Pub Date : 2024-11-04DOI: 10.1038/s41423-024-01231-0
Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai
Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.
{"title":"Targeting GSDME-mediated macrophage polarization for enhanced antitumor immunity in hepatocellular carcinoma.","authors":"Shiping Chen, Peiling Zhang, Guiqi Zhu, Biao Wang, Jialiang Cai, Lina Song, Jinglei Wan, Yi Yang, Junxian Du, Yufan Cai, Jian Zhou, Jia Fan, Zhi Dai","doi":"10.1038/s41423-024-01231-0","DOIUrl":"https://doi.org/10.1038/s41423-024-01231-0","url":null,"abstract":"<p><p>Despite the notable efficacy of anti-PD1 therapy in the management of hepatocellular carcinoma (HCC) patients, resistance in most individuals necessitates additional investigation. For this study, we collected tumor tissues from nine HCC patients receiving anti-PD1 monotherapy and conducted RNA sequencing. These findings revealed significant upregulation of GSDME, which is predominantly expressed by tumor-associated macrophages (TAMs), in anti-PD1-resistant patients. Furthermore, patients with elevated levels of GSDME+ macrophages in HCC tissues presented a poorer prognosis. The analysis of single-cell sequencing data and flow cytometry revealed that the suppression of GSDME expression in nontumor cells resulted in a decrease in the proportion of M2-like macrophages within the tumor microenvironment (TIME) of HCC while concurrently augmenting the cytotoxicity of CD8 + T cells. The non-N-terminal fragment of GSDME within macrophages combines with PDPK1, thereby activating the PI3K-AKT pathway and facilitating M2-like polarization. The small-molecule Eliprodil inhibited the increase in PDPK1 phosphorylation mediated by GSDME site 1. The combination of Eliprodil and anti-PD1 was effective in the treatment of both spontaneous HCC in c-Myc + /+;Alb-Cre + /+ mice and in a hydrodynamic tail vein injection model, which provides a promising strategy for novel combined immunotherapy.</p>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":" ","pages":""},"PeriodicalIF":21.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.jacc.2024.09.012
Yihong Sun MD , Qiang Lv MD , Yuhan Guo MD , Zhifang Wang MB , Rongjie Huang MM , Xiaohong Gao MB , Yajun Han MD , Zhuhua Yao MD , Mingqi Zheng MD , Suxin Luo MD , Yue Li MD , Xiang Gu MD , Yumin Zhang MM , Junkui Wang MD , Lang Hong MD , Xueping Ma MD , Guohai Su MD , Jianlong Sheng MD , Chunlin Lai MD , Aidong Shen MS , Chang-Sheng Ma MD
Background
Currently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia.
Objectives
REMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia.
Methods
REMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level.
Results
A total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups.
Conclusions
Recaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.
