Pub Date : 2024-10-09DOI: 10.1016/j.tips.2024.09.008
Justin W Leung, Kyle M Miller
Breast Cancer Type 1 Susceptibility Protein (BRCA)-1 existing in several functionally distinct complexes, promotes DNA repair of DNA double-strand breaks (DSBs). A recent study by Tang and colleagues identifies the lysine methyltransferase Disruptor of Telomeric Silencing 1-Like (DOT1L) involved in modifying Receptor-Associated Protein 80 (RAP80) to promote BRCA1-A complex localization and repair functions at DNA breaks. This study illuminates a potential therapeutic target for cancer radiotherapy.
乳腺癌 1 型易感蛋白(BRCA)-1 存在于多个功能不同的复合物中,可促进 DNA 双链断裂(DSB)的 DNA 修复。Tang及其同事最近的一项研究发现,赖氨酸甲基转移酶Disruptor of Telomeric Silencing 1-Like (DOT1L)参与修饰受体相关蛋白80 (RAP80),以促进BRCA1-A复合物定位和DNA断裂修复功能。这项研究为癌症放射治疗提供了一个潜在的治疗靶点。
{"title":"DOT1L: orchestrating methylation-dependent radiotheRAPy responses via BRCA1.","authors":"Justin W Leung, Kyle M Miller","doi":"10.1016/j.tips.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.tips.2024.09.008","url":null,"abstract":"<p><p>Breast Cancer Type 1 Susceptibility Protein (BRCA)-1 existing in several functionally distinct complexes, promotes DNA repair of DNA double-strand breaks (DSBs). A recent study by Tang and colleagues identifies the lysine methyltransferase Disruptor of Telomeric Silencing 1-Like (DOT1L) involved in modifying Receptor-Associated Protein 80 (RAP80) to promote BRCA1-A complex localization and repair functions at DNA breaks. This study illuminates a potential therapeutic target for cancer radiotherapy.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401423","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 : 2024-10-01Epub Date: 2024-07-24DOI: 10.1016/j.tips.2024.06.008
Yiheng Huang, Pingyi Gao, Lawrence H Young, Dake Qi
Metabolic and endocrine dysfunction of white adipose tissue (WAT) is linked to inflammation, which has been considered a key mechanism of insulin resistance (IR). However, recent studies revealed non-inflammatory mechanisms of IR in WAT, which may trigger inflammation and could be developed as a novel strategy to counteract IR.
{"title":"Targeting white adipose tissue to combat insulin resistance.","authors":"Yiheng Huang, Pingyi Gao, Lawrence H Young, Dake Qi","doi":"10.1016/j.tips.2024.06.008","DOIUrl":"10.1016/j.tips.2024.06.008","url":null,"abstract":"<p><p>Metabolic and endocrine dysfunction of white adipose tissue (WAT) is linked to inflammation, which has been considered a key mechanism of insulin resistance (IR). However, recent studies revealed non-inflammatory mechanisms of IR in WAT, which may trigger inflammation and could be developed as a novel strategy to counteract IR.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141761115","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 : 2024-10-01Epub Date: 2024-09-24DOI: 10.1016/j.tips.2024.08.006
Shweta Joshi
Spleen tyrosine kinase (SYK) is predominantly expressed in hematopoietic cells and has been extensively studied for its pivotal role in B cell malignancies and autoimmune diseases. In epithelial solid tumors, SYK shows a paradoxical role, acting as a tumor suppressor in some cancers while driving tumor growth in others. Recent preclinical studies have identified the role of SYK in the tumor microenvironment (TME), revealing that SYK signaling in immune cells, especially B cells, and myeloid cells, promote immunosuppression, tumor growth, and metastasis across various solid tumors. This review explores the emerging roles of SYK in solid tumors, the mechanisms of SYK activation, and findings from preclinical and clinical studies of SYK inhibitors as either standalone treatments or in combination with immunotherapy or chemotherapy for solid tumors.
