{"title":"Antitumor Effect of Peptide-Camptothecin Conjugate Targeting CD133 Protein.","authors":"Yang Tao, Maoxin Du, Meihua Zhu, Yinyue Wang, Yusong Fei, Yu-Qiang Zhao, Junjie Ma, Ruifeng Fan, Fang Dai, Jingchao Chen, Junlin Yin, Baomin Fan, Guangzhi Zeng","doi":"10.1021/acs.bioconjchem.4c00485","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00485","url":null,"abstract":"<p><p>The peptide-drug conjugate (PDC) has emerged as one of the new approaches for cancer therapy, which has the advantages of improved drug target ability and reduced adverse effects compared with the traditional chemotherapy. CD133 is a surface antigen specific to cancer stem cells, which are thought to be responsible for the self-renewal, proliferation, metastasis, and chemoresistance of cancer cells. A PDC for CD133 was designed by us, and it consists of CD133 targeting peptide LS-7 (amino acid sequence LQNAPRS), a pH-sensitive linker (succinyl), and a cytotoxic payload, the cytotoxic molecule camptothecin (CPT) with potent toxicity in vivo and in vitro. An antitumor study exhibited that the conjugate LS-7-CPT has not only improved its cytotoxicity in tumor cells but also retained its anticancer effect in vivo. In addition, the acute toxicity in mice of LS-7-CPT has been improved and the maximum tolerated dose has been increased by at least 56.2-fold. Pull-down and in vivo fluorescent imaging results indicated that LS-7-CPT was enriched in mice tumors by targeting CD133 protein. As far as we know, this is the first report for a PDC molecule designed for CD133, which is important for the study of CPT drug development.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Iparomlimab (QL1604) in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) unresectable or metastatic solid tumors: a pivotal, single-arm, multicenter, phase II trial","authors":"Feng Bi, Jian Dong, Chuan Jin, Zuoxing Niu, Wenhui Yang, Yifu He, Dajun Yu, Meili Sun, Teng Wang, Xianli Yin, Ruixing Zhang, Kehe Chen, Keming Wang, Zhiwu Wang, Wei Li, Zhongtao Zhang, Hangyu Zhang, Qunyi Guo, Xin Wang, Lei Han, Xizhi Zhang, Wei Shen, Liangming Zhang, Jieer Ying, Miao Wu, Weiguo Hu, Zeng Li, Xiaofen Li, Wenlei Feng, Baihui Zhang, Lingyan Li, Xiaoyan Kang, Weijian Guo","doi":"10.1186/s13045-024-01627-5","DOIUrl":"https://doi.org/10.1186/s13045-024-01627-5","url":null,"abstract":"Though several anti-PD-1/PD-L1 antibodies approved for monotherapy in microsatellite instability-high or mismatch repair-deficient unresectable/metastatic solid tumors, novel immunotherapy with better anti-tumor activity is needed in clinic. In this single-arm, multicenter, pivotal, phase II study, patients received iparomlimab (a novel humanized anti-PD-1 mAb, 200 mg or 3 mg/kg for patients with body weight < 40 kg, IV, Q3W) until disease progression, intolerable toxicities, withdrawal of consent, death, or up to 2 years. The primary endpoint was objective response rate (ORR) assessed by independent radiological review committee (IRRC). Totally, 120 patients were enrolled, of whom 60 patients failed from prior standard therapy, were enrolled in the full analysis set (FAS). As of Jan 20, 2024, the confirmed ORR per IRRC in FAS were 50.0% (30/60; 95% CI 36.8–63.2%) patients, including 4 (6.7%) complete response (CR) and 26 (43.3%) partial response (PR). In colorectal cancer (CRC) patients in FAS, the ORR reached 57.9% (22/38; 95% CI 40.8–73.7%) per IRRC, with 3 (7.9%) CR and 19 (50.0%) PR. Furtherly, the ORRs in liver metastatic or non-liver metastatic CRC patients were 52.9% (9/17, 95% CI 27.8–77.0%) vs 61.9% (13/21, 95% CI 38.4%–81.9%). The incidence of TRAE was 90.8% (any grade) and 20.8% (grade ≥ 3). Immune-related adverse events occurred in 33.3% (any grade) and 5.0% (grade ≥ 3) of patients. No iparomlimab-related death occurred. Iparomlimab presented encouraging antitumor activity with durable response and tolerable safety profile. Trial registration ClinicalTrials.gov Identifier: NCT04326829.