背景目前可用的抗丙蛋白转化酶枯草酶/kexin 9 型单克隆抗体可有效降低低密度脂蛋白胆固醇（LDL-C）水平，但需要频繁给药。Recaticimab 是一种新型人源化单克隆抗体，可抗 9 型丙蛋白转化酶枯草酶/kexin。在一项 1b/2 期试验中，雷西替单抗作为稳定他汀类药物的附加疗法，在高胆固醇血症患者中显示出强劲的 LDL-C 降幅，给药间隔可达每 12 周一次（Q12W）。REMAIN-2（RecaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia）旨在评估雷西替单抗作为他汀类药物附加疗法对非家族性高胆固醇血症患者进行 48 周治疗的有效性和安全性。在试运行期间，患者服用稳定的中度或高强度他汀类药物，同时服用或不服用胆固醇吸收抑制剂（依折麦布）或非诺贝特，疗程≥4周。低密度脂蛋白胆固醇含量≥1.8毫摩尔/升（如果患有动脉粥样硬化性心血管疾病[ASCVD]）或≥2.6毫摩尔/升（如果没有ASCVD）的患者将随机（2:2:2:1:1:1）接受雷西替单抗150毫克每4周一次（Q4W）、300毫克每8周一次（Q8W）或450毫克Q12W，或匹配的安慰剂注射（Q4W、Q8W或Q12W），共48周。主要疗效终点是低密度脂蛋白胆固醇水平从基线到第24周的百分比变化。结果共有689名随机分配的患者接受了治疗（平均年龄55.8岁；男性，64.4%；有ASCVD病史，69.5%；同时服用依折麦布，11.2%；平均基线低密度脂蛋白胆固醇为2.8毫摩尔/升）。从基线到第24周，recaticimab与安慰剂相比，LDL-C的百分比变化更明显（P <0.0001），150 mg Q4W、300 mg Q8W和450 mg Q12W方案的最小二乘平均差分别为-62.2%（95% CI：-67.0%至-57.4%）、-59.7%（95% CI：-65.0%至-54.4%）和-53.4%（95% CI：-58.7%至-48.2%）。使用雷西替单抗后，低密度脂蛋白胆固醇的降幅一直保持到第48周。非高密度脂蛋白胆固醇、载脂蛋白B和脂蛋白（a）等次要血脂变量也有利于雷西替单抗组。在治疗期间，雷西替单抗组和安慰剂组的治疗相关不良事件发生率（28.5% vs 26.6%）和严重治疗相关不良事件发生率（0.4% vs 0.4%）同样很低。结论雷西替单抗作为稳定他汀类药物治疗的附加疗法，能在第24周显著降低LDL-C水平，并在第48周保持下降趋势，为非家族性高胆固醇血症患者提供了一种新的治疗选择，用药间隔可达每12周一次。
{"title":"Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia","authors":"Yihong Sun MD , Qiang Lv MD , Yuhan Guo MD , Zhifang Wang MB , Rongjie Huang MM , Xiaohong Gao MB , Yajun Han MD , Zhuhua Yao MD , Mingqi Zheng MD , Suxin Luo MD , Yue Li MD , Xiang Gu MD , Yumin Zhang MM , Junkui Wang MD , Lang Hong MD , Xueping Ma MD , Guohai Su MD , Jianlong Sheng MD , Chunlin Lai MD , Aidong Shen MS , Chang-Sheng Ma MD","doi":"10.1016/j.jacc.2024.09.012","DOIUrl":"10.1016/j.jacc.2024.09.012","url":null,"abstract":"<div><h3>Background</h3><div>Currently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia.</div></div><div><h3>Objectives</h3><div>REMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia.</div></div><div><h3>Methods</h3><div>REMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level.</div></div><div><h3>Results</h3><div>A total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (<em>P</em> < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups.</div></div><div><h3>Conclusions</h3><div>Recaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.</div></div>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"84 20","pages":"Pages 2037-2047"},"PeriodicalIF":21.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1016/j.jacc.2024.08.069
Jonathan W. Cunningham MD, MPH , William T. Abraham MD , Ankeet S. Bhatt MD, MBA, ScM , Jessilyn Dunn PhD , G. Michael Felker MD, MHS , Sneha S. Jain MD, MBA , Christopher J. Lindsell PhD , Matthew Mace BS , Trejeeve Martyn MD, MS , Rashmee U. Shah MD, MS , Geoffrey H. Tison MD, MPH , Tala Fakhouri PhD, MPH , Mitchell A. Psotka MD, PhD , Harlan Krumholz MD , Mona Fiuzat PharmD , Christopher M. O’Connor MD , Scott D. Solomon MD , Heart Failure Collaboratory
Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial’s life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results.