脾酪氨酸激酶(SYK)主要在造血细胞中表达,因其在 B 细胞恶性肿瘤和自身免疫性疾病中的关键作用而被广泛研究。在上皮实体瘤中,SYK 表现出一种矛盾的作用,在某些癌症中充当肿瘤抑制剂,而在另一些癌症中则驱动肿瘤生长。最近的临床前研究发现了 SYK 在肿瘤微环境(TME)中的作用,揭示了免疫细胞(尤其是 B 细胞)和类髓细胞中的 SYK 信号传导促进了各种实体瘤的免疫抑制、肿瘤生长和转移。本综述探讨了 SYK 在实体瘤中的新作用、SYK 激活机制以及 SYK 抑制剂作为独立疗法或与免疫疗法或化疗联合治疗实体瘤的临床前和临床研究结果。
{"title":"New insights into SYK targeting in solid tumors.","authors":"Shweta Joshi","doi":"10.1016/j.tips.2024.08.006","DOIUrl":"10.1016/j.tips.2024.08.006","url":null,"abstract":"<p><p>Spleen tyrosine kinase (SYK) is predominantly expressed in hematopoietic cells and has been extensively studied for its pivotal role in B cell malignancies and autoimmune diseases. In epithelial solid tumors, SYK shows a paradoxical role, acting as a tumor suppressor in some cancers while driving tumor growth in others. Recent preclinical studies have identified the role of SYK in the tumor microenvironment (TME), revealing that SYK signaling in immune cells, especially B cells, and myeloid cells, promote immunosuppression, tumor growth, and metastasis across various solid tumors. This review explores the emerging roles of SYK in solid tumors, the mechanisms of SYK activation, and findings from preclinical and clinical studies of SYK inhibitors as either standalone treatments or in combination with immunotherapy or chemotherapy for solid tumors.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354509","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 : 2024-10-01DOI: 10.1016/j.tips.2024.09.005
Zenia Kaul, Pamela L Schwartzberg
Development of protective immune responses relies on a balance between proinflammatory CD4 T helper (Th) cell populations such as Th17 cells and regulatory CD4 T cells (Tregs) that keep immune activation in check. Evidence that interleukin-2-inducible T cell kinase (Itk) regulates this balance supports therapeutic applications for Itk inhibition.
保护性免疫反应的发展依赖于促炎性 CD4 T 辅助(Th)细胞群(如 Th17 细胞)和抑制免疫激活的调节性 CD4 T 细胞(Tregs)之间的平衡。有证据表明,白细胞介素-2诱导的T细胞激酶(Itk)可调节这种平衡,这为抑制Itk的治疗应用提供了支持。
{"title":"Balancing immune activation with Itk.","authors":"Zenia Kaul, Pamela L Schwartzberg","doi":"10.1016/j.tips.2024.09.005","DOIUrl":"https://doi.org/10.1016/j.tips.2024.09.005","url":null,"abstract":"<p><p>Development of protective immune responses relies on a balance between proinflammatory CD4 T helper (Th) cell populations such as Th17 cells and regulatory CD4 T cells (Tregs) that keep immune activation in check. Evidence that interleukin-2-inducible T cell kinase (Itk) regulates this balance supports therapeutic applications for Itk inhibition.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366579","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 : 2024-10-01Epub Date: 2024-09-23DOI: 10.1016/j.tips.2024.08.005
Hakan Doga, Aritra Bose, M Emre Sahin, Joao Bettencourt-Silva, Anh Pham, Eunyoung Kim, Alan Andress, Sudhir Saxena, Laxmi Parida, Jan Lukas Robertus, Hideaki Kawaguchi, Radwa Soliman, Daniel Blankenberg
Clinical trials are necessary for assessing the safety and efficacy of treatments. However, trial timelines are severely delayed with minimal success due to a multitude of factors, including imperfect trial site selection, cohort recruitment challenges, lack of efficacy, absence of reliable biomarkers, etc. Each of these factors possesses a unique computational challenge, such as data management, trial simulations, statistical analyses, and trial optimization. Recent advancements in quantum computing offer a promising opportunity to overcome these hurdles. In this opinion we uniquely explore the application of quantum optimization and quantum machine learning (QML) to the design and execution of clinical trials. We examine the current capabilities and limitations of quantum computing and outline its potential to streamline clinical trials.