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"4 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Emergence of a climate oscillation in the Arctic Ocean due to global warming","authors":"Soong-Ki Kim, Soon-Il An","doi":"10.1038/s41558-024-02171-3","DOIUrl":"https://doi.org/10.1038/s41558-024-02171-3","url":null,"abstract":"<p>Global warming is expected to be able to trigger abrupt transitions in various components of the climate system. Most studies focus on abrupt changes in the mean state of the system, while transitions in climate variability are less well understood. Here, we use multimodel simulations to show that sea-ice loss in the Arctic can trigger a critical transition in internal variability that leads to the emergence of a new climate oscillation in the Arctic Ocean. The intensified air–sea interaction due to sea-ice melt causes an oscillatory behaviour of surface temperatures on a multidecadal timescale. Our results suggest that a new mode of internal variability will emerge in the Arctic Ocean when sea ice declines below a critical threshold.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"10 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sara Canato, Rahul Sarate, Sofia Carvalho-Marques, Raquel Maia Soares, Yura Song, Sara Monteiro-Ferreira, Pauline Vieugué, Mélanie Liagre, Giancarlo Grossi, Erik Cardoso, Christine Dubois, Edward M. Conway, Silvia Schenone, Adriana Sanchez-Danes, Cedric Blanpain
{"title":"Survivin promotes stem cell competence for skin cancer initiation","authors":"Sara Canato, Rahul Sarate, Sofia Carvalho-Marques, Raquel Maia Soares, Yura Song, Sara Monteiro-Ferreira, Pauline Vieugué, Mélanie Liagre, Giancarlo Grossi, Erik Cardoso, Christine Dubois, Edward M. Conway, Silvia Schenone, Adriana Sanchez-Danes, Cedric Blanpain","doi":"10.1158/2159-8290.cd-24-0263","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0263","url":null,"abstract":"Stem cells (SCs) and not progenitors (Ps) act as cells of origin of Basal Cell Carcinoma (BCC). The mechanisms promoting BCC formation in SCs or restricting tumour development in Ps are currently unknown. In this study, we transcriptionally profiled SCs and Ps and found that Survivin, a pleiotropic factor that promotes cell division and inhibits apoptosis was preferentially expressed in SCs. Using genetic gain and loss of function mouse models, we showed that Survivin deletion in oncogene-expressing SCs prevents BCC formation. Survivin overexpression renders Ps competent to BCC formation by promoting cell survival and division while preventing apoptosis and differentiation. We identified SGK1, as a key downstream factor of Survivin, and its inhibition prevents BCC formation. This study uncovers the role and mechanisms by which Survivin regulates the competence of SCs to initiate BCC formation promoting the survival of oncogene-expressing SCs and self-renewing division while restricting differentiation and apoptosis.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"245 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms","authors":"Xiaojuan Yang, Hong Wu","doi":"10.1186/s13045-024-01631-9","DOIUrl":"https://doi.org/10.1186/s13045-024-01631-9","url":null,"abstract":"Variants in the RAS family (HRAS, NRAS and KRAS) are among the most common mutations found in cancer. About 19% patients with cancer harbor RAS mutations, which are typically associated with poor clinical outcomes. Over the past four decades, KRAS has long been considered an undruggable target due to the absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements in drug design have made RAS-targeting therapies viable, particularly with the approval of direct KRASG12C inhibitors, such as sotorasib and adagrasib, for treating non-small cell lung cancer (NSCLC) with KRASG12C mutations. Other KRAS-mutant inhibitors targeting KRASG12D are currently being developed for use in the clinic, particularly for treating highly refractory malignancies like pancreatic cancer. Herein, we provide an overview of RAS signaling, further detailing the roles of the RAS signaling pathway in carcinogenesis. This includes a summary of RAS mutations in human cancers and an emphasis on therapeutic approaches, as well as de novo, acquired, and adaptive resistance in various malignancies.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"2 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mengyang Zhou, Michael D. Tyka, David T. Ho, Elizabeth Yankovsky, Scott Bachman, Thomas Nicholas, Alicia R. Karspeck, Matthew C. Long
