOM microbiota, human milk oligosaccharides (HMOs), and the infant gut microbiota shows positive correlations only between Acinetobacter in the infant gut and Acinetobacter and Staphylococcus in MOM. This study suggests that NEC protection from MOM is not modulated through the MOM microbiota. Thus, "'restoring" the MOM microbiota in donor human milk is unlikely to reduce NEC, and emphasis should instead focus on increasing fresh maternal human milk intake and researching different therapies for NEC prevention.
坏死性小肠结肠炎(NEC)是极早产儿的一种严重肠道疾病,母乳(MOM)可提供保护,但 MOM 微生物群对 NEC 风险的影响尚未得到探讨。在此,我们通过一项横断面研究分析了 110 名早产儿(48 名 NEC,62 名对照组)的母乳微生物群。母乳中含有可存活的细菌,但 NEC 和对照组之间的 MOM 微生物群没有显著差异。MOM 微生物群、母乳低聚糖(HMOs)和婴儿肠道微生物群之间的综合分析表明,婴儿肠道中的醋杆菌与 MOM 中的醋杆菌和葡萄球菌之间存在正相关。这项研究表明,MOM 对 NEC 的保护作用并不是通过 MOM 微生物群来调节的。因此,"恢复 "供体母乳中的 MOM 微生物群不太可能减少 NEC,重点应放在增加新鲜母体母乳摄入量和研究不同的 NEC 预防疗法上。
{"title":"Human milk microbiota, oligosaccharide profiles, and infant gut microbiome in preterm infants diagnosed with necrotizing enterocolitis.","authors":"Andrea C Masi, Lauren C Beck, John D Perry, Claire L Granger, Alice Hiorns, Gregory R Young, Lars Bode, Nicholas D Embleton, Janet E Berrington, Christopher J Stewart","doi":"10.1016/j.xcrm.2024.101708","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101708","url":null,"abstract":"<p><p>Necrotizing enterocolitis (NEC) is a severe intestinal disease of very preterm infants with mother's own milk (MOM) providing protection, but the contribution of the MOM microbiota to NEC risk has not been explored. Here, we analyze MOM of 110 preterm infants (48 NEC, 62 control) in a cross-sectional study. Breast milk contains viable bacteria, but there is no significant difference in MOM microbiota between NEC and controls. Integrative analysis between MOM microbiota, human milk oligosaccharides (HMOs), and the infant gut microbiota shows positive correlations only between Acinetobacter in the infant gut and Acinetobacter and Staphylococcus in MOM. This study suggests that NEC protection from MOM is not modulated through the MOM microbiota. Thus, \"'restoring\" the MOM microbiota in donor human milk is unlikely to reduce NEC, and emphasis should instead focus on increasing fresh maternal human milk intake and researching different therapies for NEC prevention.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104786","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}
Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials.
特定的酪氨酸激酶抑制剂(TKIs)可抑制表皮生长因子受体(EGFR)的活化突变,从而改变了肺癌治疗的格局。然而,由于继发性突变和AXL(AXL受体酪氨酸激酶)等旁路受体的存在,大多数接受第一代、第二代或第三代TKIs(如奥西美替尼)治疗的患者最终会出现耐药性。为了抑制 AXL 和奥希替尼的耐药性,我们比较了两种抗 AXL 药物,一种是抗体(mAb654),另一种是 TKI(bemcentinib)。虽然奥希替尼和抗AXL药物的组合都无法防止复发,但奥希替尼、西妥昔单抗(一种抗表皮生长因子受体(EGFR)抗体)和任一种抗AXL药物的三联疗法最初是有效的。然而,长期监测发现,含 mAb654 的三联疗法更具优势,这可能是由于诱导了受体内吞、激活了免疫机制或禁用了内在突变体。因此,我们构建了一种能同时与 AXL 和表皮生长因子受体结合的双特异性抗体。该双特异性抗体与奥希替尼联用时,能持续抑制肿瘤复发,因此值得进行临床试验。
{"title":"A bispecific antibody targeting EGFR and AXL delays resistance to osimertinib.","authors":"Arturo Simoni-Nieves, Moshit Lindzen, Suvendu Giri, Nitin Gupta, Rishita Chatterjee, Boobash-Raj Selvadurai, Marieke Van Daele, Danielle Love, Yuya Haga, Donatella Romaniello, Tomer-Meir Salame, Mirie Zerbib, Roni Oren, Yasuo Tsutsumi, Mattia Lauriola, Ilaria Marrocco, Yosef Yarden","doi":"10.1016/j.xcrm.2024.101703","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101703","url":null,"abstract":"<p><p>Activating EGFR (epidermal growth factor receptor) mutations can be inhibited by specific tyrosine kinase inhibitors (TKIs), which have changed the landscape of lung cancer therapy. However, due to secondary mutations and bypass receptors, such as AXL (AXL receptor tyrosine kinase), drug resistance eventually emerges in most patients treated with the first-, second-, or third-generation TKIs (e.g., osimertinib). To inhibit AXL and resistance to osimertinib, we compare two anti-AXL drugs, an antibody (mAb654) and a TKI (bemcentinib). While no pair of osimertinib and an anti-AXL drug is able to prevent relapses, triplets combining osimertinib, cetuximab (an anti-EGFR antibody), and either anti-AXL drug are initially effective. However, longer monitoring uncovers superiority of the mAb654-containing triplet, possibly due to induction of receptor endocytosis, activation of immune mechanisms, or disabling intrinsic mutators. Hence, we constructed a bispecific antibody that engages both AXL and EGFR. When combined with osimertinib, the bispecific antibody consistently inhibits tumor relapses, which warrants clinical trials.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104783","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}
Pub Date : 2024-08-21DOI: 10.1016/j.xcrm.2024.101699
Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy
Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.
{"title":"Proteo-metabolomics and patient tumor slice experiments point to amino acid centrality for rewired mitochondria in fibrolamellar carcinoma.","authors":"Donald Long, Marina Chan, Mingqi Han, Zeal Kamdar, Rosanna K Ma, Pei-Yin Tsai, Adam B Francisco, Joeva Barrow, David B Shackelford, Mark Yarchoan, Matthew J McBride, Lukas M Orre, Nathaniel M Vacanti, Taranjit S Gujral, Praveen Sethupathy","doi":"10.1016/j.xcrm.2024.101699","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101699","url":null,"abstract":"<p><p>Fibrolamellar carcinoma (FLC) is a rare, lethal, early-onset liver cancer with a critical need for new therapeutics. The primary driver in FLC is the fusion oncoprotein, DNAJ-PKAc, which remains challenging to target therapeutically. It is critical, therefore, to expand understanding of the FLC molecular landscape to identify druggable pathways/targets. Here, we perform the most comprehensive integrative proteo-metabolomic analysis of FLC. We also conduct nutrient manipulation, respirometry analyses, as well as key loss-of-function assays in FLC tumor tissue slices from patients. We propose a model of cellular energetics in FLC pointing to proline anabolism being mediated by ornithine aminotransferase hyperactivity and ornithine transcarbamylase hypoactivity with serine and glutamine catabolism fueling the process. We highlight FLC's potential dependency on voltage-dependent anion channel (VDAC), a mitochondrial gatekeeper for anions including pyruvate. The metabolic rewiring in FLC that we propose in our model, with an emphasis on mitochondria, can be exploited for therapeutic vulnerabilities.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":null,"pages":null},"PeriodicalIF":11.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104789","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}