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{"title":"Accelerating drug discovery, development, and clinical trials by artificial intelligence.","authors":"Yilun Zhang, Mohamed Mastouri, Yang Zhang","doi":"10.1016/j.medj.2024.07.026","DOIUrl":"10.1016/j.medj.2024.07.026","url":null,"abstract":"<p><p>Artificial intelligence (AI) has profoundly advanced the field of biomedical research, which also demonstrates transformative capacity for innovation in drug development. This paper aims to deliver a comprehensive analysis of the progress in AI-assisted drug development, particularly focusing on small molecules, RNA, and antibodies. Moreover, this paper elucidates the current integration of AI methodologies within the industrial drug development framework. This encompasses a detailed examination of the industry-standard drug development process, supplemented by a review of medications presently undergoing clinical trials. Conclusively, the paper tackles a predominant obstacle within the AI pharmaceutical sector: the absence of AI-conceived drugs receiving approval. This paper also advocates for the adoption of large language models and diffusion models as a viable strategy to surmount this challenge. This review not only underscores the significant potential of AI in drug discovery but also deliberates on the challenges and prospects within this dynamically progressing field.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large-scale pretrained frame generative model enables real-time low-dose DSA imaging: An AI system development and multi-center validation study.","authors":"Huangxuan Zhao, Ziyang Xu, Lei Chen, Linxia Wu, Ziwei Cui, Jinqiang Ma, Tao Sun, Yu Lei, Nan Wang, Hongyao Hu, Yiqing Tan, Wei Lu, Wenzhong Yang, Kaibing Liao, Gaojun Teng, Xiaoyun Liang, Yi Li, Congcong Feng, Tong Nie, Xiaoyu Han, Dongqiao Xiang, Charles B L M Majoie, Wim H van Zwam, Aad van der Lugt, P Matthijs van der Sluijs, Theo van Walsum, Yun Feng, Guoli Liu, Yan Huang, Wenyu Liu, Xuefeng Kan, Ruisheng Su, Weihua Zhang, Xinggang Wang, Chuansheng Zheng","doi":"10.1016/j.medj.2024.07.025","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.025","url":null,"abstract":"<p><strong>Background: </strong>Digital subtraction angiography (DSA) devices are commonly used in numerous interventional procedures across various parts of the body, necessitating multiple scans per procedure, which results in significant radiation exposure for both doctors and patients. Inspired by generative artificial intelligence techniques, this study proposes GenDSA, a large-scale pretrained multi-frame generative model-based real-time and low-dose DSA imaging system.</p><p><strong>Methods: </strong>GenDSA was developed to generate 1-, 2-, and 3-frame sequences following each real frame. A large-scale dataset comprising ∼3 million DSA images from 27,117 patients across 10 hospitals was constructed to pretrain, fine-tune, and validate GenDSA. Two other datasets from 25 hospitals were used for evaluation. Objective evaluations included SSIM and PSNR. Five interventional radiologists independently assessed the quality of the generated frames using the Likert scale and visual Turing test. Scoring consistency among the radiologists was measured using the Kendall coefficient of concordance (W). The Fleiss' kappa values were used for inter-rater agreement analysis for visual Turing tests.</p><p><strong>Findings: </strong>Using only one-third of the clinical radiation dose, videos generated by GenDSA were perfectly consistent with real videos. Objective evaluations demonstrated that GenDSA's performance (PSNR = 36.83, SSIM = 0.911, generation time = 0.07 s/frame) surpassed state-of-the-art algorithms. Subjective ratings and statistical results from five doctors indicated no significant difference between real and generated videos. Furthermore, the generated videos were comparable to real videos in overall quality (4.905 vs. 4.935) and lesion assessment (4.825 vs. 4.860).</p><p><strong>Conclusions: </strong>With clear clinical and translational values, the developed GenDSA can significantly reduce radiation damage to both doctors and patients during DSA-guided procedures.