{"title":"Mapping the global variation in the efficiency of ocean alkalinity enhancement for carbon dioxide removal","authors":"Mengyang Zhou, Michael D. Tyka, David T. Ho, Elizabeth Yankovsky, Scott Bachman, Thomas Nicholas, Alicia R. Karspeck, Matthew C. Long","doi":"10.1038/s41558-024-02179-9","DOIUrl":"https://doi.org/10.1038/s41558-024-02179-9","url":null,"abstract":"<p>To limit global warming to below 2 °C by 2100, CO<sub>2</sub> removal from the atmosphere will be necessary. One promising method for achieving CO<sub>2</sub> removal at scale is ocean alkalinity enhancement (OAE), but there are challenges with incomplete air–sea CO<sub>2</sub> equilibration, which reduces the efficiency of carbon removal. Here, we present global maps of OAE efficiency, and assess the seasonal variation in efficiency. We find that the equilibration kinetics have two characteristic timescales: rapid surface equilibration followed by a slower second phase, which represents the re-emergence of excess alkalinity that was initially subducted. These kinetics vary considerably with latitude and the season of alkalinity release, which are critical factors for determining the placement of potential OAE deployments. Additionally, we quantify the spatial and temporal scales of the induced CO<sub>2</sub> uptake, which helps identify the requirements for modelling OAE in regional ocean models.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"69 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tala FNU, Peiguo Shi, Wanwei Zhang, Sanny S.W. Chung, Christopher B. Damoci, Yinshan Fang, Qi-Yue Chen, Anjali Saqi, Yuefeng Huang, Xuebing Wu, Chao Lu, Dian Yang, Timothy C. Wang, Jianwen Que
{"title":"Sympathetic Neurons Promote Small Cell Lung Cancer Through the Beta-2 Adrenergic Receptor","authors":"Tala FNU, Peiguo Shi, Wanwei Zhang, Sanny S.W. Chung, Christopher B. Damoci, Yinshan Fang, Qi-Yue Chen, Anjali Saqi, Yuefeng Huang, Xuebing Wu, Chao Lu, Dian Yang, Timothy C. Wang, Jianwen Que","doi":"10.1158/2159-8290.cd-24-0718","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0718","url":null,"abstract":"The vagal nerve is linked to tumorigenesis in multiple tissues including small cell lung cancer (SCLC). However, the role of sympathetic neuron in SCLC development remains unknown. Here, we observed a significant reduction in tumor growth following chemical denervation of local sympathetic nerves in a mouse model of SCLC. Further study identified that β2-adrenergic receptor (ADRB2) on cancer cells mediated the crosstalk with nerve fibers. Genetic deletion or pharmacological inhibition of ADRB2 led to reduced tumor growth and improved survival. Moreover, blocking ADRB2 also reduced the growth of human SCLC organoids and xenografts. Further studies revealed that ADRB2 promoted cancer cell expansion through activating Protein Kinase A (PKA) signaling. Consistently, inhibition of PKA also reduced the growth of SCLC cells. These findings offer the initial insight into the role played by sympathetic neurons in the development of SCLC and may open a new therapeutic avenue to treat this deadly malignancy.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"70 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael Dietze, Ethan P. White, Antoinette Abeyta, Carl Boettiger, Nievita Bueno Watts, Cayelan C. Carey, Rebecca Chaplin-Kramer, Ryan E. Emanuel, S. K. Morgan Ernest, Renato J. Figueiredo, Michael D. Gerst, Leah R. Johnson, Melissa A. Kenney, Jason S. McLachlan, Ioannis Ch. Paschalidis, Jody A. Peters, Christine R. Rollinson, Juniper Simonis, Kira Sullivan-Wiley, R. Quinn Thomas, Glenda M. Wardle, Alyssa M. Willson, Jacob Zwart
{"title":"Near-term ecological forecasting for climate change action","authors":"Michael Dietze, Ethan P. White, Antoinette Abeyta, Carl Boettiger, Nievita Bueno Watts, Cayelan C. Carey, Rebecca Chaplin-Kramer, Ryan E. Emanuel, S. K. Morgan Ernest, Renato J. Figueiredo, Michael D. Gerst, Leah R. Johnson, Melissa A. Kenney, Jason S. McLachlan, Ioannis Ch. Paschalidis, Jody A. Peters, Christine R. Rollinson, Juniper Simonis, Kira Sullivan-Wiley, R. Quinn Thomas, Glenda M. Wardle, Alyssa M. Willson, Jacob Zwart","doi":"10.1038/s41558-024-02182-0","DOIUrl":"https://doi.org/10.1038/s41558-024-02182-0","url":null,"abstract":"<p>A substantial increase in predictive capacity is needed to anticipate and mitigate the widespread change in ecosystems and their services in the face of climate and