{"title":"How can quantum computing be applied in clinical trial design and optimization?","authors":"Hakan Doga, Aritra Bose, M Emre Sahin, Joao Bettencourt-Silva, Anh Pham, Eunyoung Kim, Alan Andress, Sudhir Saxena, Laxmi Parida, Jan Lukas Robertus, Hideaki Kawaguchi, Radwa Soliman, Daniel Blankenberg","doi":"10.1016/j.tips.2024.08.005","DOIUrl":"10.1016/j.tips.2024.08.005","url":null,"abstract":"<p><p>Clinical trials are necessary for assessing the safety and efficacy of treatments. However, trial timelines are severely delayed with minimal success due to a multitude of factors, including imperfect trial site selection, cohort recruitment challenges, lack of efficacy, absence of reliable biomarkers, etc. Each of these factors possesses a unique computational challenge, such as data management, trial simulations, statistical analyses, and trial optimization. Recent advancements in quantum computing offer a promising opportunity to overcome these hurdles. In this opinion we uniquely explore the application of quantum optimization and quantum machine learning (QML) to the design and execution of clinical trials. We examine the current capabilities and limitations of quantum computing and outline its potential to streamline clinical trials.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354508","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 : 2024-10-01Epub Date: 2024-09-05DOI: 10.1016/j.tips.2024.08.001
Nanna E Andersen, Wolfgang Boehmerle, Petra Huehnchen, Tore B Stage
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy. The frequency of CIPN ranges from one in three to almost all patients depending on type of chemotherapy and dose. It causes symptoms that can range from sensitivity to touch and numbness to neuropathic pain in hands and feet. CIPN is notoriously difficult to grade objectively and has mostly relied on a clinician- or patient-based rating that is subjective and poorly reproducible. Thus, considerable effort has been aimed at identifying objective biomarkers of CIPN. Recent in vitro, animal, and clinical studies suggest that neurofilament light chain (NFL), a structural neuronal protein, may be an objective biomarker of CIPN. NFL released from cells to cell culture media reflects in vitro neurotoxicity, while NFL in serum reflects neuronal damage caused by chemotherapy in rodent models. Finally, NFL in serum may be a diagnostic biomarker of CIPN, but its prognostic ability to predict CIPN requires prospective evaluation. We discuss current limitations and future perspectives on the use of NFL as a preclinical and clinical biomarker of CIPN.
{"title":"Neurofilament light chain as a biomarker of chemotherapy-induced peripheral neuropathy.","authors":"Nanna E Andersen, Wolfgang Boehmerle, Petra Huehnchen, Tore B Stage","doi":"10.1016/j.tips.2024.08.001","DOIUrl":"10.1016/j.tips.2024.08.001","url":null,"abstract":"<p><p>Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy. The frequency of CIPN ranges from one in three to almost all patients depending on type of chemotherapy and dose. It causes symptoms that can range from sensitivity to touch and numbness to neuropathic pain in hands and feet. CIPN is notoriously difficult to grade objectively and has mostly relied on a clinician- or patient-based rating that is subjective and poorly reproducible. Thus, considerable effort has been aimed at identifying objective biomarkers of CIPN. Recent in vitro, animal, and clinical studies suggest that neurofilament light chain (NFL), a structural neuronal protein, may be an objective biomarker of CIPN. NFL released from cells to cell culture media reflects in vitro neurotoxicity, while NFL in serum reflects neuronal damage caused by chemotherapy in rodent models. Finally, NFL in serum may be a diagnostic biomarker of CIPN, but its prognostic ability to predict CIPN requires prospective evaluation. We discuss current limitations and future perspectives on the use of NFL as a preclinical and clinical biomarker of CIPN.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146303","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 : 2024-10-01Epub Date: 2024-07-16DOI: 10.1016/j.tips.2024.06.005
Dai-Qiang Liu, Wei Mei, Ya-Qun Zhou, Hong Xi
Transient receptor potential melastatin (TRPM) channels have emerged as potential therapeutic targets for cerebral ischemia-reperfusion (I/R) injury. We highlight recent findings on the involvement of TRPM channels in oxidative stress, mitochondrial dysfunction, inflammation, and calcium overload. We also discuss the challenges and future directions in targeting TRPM channels for cerebral I/R injury.