</p><p><strong>Funding: </strong>This study was supported by the National Key R&D Program and the National Natural Science Foundation of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilirubin metabolism in early life and respiratory health during preschool age: A combined analysis of two independent birth cohorts.","authors":"Min Kim, Nicklas Brustad, Anders U Eliasen, Mina Ali, Tingting Wang, Morten A Rasmussen, Madeleine Ernst, David Hougaard, Augusto A Litonjua, Craig E Wheelock, Rachel S Kelly, Yulu Chen, Nicole Prince, Paul A Townsend, Jakob Stokholm, Scott T Weiss, Klaus Bønnelykke, Jessica Lasky-Su, Bo Chawes","doi":"10.1016/j.medj.2024.07.021","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.021","url":null,"abstract":"<p><strong>Background: </strong>Bilirubin has antioxidant properties, and elevated levels within the normal range have been associated with improved lung function and decreased risk of asthma in adults, but studies of young children are scarce. Here, we investigate associations between bilirubin in early life and respiratory health endpoints during preschool age in two independent birth cohorts.</p><p><strong>Methods: </strong>Bilirubin metabolites were assessed at ages 0.5, 1.5, and 6 years in COPSAC₂₀₁₀ (Copenhagen Prospective Studies on Asthma in Childhood 2010) and ages 1, 3, and 6 years in the VDAART (The Vitamin D Antenatal Asthma Reduction Trial) cohort. Meta-analyses were done to summarize the relationship between levels of bilirubin metabolites and asthma, infections, lung function, and allergic sensitization until age 6 across the cohorts. Interaction with the glucuronosyltransferase family 1 member A1 (UGT1A) genotype encoding for an enzyme in the bilirubin metabolism was explored, and metabolomics data were integrated to study underlying mechanisms.</p><p><strong>Findings: </strong>Increasing bilirubin (Z,Z) at ages 1.5-3 years was associated with an increased risk of allergic sensitization (adjusted relative risk [aRR] = 1.85 [1.20-2.85], p = 0.005), and age 6 bilirubin (Z,Z) also showed a trend of association with allergic sensitization at age 6 (aRR = 1.31 [0.97-1.77], p = 0.08), which showed significant interaction for the age 6 bilirubin (Z,Z)xUGT1A genotype. Further, increasing bilirubin (E,E), bilirubin (Z,Z), and biliverdin at ages 1.5-3 years was associated with a lower forced expiratory volume at age 6 (aRR range = 0.81-0.91, p < 0.049) but without a significant interaction with the UGT1A genotype (p interactions > 0.05). Network analysis showed a significant correlation between bilirubin metabolism and acyl carnitines. There were no associations between bilirubin metabolites and the risk of asthma and infections.</p><p><strong>Conclusions: </strong>Bilirubin metabolism in early life may play a role in childhood respiratory health, particularly in children with specific UGT1A genotypes.</p><p><strong>Funding: </strong>The Lundbeck Foundation (Grant no R16-A1694), The Ministry of Health (Grant no 903516), Danish Council for Strategic Research (Grant no 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. This project has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement No. 946228). The Vitamin D Antenatal Asthma Reduction Trial (VDDART, ClinicalTrials.gov identifier: NCT00920621) was supported by grant U01HL091528 from NHLBI, U54TR001012 from the National Centers for Advancing Translational Sciences (NCATS). Metabolomics work by VDAART was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant R01HL123915 and R01HL141826. S.T.W. was suppo","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of omega-3 fatty acids on hypertriglyceridemia, lipidomics, and gut microbiome in patients with type 2 diabetes.","authors":"Jieli Lu, Ruixin Liu, Huahui Ren, Shuangyuan Wang, Chunyan Hu, Zhun Shi, Mian Li, Wei Liu, Qin Wan, Qing Su, Qifu Li, Hongting Zheng, Shen Qu, Fangming Yang, Hongyi Ji, Hong Lin, Hongyan Qi, Xueyan Wu, Kui Wu, Yuhong Chen, Yu Xu, Min Xu, Tiange Wang, Jie Zheng, Guang Ning, Ruizhi Zheng, Yufang Bi, Huanzi Zhong, Weiqing Wang","doi":"10.1016/j.medj.2024.07.024","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.024","url":null,"abstract":"<p><strong>Background: </strong>Fish oil (FO), a mixture of omega-3 fatty acids mainly comprising docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has been recommended for patients with type 2 diabetes (T2D) and hypertriglyceridemia. However, its effects on lipidomic profiles and gut microbiota and the factors influencing triglyceride (TG) reduction remain unclear.</p><p><strong>Methods: </strong>We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 309 Chinese patients with T2D with hypertriglyceridemia (ClinicalTrials.gov: NCT03120299). Participants were randomly assigned (1:1) to receive either 4 g FO or corn oil for 12 weeks. The primary outcome was changes in serum TGs and the lipidomic profile, and the secondary outcome included changes in the gut microbiome and other metabolic variables.