撰文丨王聪 编辑丨王多鱼 排版丨水成文 近日， 俄勒冈健康与科学大学、圣路易斯华盛顿大学的研究人员在 Cell 子刊 Cell Reports Medicine 上发 表了题为： Intracranial injection of genetically modified, mosquito non-transmissible Zika virus: Safety in primates and ramifications for brain tumor therapy 的研究论文。这项研究还登上了 Cell Press 头条。 胶质母细胞瘤 （GBM） 是一种侵袭性脑肿瘤，其中位生存期不足 21 个月。免疫检查点抑制剂、多肽疫苗 以及树突状细胞疫苗，在临床试验中均未显示出显著益处。在过去的二十年里，胶质母细胞瘤的护理标准 基本保持不变，包括手术、放疗、化疗，以及最近的抗有丝分裂肿瘤治疗电场。 胶质母细胞瘤在经过最大力度治疗后，通常会在 6 个月内复发，这给临床治疗带来了巨大挑战。 胶质母细 胞瘤干细胞 （GSC） 的高度异质性亚群对标准疗法具有抗性，其可能是复发的潜在驱动因素。此外，其 肿瘤微环境 （TME ...

Core Viewpoint - The study highlights the role of Cathepsin-D (CTSD) in immune evasion in microsatellite stable colorectal cancer (MSS CRC), suggesting that targeting CTSD can enhance the efficacy of anti-PD-1 therapies [2][3][5]. Group 1: Research Findings - CTSD is overexpressed in colorectal cancer, leading to immune evasion and treatment resistance [7]. - CTSD promotes the degradation of MHC-I through the lysosomal pathway, which hinders its recycling to the cell surface [5][7]. - Gene knockout or pharmacological inhibition of CTSD can block immune evasion and enhance the efficacy of anti-PD-1 therapy [6][9]. Group 2: Implications for Treatment - Targeting CTSD in conjunction with anti-PD-1 immunotherapy could potentially improve treatment outcomes for patients with MSS CRC [8][9].

Core Viewpoint - The article discusses the challenges and advancements in immunotherapy for pancreatic ductal adenocarcinoma (PDAC), highlighting a recent phase 1/2 clinical trial that demonstrates the safety and feasibility of autologous multiantigen-targeted T cell therapy for PDAC patients [2][3]. Summary by Sections Immunotherapy Challenges - PDAC presents significant challenges for effective immunotherapy due to weak expression of target antigens and frequent upregulation of immunosuppressive molecules, leading to a "cold tumor" microenvironment [2]. - The heterogeneity of tumor antigen expression can result in rapid adaptation and modulation of target antigens, hindering the potential of T cell monotherapy [2]. Clinical Trial Overview - A phase 1/2 clinical trial named TACTOPS was conducted to evaluate the safety and feasibility of an autologous non-engineered T cell product administered monthly at a dose of 1×10^7 cells/m² [7]. - The trial included three arms: patients responsive to first-line chemotherapy (Group A, n=13), patients resistant to first-line chemotherapy (Group B, n=12), and patients with resectable disease (Group C, n=12) [7]. Trial Results - Among 56 participants, 37 received the infusion with only one treatment-related serious adverse event reported [8]. - Disease control rates were 84.6% for Group A and 25% for Group B, while 2 out of 9 patients in Group C remained disease-free after 66 months of follow-up [8]. - The infused cells persisted for 12 months post-treatment, with responders showing higher levels of tumor-directed T cells compared to non-responders [8]. Conclusion and Future Directions - The study confirms the feasibility of generating autologous multi-tumor-associated antigen (mTAA) T cells for patients at all stages of pancreatic cancer, with a maximum of six infusions at a dose of 1×10^7 cells/m² being safe [8]. - The clinical outcomes are associated with the peripheral expansion of mTAA-targeted T cell clones and the emergence of antigen spreading during treatment, suggesting further research into TAA T cells as a standalone therapy or in combination with other novel immunotherapies or standard treatments [8].