{"title":"Targeting TRPM channels for cerebral ischemia-reperfusion injury.","authors":"Dai-Qiang Liu, Wei Mei, Ya-Qun Zhou, Hong Xi","doi":"10.1016/j.tips.2024.06.005","DOIUrl":"10.1016/j.tips.2024.06.005","url":null,"abstract":"<p><p>Transient receptor potential melastatin (TRPM) channels have emerged as potential therapeutic targets for cerebral ischemia-reperfusion (I/R) injury. We highlight recent findings on the involvement of TRPM channels in oxidative stress, mitochondrial dysfunction, inflammation, and calcium overload. We also discuss the challenges and future directions in targeting TRPM channels for cerebral I/R injury.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141634629","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 : 2024-10-01Epub Date: 2024-09-05DOI: 10.1016/j.tips.2024.08.008
Manon Defaye, Christophe Altier
Maintaining gut homeostasis requires a complex interplay between the nervous and immune systems and the microbiome, but the nature of their interactions remains unclear. Chiu and Benoist's teams employed designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetics to target specific neuronal cell types and evaluate their effects on both the gut immune system and the microbiota.
{"title":"Spare the pain for your gut Treg cells!","authors":"Manon Defaye, Christophe Altier","doi":"10.1016/j.tips.2024.08.008","DOIUrl":"10.1016/j.tips.2024.08.008","url":null,"abstract":"<p><p>Maintaining gut homeostasis requires a complex interplay between the nervous and immune systems and the microbiome, but the nature of their interactions remains unclear. Chiu and Benoist's teams employed designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetics to target specific neuronal cell types and evaluate their effects on both the gut immune system and the microbiota.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146304","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 : 2024-10-01DOI: 10.1016/j.tips.2024.09.006
Jie Ting Low, Ping-Chih Ho, Mai Matsushita
Overcoming resistance to immunotherapy in cancer is challenging due, in part, to tumor-associated macrophages (TAMs) co-expressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA) in tumor microenvironments (TME) with sparse T cell infiltration. In a recent article, Vanmeerbeek et al. found that blocking TIM3 or VISTA on IL-4-supported TAMs, in combination with paclitaxel (PTX), reprogrammed TAMs to attack cancer cells, highlighting a potential new therapeutic strategy.
{"title":"TAM-tastic: from resistance to resilience in cancer.","authors":"Jie Ting Low, Ping-Chih Ho, Mai Matsushita","doi":"10.1016/j.tips.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.tips.2024.09.006","url":null,"abstract":"<p><p>Overcoming resistance to immunotherapy in cancer is challenging due, in part, to tumor-associated macrophages (TAMs) co-expressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA) in tumor microenvironments (TME) with sparse T cell infiltration. In a recent article, Vanmeerbeek et al. found that blocking TIM3 or VISTA on IL-4-supported TAMs, in combination with paclitaxel (PTX), reprogrammed TAMs to attack cancer cells, highlighting a potential new therapeutic strategy.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366580","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 : 2024-09-20DOI: 10.1016/j.tips.2024.08.004
Cheuk-Him Man, Changzheng Li, Xi Xu, Meng Zhao
Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.
{"title":"Metabolic regulation in normal and leukemic stem cells","authors":"Cheuk-Him Man, Changzheng Li, Xi Xu, Meng Zhao","doi":"10.1016/j.tips.2024.08.004","DOIUrl":"https://doi.org/10.1016/j.tips.2024.08.004","url":null,"abstract":"<p>Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) are crucial for ensuring hematopoietic homeostasis and driving leukemia progression, respectively. Recent research has revealed that metabolic adaptations significantly regulate the function and survival of these stem cells. In this review, we provide an overview of how metabolic pathways regulate oxidative and proteostatic stresses in HSCs during homeostasis and aging. Furthermore, we highlight targetable metabolic pathways and explore their interactions with epigenetics and the microenvironment in addressing the chemoresistance and immune evasion capacities of LSCs. The metabolic differences between HSCs and LSCs have profound implications for therapeutic strategies.</p>","PeriodicalId":23250,"journal":{"name":"Trends in pharmacological sciences","volume":null,"pages":null},"PeriodicalIF":13.8,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142264601","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}