</p><p><strong>Findings: </strong>The FO group had significantly better TG reduction (mean [95% confidence interval (CI)]: -1.51 [-2.01, -1.01] mmol/L) compared to the corn oil group (-0.66 [-1.15, -0.16] mmol/L, p = 0.02). FO significantly altered the serum lipid profile by reducing low-unsaturated TG species and increasing those containing DHA or EPA. FO had minor effects on gut microbiota, while baseline microbial features predicted the TG response to FO better than phenotypic or lipidomic features, potentially mediated by specific lipid metabolites. A total of 9 lipid metabolites significantly mediated the link between 4 baseline microbial variables and the TG response to FO supplementation.</p><p><strong>Conclusions: </strong>Our findings demonstrate differential impacts of omega-3 fatty acids on lipidomic and microbial profiles in T2D and highlight the importance of baseline gut microbiota characteristics in predicting the TG-lowering efficacy of FO.</p><p><strong>Funding: </strong>This study was funded by the National Nature Science Foundation.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Zinc for GNAO1 encephalopathy: Preclinical profiling and a clinical case.","authors":"Yonika A Larasati, Moritz Thiel, Alexey Koval, Denis N Silachev, Anne Koy, Vladimir L Katanaev","doi":"10.1016/j.medj.2024.07.023","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.023","url":null,"abstract":"<p><strong>Background: </strong>De novo pathogenic variants in GNAO1-the gene encoding the major neuronal G protein Gαo-cause pediatric encephalopathies and other neurological deficiencies largely refractory to available therapies. Zn²⁺ emerged to restore guanosine triphosphate hydrolysis and cellular interactions of pathogenic Gαo; dietary zinc salt supplementation improves lifespan and motoric function in a Drosophila disease model.</p><p><strong>Methods: </strong>Using biochemical, animal, and first-in-human studies, we provide support for the patient stratification and application of zinc acetate in GNAO1-associated disorders.</p><p><strong>Findings: </strong>We show that 16 different pathogenic missense variants cluster in three distinct groups in their responsiveness to Zn²⁺, and we provide the safety study in a mouse disease model. We further describe treatment of a 3-year-old patient with the common pathogenic GNAO1 variant c607G>A, p.Gly203Arg with oral 50 mg zinc (in the form of zinc acetate) daily, as applied in Wilson's disease. During 11 months of treatment, the patient shows cessation of daily dyskinetic crises, improved Burke-Fahn Marsden Dystonia Rating Scale movement score, reduction in epileptic seizures, and an excellent safety profile.</p><p><strong>Conclusions: </strong>Our findings warrant a large-scale clinical trial and might set the new standard of care for GNAO1-related disorders.</p><p><strong>Funding: </strong>This work was funded by the Russian Science Foundation (grant #21-15-00138) and GNAO1 España.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ticagrelor monotherapy in ST-elevation myocardial infarction: An individual patient-level meta-analysis from TICO and T-PASS trials.","authors":"Yong-Joon Lee, Deok-Kyu Cho, Jun-Won Lee, Sanghoon Shin, Sung Woo Kwon, Yongsung Suh, Tae Soo Kang, Jong-Kwan Park, Jang-Whan Bae, Woong Cheol Kang, Seunghwan Kim, Seung-Jun Lee, Sung-Jin Hong, Chul-Min Ahn, Jung-Sun Kim, Byeong-Keuk Kim, Young-Guk Ko, Donghoon Choi, Yangsoo Jang, Kyeong Ho Yun, Myeong-Ki Hong","doi":"10.1016/j.medj.2024.07.019","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.019","url":null,"abstract":"<p><strong>Background: </strong>Patients with ST-elevation myocardial infarction (STEMI) tend to be excluded or under-represented in randomized clinical trials evaluating the effects of potent P2Y12 inhibitor monotherapy after short-term dual antiplatelet therapy (DAPT).</p><p><strong>Methods: </strong>Individual patient data were pooled from randomized clinical trials that included STEMI patients undergoing drug-eluting stent (DES) implantation and compared ticagrelor monotherapy after short-term (≤3 months) DAPT versus ticagrelor-based 12-month DAPT in terms of centrally adjudicated clinical outcomes. The co-primary outcomes were efficacy outcome (composite of all-cause death, myocardial infarction, or stroke) and safety outcome (Bleeding Academic Research Consortium type 3 or 5 bleeding) at 1 year.</p><p><strong>Findings: </strong>The pooled cohort contained 2,253 patients with STEMI. The incidence of the primary efficacy outcome did not differ between the ticagrelor monotherapy group and the ticagrelor-based DAPT group (1.8% versus 2.0%; hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.49-1.61; p = 0.684). There was no difference in cardiac death between the groups (0.6% versus 0.7%; HR = 0.89; 95% CI = 0.32-2.46; p = 0.822). The incidence of the primary safety outcome was significantly lower in the ticagrelor monotherapy group (2.3% versus 4.0%; HR = 0.56; 95% CI = 0.35-0.92; p = 0.020). No heterogeneity of treatment effects was observed for the primary outcomes across subgroups.