撰文丨王聪 编辑丨王多鱼 排版丨水成文 该研究受 生成式人工智能 （generative AI ） 的启发，提出了 一种通用于 DSA 设备的 生成式人工智能低 剂量成像系统 —— GenDSA 。 该系统生成的 DSA 视频序列仅需使用 1/3 的扫描帧率就能生成与全帧率 几乎一致的视频序列。 使用 GenDSA 系统后，辐射剂量可降低至临床现有方案的 1/3，而不影响临床诊疗 效率 。 数字减影血管造影 （ Digital subtraction angiography， DSA） 设备广泛应用于多种疾病的介入治疗指 导，全球每日接受该检查的患者超过 10 万人次。然而，此类操作每次都需要多次扫描，会使患者及医务人 员暴露于 电离辐射 ，增加健康风险。尽管已有多种低剂量 DSA 成像技术被提出，但均未经过前瞻性临床 验证。 2026 年 1 月 2 日，华中科技大学同济医学院附属协和医院 郑传胜 、华中科技大学电子信息与通信学院 王兴刚 、武汉大学计算机学院 杜博 、 华盛顿大学医学院 朱成成 、 华中科技大学同济医学院附属协和医 院 阚雪锋 、 赵 煌旋 等人在 Nature Medicine 期刊发表 ...

Core Viewpoint - The research published in Nature Aging reveals that PIEZO1 can sense shear stress in blood flow, inducing hematopoietic stem cell (HSC) proliferation and myeloid differentiation, with implications for understanding inflammation-induced aging [2][5]. Group 1: Research Findings - The study identifies that shear stress affects both mouse and human HSCs through PIEZO1-mediated ion flow and calcium influx, regulated by the JAM3 and CAPN2 signaling pathways [5]. - The use of PIEZO1 antagonist GsMTx4 can inhibit HSC activation, thereby alleviating inflammation-induced aging in mice [5]. - These findings link the mechanical sensor PIEZO1 to HSC proliferation and myeloid differentiation, highlighting its critical role in accelerating inflammation-induced aging processes [5].

Core Viewpoint - The article discusses the development of a new RNA editing platform called AIM (adjustable RNA information manipulation), which allows for controllable and precise manipulation of multiple nucleotides within a targeted RNA region, overcoming the limitations of existing single-point RNA editing tools [2][3]. Group 1: AIM Platform Overview - The AIM platform consists of three core components: dCas13 protein for RNA targeting, a rationally designed single-strand RNA deaminase TadA, and a specially designed loop-forming gRNA (LF-gRNA) that induces a local single-stranded "loop region" on the target RNA, exposing bases for effective editing [5][6]. - The LF-gRNA also forms a double-stranded structure with the target RNA on both sides, effectively preventing off-target editing [6]. Group 2: Editing Capabilities - The research team developed three types of AIM systems with different functionalities: AIM-A/AIM-Amax for precise A-to-I editing, AIM-C/AIM-Cmax for pure C-to-U editing, and AIM-A&C/AIM-A&Cmax for simultaneous editing of A and C within the same RNA molecule [8]. - This expansion from a single editing mode to multiple functionalities allows AIM to meet diverse RNA regulatory needs [8]. Group 3: Applications and Potential - The AIM platform demonstrated unique advantages in multi-site editing, particularly in the context of read-through of the premature stop codon UAA, where two adenine bases needed to be edited simultaneously [9]. - In cystic fibrosis cell models and Duchenne muscular dystrophy mouse models, the team observed full-length protein expression and functional recovery, showcasing the potential of AIM in disease treatment [9]. - AIM was also applied to manipulate RNA information related to post-translational modifications, allowing for regulation of protein stability through editing of key phosphorylation-related codons [9]. Group 4: Safety and Specificity - Systematic safety assessments indicated that AIM maintains a low level of off-target editing events at the RNA level and does not significantly impact global gene expression [10]. - Evaluations of potential DNA off-target risks showed no significant differences in editing levels compared to negative controls, and no immune activation responses were detected in cell and animal models, indicating high specificity and good safety of the AIM platform [10]. Group 5: Future Prospects - The AIM platform enables precise manipulation of multiple bases within specific RNA regions and expands editing modes to include A-to-I, C-to-U, and simultaneous A&C editing, while demonstrating good specificity and safety [10]. - Future applications of AIM may include precise manipulation of RNA secondary structures, translation regulatory elements, and RNA-RNA or RNA-protein interaction sites, making it an important tool for understanding and reshaping RNA functions [10].