{"title":"Artificial Intelligence in Cardiovascular Clinical Trials","authors":"Jonathan W. Cunningham MD, MPH , William T. Abraham MD , Ankeet S. Bhatt MD, MBA, ScM , Jessilyn Dunn PhD , G. Michael Felker MD, MHS , Sneha S. Jain MD, MBA , Christopher J. Lindsell PhD , Matthew Mace BS , Trejeeve Martyn MD, MS , Rashmee U. Shah MD, MS , Geoffrey H. Tison MD, MPH , Tala Fakhouri PhD, MPH , Mitchell A. Psotka MD, PhD , Harlan Krumholz MD , Mona Fiuzat PharmD , Christopher M. O’Connor MD , Scott D. Solomon MD , Heart Failure Collaboratory","doi":"10.1016/j.jacc.2024.08.069","DOIUrl":"10.1016/j.jacc.2024.08.069","url":null,"abstract":"<div><div>Randomized clinical trials are the gold standard for establishing the efficacy and safety of cardiovascular therapies. However, current pivotal trials are expensive, lengthy, and insufficiently diverse. Emerging artificial intelligence (AI) technologies can potentially automate and streamline clinical trial operations. This review describes opportunities to integrate AI throughout a trial’s life cycle, including designing the trial, identifying eligible patients, obtaining informed consent, ascertaining physiological and clinical event outcomes, interpreting imaging, and analyzing or disseminating the results. Nevertheless, AI poses risks, including generating inaccurate results, amplifying biases against underrepresented groups, and violating patient privacy. Medical journals and regulators are developing new frameworks to evaluate AI research tools and the data they generate. Given the high-stakes role of randomized trials in medical decision making, AI must be integrated carefully and transparently to protect the validity of trial results.</div></div>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"84 20","pages":"Pages 2051-2062"},"PeriodicalIF":21.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1038/s41593-024-01805-1
George Andrew S. Inglis
{"title":"Astrocytes facilitate brain metastases","authors":"George Andrew S. Inglis","doi":"10.1038/s41593-024-01805-1","DOIUrl":"10.1038/s41593-024-01805-1","url":null,"abstract":"","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"27 11","pages":"2053-2053"},"PeriodicalIF":21.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-04DOI: 10.1038/s41562-024-02023-2
Gordon Pennycook, Adam J. Berinsky, Puneet Bhargava, Hause Lin, Rocky Cole, Beth Goldberg, Stephan Lewandowsky, David G. Rand
Misinformation is a major focus of intervention efforts. Psychological inoculation—an intervention intended to help people identify manipulation techniques—is being adopted at scale around the globe. Yet the efficacy of this approach for increasing belief accuracy remains unclear, as prior work uses synthetic materials that do not contain claims of truth. To address this issue, we conducted five studies with 7,286 online participants using a set of news headlines based on real-world true/false content in which we systematically varied the presence or absence of emotional manipulation. Although an emotional manipulation inoculation did help participants identify emotional manipulation, there was no improvement in participants’ ability to tell truth from falsehood. However, when the inoculation was paired with an intervention that draws people’s attention to accuracy, the combined intervention did successfully improve truth discernment (by increasing belief in true content). These results provide evidence for synergy between popular misinformation interventions.
{"title":"Inoculation and accuracy prompting increase accuracy discernment in combination but not alone","authors":"Gordon Pennycook, Adam J. Berinsky, Puneet Bhargava, Hause Lin, Rocky Cole, Beth Goldberg, Stephan Lewandowsky, David G. Rand","doi":"10.1038/s41562-024-02023-2","DOIUrl":"https://doi.org/10.1038/s41562-024-02023-2","url":null,"abstract":"<p>Misinformation is a major focus of intervention efforts. Psychological inoculation—an intervention intended to help people identify manipulation techniques—is being adopted at scale around the globe. Yet the efficacy of this approach for increasing belief accuracy remains unclear, as prior work uses synthetic materials that do not contain claims of truth. To address this issue, we conducted five studies with 7,286 online participants using a set of news headlines based on real-world true/false content in which we systematically varied the presence or absence of emotional manipulation. Although an emotional manipulation inoculation did help participants identify emotional manipulation, there was no improvement in participants’ ability to tell truth from falsehood. However, when the inoculation was paired with an intervention that draws people’s attention to accuracy, the combined intervention did successfully improve truth discernment (by increasing belief in true content). These results provide evidence for synergy between popular misinformation interventions.</p>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"20 1","pages":""},"PeriodicalIF":29.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142574710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-02DOI: 10.1016/j.jacc.2024.06.049
Lisa E Vaughan, Yoshihisa Kanaji, Sonja Suvakov, Santosh Parashuram, Yvonne S Butler Tobah, Alanna M Chamberlain, Suzette J Bielinski, Natasa Milic, Rajiv Gulati, Karl A Nath, Amir Lerman, Vesna D Garovic
Background: Angiographic evidence of the anatomy of coronary arteries and the type of coronary artery lesions in women with a history of hypertensive disorders of pregnancy (HDP) are poorly documented.