</p><p><strong>Conclusions: </strong>In patients with STEMI treated with DES implantation, ticagrelor monotherapy after short-term DAPT was associated with lower major bleeding without an increase in the risk of ischemic events compared with ticagrelor-based 12-month DAPT. Further research is necessary to extend these findings to non-Asian patients.</p><p><strong>Funding: </strong>This study was funded by Biotronik (Bülach, Switzerland).</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pembrolizumab plus chemotherapy in frontline treatment of advanced ovarian cancer: Clinical and translational results from a phase 2 trial.","authors":"Jeffrey A How, Minghao Dang, Sanghoon Lee, Bryan Fellman, Shannon N Westin, Anil K Sood, Nicole D Fleming, Aaron Shafer, Ying Yuan, Jinsong Liu, Li Zhao, Joseph Celestino, Richard Hajek, Margaret B Morgan, Edwin R Parra, Caddie D Laberiano Fernandez, Claudio A Arrechedera, Luisa Maren Solis Soto, Kathleen M Schmeler, Alpa Nick, Karen H Lu, Robert Coleman, Linghua Wang, Amir A Jazaeri","doi":"10.1016/j.medj.2024.07.022","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.022","url":null,"abstract":"<p><strong>Background: </strong>The efficacy and feasibility of pembrolizumab combined with chemotherapy in frontline management of advanced high-grade epithelial ovarian cancer (EOC) is unknown. Additionally, modification of the tumor microenvironment following neoadjuvant therapy is not well understood.</p><p><strong>Methods: </strong>In this single-arm phase 2 trial (this study was registered at ClinicalTrials.gov: NCT02520154), eligible patients received up to 4 cycles of neoadjuvant chemotherapy followed by interval cytoreduction, 3 cycles of adjuvant intravenous carboplatin/weekly paclitaxel/pembrolizumab, and finally maintenance pembrolizumab until progression or toxicity (maximum 20 cycles). The primary endpoint was progression-free survival (PFS). Secondary endpoints included feasibility, toxicity, and overall survival (OS). PD-L1 staining, multiplex immunofluorescence staining, RNA sequencing, reverse-phase protein array analyses were performed on pre- and post-chemotherapy samples.</p><p><strong>Findings: </strong>Thirty-one eligible patients were enrolled. Median PFS and OS was 14.88 (95% CI 12.39-23.00) and 57.43 months (95% CI 30.88-not reached), respectively. Among those with PD-L1 combined positive score (CPS) ≥10, the median PFS and OS were not reached compared to those with CPS <10 (10.50 and 30.90 months, respectively). Feasibility was met, with all patients completing their planned adjuvant cycles. Treatment discontinuation due to immune-related toxicity occurred in 6 patients (20%). Chemotherapy resulted in an infiltration of anti-tumor immune cells in the tumor microenvironment. Samples of patients with the best PFS demonstrated increased expression of NF-κB, TGF-β, and β-catenin signaling.</p><p><strong>Conclusions: </strong>Pembrolizumab with chemotherapy was feasible and resulted in PFS within the historical range for this EOC population. Patients with CPS ≥10 may benefit more from this regimen, and future studies should investigate this potential biomarker.</p><p><strong>Funding: </strong>This investigator-initiated trial was funded by Merck.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Homoharringtonine synergizes with venetoclax in early T cell progenitor acute lymphoblastic leukemia: Bench and bed.","authors":"Shanshan Suo, Shu Sun, Le Xuan Truong Nguyen, Jiejing Qian, Fenglin Li, Dandan Zhao, Wenjuan Yu, Yinjun Lou, Honghu Zhu, Hongyan Tong, Min Yang, Xin Huang, Shuqi Zhao, Junjing Qiao, Chen Liang, Huafeng Wang, Yi Zhang, Xiang Zhang, Dinh Hoa Hoang, Fang Chen, Hyunjun Kang, Melissa Valerio, Jie Sun, Lucy Ghoda, Ling Li, Guido Marcucci, Bin Zhang, Jie Jin","doi":"10.1016/j.medj.2024.07.018","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.018","url":null,"abstract":"<p><strong>Background: </strong>Early T cell precursor acute lymphoblastic leukemia (ETP-ALL) is a distinct subtype of T-ALL with a poor prognosis. To find a cure, we examined the synergistic effect of homoharringtonine (HHT) in combination with the BCL-2 inhibitor venetoclax (VEN) in ETP-ALL.