Core Viewpoint - RNA-targeted small molecule drugs are emerging as a new frontier in the biopharmaceutical field, addressing the challenge of lacking precise tertiary structure information for most disease-related RNAs, which traditional computational methods rely on for predicting interactions with small molecules [2][5]. Group 1: SMRTnet Development - The research teams from Tsinghua University and Peking University developed a deep learning tool named SMRTnet, which predicts small molecule-RNA interactions without relying on RNA tertiary structures, thus expanding the range of targetable RNA [2][5]. - SMRTnet integrates two large language models, convolutional neural networks, and graph attention networks, utilizing only RNA sequence and secondary structure information to predict binding capabilities [5]. Group 2: Performance and Validation - SMRTnet demonstrated robust performance, achieving an average area under the receiver operating characteristic curve (auROC) of 0.830-0.844 in five-fold cross-validation, significantly outperforming existing tools [9]. - In bait evaluation tasks, SMRTnet's average ranking reached 92.6%, far exceeding four molecular docking tools (27.3%-46.6%) and two deep learning tools (16.0%-23.8%), indicating its superior ability to identify true binding molecules [9]. - The model's performance was notably affected when using predicted secondary structures instead of experimentally determined ones, highlighting the importance of accurate experimental data [10]. Group 3: Binding Site Prediction - SMRTnet can also identify small molecule binding sites on RNA, quantifying the contribution of each nucleotide to the predicted binding score using the Grad-CAM algorithm [12]. - The accuracy of binding site predictions was validated against experimentally determined sites, achieving an average auROC of 0.695-0.793 across multiple datasets [13]. - Out of 190 predicted small molecule-RNA interactions, 40 were experimentally validated as binding molecules, yielding an average validation rate of 21.1% [14]. Group 4: Case Study on MYC IRES - The research focused on MYC IRES, a target considered "undruggable," showing a positive correlation between predicted binding scores and experimental validation rates, with a validation rate of 28.6% for scores between 0.9-1.0 [16]. - Among 15 identified MYC IRES binders, the team highlighted IHT (Irinotecan Hydrochloride Trihydrate) for its favorable drug development characteristics [17]. - IHT was predicted to bind at a specific site on MYC IRES, and experimental validation confirmed the reliability of SMRTnet's predictions, demonstrating significant reductions in MYC mRNA and protein levels in HeLa cells [19]. Group 5: Future Prospects - SMRTnet represents a significant advancement in predicting small molecule-RNA interactions, overcoming traditional method limitations and broadening the scope of disease-related RNA targets [21]. - The accumulation of multi-omics data, including chemical-RNA interaction genomics and functional screening, is expected to enhance AI methods for predicting binding interactions and downstream biological effects, accelerating RNA-targeted drug development [21]. - The study illustrates the potential of AI-driven approaches in RNA-targeted small molecule therapy, with expectations for breakthrough advancements in the coming years as data quality and algorithm optimization improve [21].