biodiversity crises. In this era of accelerating change, we cannot rely on historical patterns or focus primarily on long-term projections that extend decades into the future. In this Perspective, we discuss the potential of near-term (daily to decadal) iterative ecological forecasting to improve decision-making on actionable time frames. We summarize the current status of ecological forecasting and focus on how to scale up, build on lessons from weather forecasting, and take advantage of recent technological advances. We also highlight the need to focus on equity, workforce development, and broad cross-disciplinary and non-academic partnerships.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"9 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mapping oceanic carbon potential","authors":"Darren Pilcher","doi":"10.1038/s41558-024-02135-7","DOIUrl":"https://doi.org/10.1038/s41558-024-02135-7","url":null,"abstract":"Ocean alkalinity enhancement is a commonly touted method for marine carbon dioxide removal but many questions remain, including its capacity for large-scale carbon removal. Computer models have now been used to map the timescales and efficiency of carbon removal at global scale, revealing important regional differences.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"24 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Emma Verheye, Daliya Kancheva, Hatice Satilmis, Niels Vandewalle, Rong Fan, Pauline M. R. Bardet, Emile J. Clappaert, Kevin Verstaen, Ann De Becker, Karin Vanderkerken, Kim De Veirman, Damya Laoui
{"title":"A single-cell transcriptomic map of the murine and human multiple myeloma immune microenvironment across disease stages","authors":"Emma Verheye, Daliya Kancheva, Hatice Satilmis, Niels Vandewalle, Rong Fan, Pauline M. R. Bardet, Emile J. Clappaert, Kevin Verstaen, Ann De Becker, Karin Vanderkerken, Kim De Veirman, Damya Laoui","doi":"10.1186/s13045-024-01629-3","DOIUrl":"https://doi.org/10.1186/s13045-024-01629-3","url":null,"abstract":"The long-term effectiveness of immunotherapies against Multiple Myeloma (MM) remains elusive, demonstrated by the inevitable relapse in patients. This underscores the urgent need for an in-depth analysis of the MM tumor-immune microenvironment (TME). Hereto, a representative immunocompetent MM mouse model can offer a valuable approach to study the dynamic changes within the MM-TME and to uncover potential resistance mechanisms hampering effective and durable therapeutic strategies in MM. We generated a comprehensive single-cell RNA-sequencing atlas of the MM-TME in bone marrow and spleen encompassing different stages of disease, using the immunocompetent 5T33MM mouse model. Through comparative analysis, we correlated our murine dataset with the pathogenesis in MM patients by reanalyzing publicly available datasets of human bone marrow samples across various disease stages. Using flow cytometry, we validated the dynamic changes upon disease progression in the 5T33MM model. Furthermore, interesting target populations, as well as the immune-boosting anti-CD40 agonist (αCD40) therapy were tested ex vivo on murine and human primary samples and in vivo using the 5T33MM model. In this study, we identified the heterogenous and dynamic changes within the TME of murine and human MM. We found that the MM-TME was characterized by an increase in T cells, accompanied with an exhausted phenotype. Although neutrophils appeared to be rather innocuous at early disease stages, they acquired a pro-tumorigenic phenotype during MM progression. Moreover, conventional dendritic cells (cDCs) showed a less activated phenotype in MM, underscoring the potential of immune-boosting therapies such as αCD40 therapy. Importantly, we provided the first pre-clinical evaluation of αCD40 therapy and demonstrated successful induction of cDC- and T-cell activation, accompanied by a significant short-term anti-tumor response. This resource provides a comprehensive and detailed immune atlas of the evolution in human and murine MM disease progression. Our findings can contribute to immune-based patient stratification and facilitate the development of novel and durable (immune) therapeutic strategies in MM.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"8 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}