Objectives: This study sought to determine the role of a history of HDP as a unique risk factor for early coronary artery disease (CAD) and type of acute coronary syndrome (ACS) (ie, atherosclerotic vs myocardial infarction with nonobstructive coronary arteries [MINOCA]) in women who underwent coronary angiography.
Methods: This study used a population-based cohort of parous female patients with incident CAD who underwent coronary angiography and age-matched control subjects. The SYNTAX (Synergy between PCI [percutaneous coronary intervention] with TAXUS [Boston Scientific] and Cardiac Surgery) score was assessed to determine the complexity and degree of CAD; MINOCA was diagnosed in the presence of clinical acute myocardial infarction in the absence of obstructive coronary disease.
Results: A total of 506 parous female Olmsted County, Minnesota (USA) residents had incident CAD and angiographic data from November 7, 2002 to December 31, 2016. Women with HDP were younger than normotensive women at the time of the event (median: 64.8 years vs 71.8 years; P = 0.030). There was a strong association between HDP and ACS (unadjusted P = 0.018). Women with HDP compared with women with normotensive pregnancies were more likely to have a higher SYNTAX score (OR: 2.28; 95% CI: 1.02-5.12; P = 0.046), and MINOCA (OR: 2.08; 95% CI: 1.02-4.25; P = 0.044).
Conclusions: A history of HDP is associated with CAD earlier in life and with a future risk for myocardial infarction with both obstructive and nonobstructive coronary arteries. This study underscores the need for timely detection and treatment of nonobstructive disease, in addition to traditional risk factors.
{"title":"Hypertensive Disorders of Pregnancy Increase the Risk for Myocardial Infarction: A Population-Based Study.","authors":"Lisa E Vaughan, Yoshihisa Kanaji, Sonja Suvakov, Santosh Parashuram, Yvonne S Butler Tobah, Alanna M Chamberlain, Suzette J Bielinski, Natasa Milic, Rajiv Gulati, Karl A Nath, Amir Lerman, Vesna D Garovic","doi":"10.1016/j.jacc.2024.06.049","DOIUrl":"10.1016/j.jacc.2024.06.049","url":null,"abstract":"<p><strong>Background: </strong>Angiographic evidence of the anatomy of coronary arteries and the type of coronary artery lesions in women with a history of hypertensive disorders of pregnancy (HDP) are poorly documented.</p><p><strong>Objectives: </strong>This study sought to determine the role of a history of HDP as a unique risk factor for early coronary artery disease (CAD) and type of acute coronary syndrome (ACS) (ie, atherosclerotic vs myocardial infarction with nonobstructive coronary arteries [MINOCA]) in women who underwent coronary angiography.</p><p><strong>Methods: </strong>This study used a population-based cohort of parous female patients with incident CAD who underwent coronary angiography and age-matched control subjects. The SYNTAX (Synergy between PCI [percutaneous coronary intervention] with TAXUS [Boston Scientific] and Cardiac Surgery) score was assessed to determine the complexity and degree of CAD; MINOCA was diagnosed in the presence of clinical acute myocardial infarction in the absence of obstructive coronary disease.</p><p><strong>Results: </strong>A total of 506 parous female Olmsted County, Minnesota (USA) residents had incident CAD and angiographic data from November 7, 2002 to December 31, 2016. Women with HDP were younger than normotensive women at the time of the event (median: 64.8 years vs 71.8 years; P = 0.030). There was a strong association between HDP and ACS (unadjusted P = 0.018). Women with HDP compared with women with normotensive pregnancies were more likely to have a higher SYNTAX score (OR: 2.28; 95% CI: 1.02-5.12; P = 0.046), and MINOCA (OR: 2.08; 95% CI: 1.02-4.25; P = 0.044).</p><p><strong>Conclusions: </strong>A history of HDP is associated with CAD earlier in life and with a future risk for myocardial infarction with both obstructive and nonobstructive coronary arteries. This study underscores the need for timely detection and treatment of nonobstructive disease, in addition to traditional risk factors.</p>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":" ","pages":""},"PeriodicalIF":21.7,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142583308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.jtho.2024.07.002
Objectives
The use of tumor-informed circulating tumor DNA (ctDNA) testing in patients with early-stage disease before surgery is limited, mainly owing to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected NSCLC.