Core Viewpoint - The research reveals the atomic structure of pathological human islet amyloid polypeptide (hIAPP) fibrils, providing a significant foundation for understanding the mechanisms of type 2 diabetes (T2D) and developing treatment strategies [7]. Group 1: Research Findings - The study analyzed hIAPP fibrils extracted from pancreatic tissues of three T2D patients using cryo-electron microscopy (cryo-EM) [4]. - The hIAPP fibrils exhibited a uniform morphology, consisting of two symmetrical protofibrils, containing amino acid residues 2-37, and forming an Ω-shaped spatial fold [4]. - Additional electron density observed in pancreatic hIAPP fibrils suggests potential ligand binding, which may significantly impact the pathogenesis of T2D [4][5]. Group 2: Structural Insights - The core findings include the atomic structure of hIAPP fibrils derived from T2D patients [5]. - The hIAPP fibrils display an unprecedented Ω-shaped folding structure with a conserved core region [5]. - Structural similarities were observed between pathological hIAPP fibrils and Aβ fibrils [5].

Core Viewpoint - Neoadjuvant immune checkpoint blockade (NICB) therapy has become a first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC), significantly improving progression-free survival for patients. However, the pathological complete response (pCR) rate is ≤40%, indicating a need to elucidate the mechanisms of resistance to NICB to optimize treatment outcomes [3][7]. Group 1 - A recent study identified a subset of senescent EGR1+ B cells associated with poor pathological responses in ESCC patients undergoing NICB therapy, highlighting the role of these cells in treatment failure [8][11]. - EGR1 is a key transcription factor regulating B cell senescence, and the presence of EGR1+ B cells serves as a predictive marker for poor prognosis across multiple cohorts [8][11]. - The senescent B cells drive chronic inflammation in the tumor microenvironment (TME) through a senescence-associated secretory phenotype (SASP), which induces immunosuppressive TREM2+ tumor-associated macrophages (TAMs), ultimately inhibiting anti-tumor immune responses [8][11]. Group 2 - Fisetin, a natural flavonoid found in various fruits and vegetables, has been shown to alleviate B cell senescence and enhance the efficacy of NICB therapy [10][14]. - The study emphasizes that targeting B cell senescence could be a viable strategy to improve the effectiveness of NICB in treating ESCC [14].

Core Viewpoint - The article discusses the growing global issue of sleep deprivation and the ineffective solutions often promoted online, highlighting the importance of understanding circadian rhythms for better sleep quality [3][4]. Group 1: Circadian Rhythm Science - Over the past 50 years, circadian rhythm science has revealed a network of biological clocks in the human body that require regular calibration from sunlight and daily routines to function optimally [7]. - Disruption of circadian rhythms can lead to cognitive decline, emotional instability, and increased risks of various health issues, including diabetes and heart disease [7]. - Three key points for improving sleep and overall health are distinguishing between light and dark, maintaining regular meal times, and keeping consistent sleep schedules [7]. Group 2: Light Exposure - Bright light exposure during the day is crucial for synchronizing circadian rhythms and promoting melatonin production at night, which is essential for sleep [8][9]. - Indoor lighting often fails to provide the necessary light intensity for proper circadian signaling, leading to potential sleep issues [10]. - Studies indicate that individuals who receive more daylight exposure tend to have better sleep quality, while poor light exposure patterns can shorten lifespan [9][10]. Group 3: Meal Timing and Quality - Meal timing is closely linked to circadian rhythms; eating later in the evening can disrupt biological clocks and negatively impact sleep [11]. - It is recommended to have dinner at least three hours before bedtime and to avoid late-night snacking [11][12]. - The quality of food consumed also affects sleep; diets high in sugar and saturated fats can lead to disrupted sleep patterns, while plant-based foods may improve sleep quality [12]. Group 4: Sleep Consistency - Aligning sleep schedules with individual biological clocks is essential for maximizing sleep benefits, as irregular sleep patterns can lead to increased health risks [13]. - Many individuals rely on alarms to wake up, indicating a misalignment between their natural sleep patterns and daily schedules [13]. - Consistent sleep routines can enhance overall health and reduce the risk of sleep-related issues [14].