</p><p><strong>Methods: </strong>Using in vitro cellular assays and ETP-ALL xenograft models, we first investigated the synergistic activity of HHT and VEN in ETP-ALL. Next, to explore the underlying mechanism, we employed single-cell RNA sequencing of primary ETP-ALL cells treated with HHT or VEN alone or in combination and validated the results with western blot assays. Based on the promising preclinical results and given that both drugs have been approved for clinical use, we then assessed this combination in clinical practice.</p><p><strong>Findings: </strong>Our results showed that HHT synergizes strongly with VEN both in vitro and in vivo in ETP-ALL. Mechanistic studies demonstrated that the HHT/VEN combination concurrently downregulated key anti-apoptotic proteins, i.e., MCL1, leading to enhanced apoptosis. Importantly, the clinical results were very promising. Six patients with ETP-ALL with either refractory/relapsed (R/R) or newly diagnosed disease were treated with an HHT/VEN-based regimen. All patients achieved complete remission (CR) after only one cycle of treatment.</p><p><strong>Conclusions: </strong>Our findings demonstrate that a combination of HHT/VEN is effective on ETP-ALL and represents the \"backbone\" of a promising and safe regimen for newly diagnosed and R/R patients with ETP-ALL.</p><p><strong>Funding: </strong>This work was funded by the National Cancer Institute, Gehr Family Foundation, George Hoag Family Foundation, National Natural Science Foundation of China, and Key Research and Development Program of Zhejiang Province of China.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interlesional response heterogeneity is associated with the prognosis of abiraterone treatment in metastatic castration-resistant prostate cancer.","authors":"Jian Pan, Junlong Wu, Beihe Wang, Bin Zhu, Xiaohang Liu, Hualei Gan, Yu Wei, Shengming Jin, Xiaoxin Hu, Qifeng Wang, Shaoli Song, Chang Liu, Dingwei Ye, Yao Zhu","doi":"10.1016/j.medj.2024.07.020","DOIUrl":"https://doi.org/10.1016/j.medj.2024.07.020","url":null,"abstract":"<p><strong>Background: </strong>Interlesional response heterogeneity (ILRH) poses challenges to the treatment of metastatic castration-resistant prostate cancer (mCRPC). Currently, there are no prospective clinical trials exploring the prognostic significance of ILRH on paired positron emission tomography/computed tomography (PET/CT) in the context of abiraterone therapy.</p><p><strong>Methods: </strong>In this prospective study, we enrolled patients with mCRPC treated with abiraterone (ClinicalTrials.gov: NCT05188911; ChiCTR.org.cn: ChiCTR2000034708). ⁶⁸Ga-prostate-specific membrane antigen (PSMA)+¹⁸F-fluorodeoxyglucose (FDG) PET/CT and circulating tumor DNA (ctDNA) monitoring were performed at baseline and week 13. Patients were grouped by their early ILRH measurement. The primary endpoint was to evaluate the predictive role of ILRH for conventional progression-free survival (PFS) through the concordance index (C-index) assessment. Conventional PFS was defined as the time from medication to conventional radiographic progression, clinical progression, or death.</p><p><strong>Findings: </strong>Ultimately, 33 patients were included with a median follow-up of 28.7 months. Baseline+week 13 PSMA PET/CT revealed that 33.3% of patients showed ILRH. Those patients with hetero-responding disease had significantly different PFS compared to the responding and non-responding groups (hazard ratio: responding group = reference, hetero-responding group = 4.0, non-responding group = 5.8; p < 0.0001). The C-index of ILRH on paired PSMA PET/CT (0.742 vs. 0.660) and FDG PET/CT (0.736 vs. 0.668) for conventional PFS was higher than that of PSA response. In an exploratory analysis, PSMA-/FDG+ lesions at week 13 were identified as a strong surrogate for poor conventional PFS (p = 0.039).</p><p><strong>Conclusions: </strong>ILRH on both baseline+week 13 PSMA and FDG PET/CT strongly associated with conventional PFS.</p><p><strong>Funding: </strong>This study was funded by the Ministry of Science and Technology of China and Shanghai.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapy for HFpEF: A step forward brings new hope for people with obesity and diabetes.","authors":"Lee-Ling Lim, Kamlesh Khunti","doi":"10.1016/j.medj.2024.06.011","DOIUrl":"https://doi.org/10.1016/j.medj.2024.06.011","url":null,"abstract":"<p><p>The STEP-HFpEF DM trial¹ showed that semaglutide improved body weight, systemic inflammation, and heart failure symptoms in people with obesity-related heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes. By addressing both metabolic and cardiovascular risk, semaglutide is a promising therapeutic option for HFpEF in addition to SGLT2i.</p>","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}