Method
We analyzed presurgical plasma samples from 895 patients with EGFR and anaplastic lymphoma kinase-wild-type, clinical stage I or II NSCLC. The ctDNA status was evaluated for its prognostic significance in relation to tumor volume, metabolic activity, histologic diagnosis, histologic subtypes, and clinical-to-pathologic TNM upstaging.
Results
Presurgical ctDNA detection was observed in 55 of 414 patients (13%) with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (2-year recurrence-free survival 69% versus 91%; log-rank p < 0.001), approaching that of clinical stage II LUAD. Presurgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume and positron emission tomography avidity interacted to predict presurgical ctDNA detection. Moreover, presurgical ctDNA detection was predictive of the postsurgical discovery of International Association for the Study of Lung Cancer grade 3 tumors (p < 0.001) and pathologic TNM upstaging (p < 0.001). Notably, presurgical ctDNA detection strongly correlated with higher programmed death-ligand 1 expression in tumors (positive rates 28% versus 55%, p < 0.001), identifying a subgroup likely to benefit from anti–programmed death-ligand 1 therapies.
Conclusion
These findings support the integration of ctDNA testing into routine diagnostic workflows in early-stage NSCLC without the need for tumor tissue profiling. Furthermore, it is clinically useful in identifying patients at high risk who might benefit from innovative treatments, including neoadjuvant immune checkpoint inhibitors.
{"title":"Clinical Utility of Tumor-Naïve Presurgical Circulating Tumor DNA Detection in Early-Stage NSCLC","authors":"","doi":"10.1016/j.jtho.2024.07.002","DOIUrl":"10.1016/j.jtho.2024.07.002","url":null,"abstract":"<div><h3>Objectives</h3><div>The use of tumor-informed circulating tumor DNA (ctDNA) testing in patients with early-stage disease before surgery is limited, mainly owing to restricted tissue access and extended turnaround times. This study aimed to evaluate the clinical value of a tumor-naïve, methylation-based cell-free DNA assay in a large cohort of patients with resected NSCLC.</div></div><div><h3>Method</h3><div>We analyzed presurgical plasma samples from 895 patients with <em>EGFR</em> and anaplastic lymphoma kinase-wild-type, clinical stage I or II NSCLC. The ctDNA status was evaluated for its prognostic significance in relation to tumor volume, metabolic activity, histologic diagnosis, histologic subtypes, and clinical-to-pathologic TNM upstaging.</div></div><div><h3>Results</h3><div>Presurgical ctDNA detection was observed in 55 of 414 patients (13%) with clinical stage I lung adenocarcinoma (LUAD) and was associated with poor recurrence-free survival (2-year recurrence-free survival 69% versus 91%; log-rank <em>p</em> < 0.001), approaching that of clinical stage II LUAD. Presurgical ctDNA detection was not prognostic in patients with clinical stage II LUAD or non-LUAD. Within LUAD, tumor volume and positron emission tomography avidity interacted to predict presurgical ctDNA detection. Moreover, presurgical ctDNA detection was predictive of the postsurgical discovery of International Association for the Study of Lung Cancer grade 3 tumors (<em>p</em> < 0.001) and pathologic TNM upstaging (<em>p</em> < 0.001). Notably, presurgical ctDNA detection strongly correlated with higher programmed death-ligand 1 expression in tumors (positive rates 28% versus 55%, <em>p</em> < 0.001), identifying a subgroup likely to benefit from anti–programmed death-ligand 1 therapies.</div></div><div><h3>Conclusion</h3><div>These findings support the integration of ctDNA testing into routine diagnostic workflows in early-stage NSCLC without the need for tumor tissue profiling. Furthermore, it is clinically useful in identifying patients at high risk who might benefit from innovative treatments, including neoadjuvant immune checkpoint inhibitors.</div></div>","PeriodicalId":21,"journal":{"name":"ACS Nano","volume":"19 11","pages":"Pages 1512-1524"},"PeriodicalIF":21.0,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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