TCHP

乳腺癌是全球范围内发病率和肿瘤相关死亡率均较高的一种恶性肿瘤。根据肿瘤细胞表达的受体类型，乳腺癌一般可分为3种类型，包括三阴性乳腺癌（TNBC，常被称为“最毒”乳腺癌）、HER2阳性和激素受体（HR）阳性/人表皮生长因子受体2（HER2）阴性乳腺癌（“最常见”乳腺癌）。“最毒”乳腺癌前沿进展三阴性乳腺癌（TNBC）约占所有乳腺癌病例的15%~20%，这部分乳腺癌患者通常预后较差，超过50%的患者在确诊治疗后3~5年内就会出现复发。TNBC相关前沿进展给患者带来了新的治疗策略。总生存率高达90%！“最毒”乳腺癌克星，水平越高，结局越好 临床上一般建议对大多数早期TNBC患者进行辅助或新辅助化疗。化疗药物的种类和数量是根据肿瘤大小和有无淋巴结转移来选择的。而一种与较低TNBC复发风险相关的预后标志物，可以帮助识别那些在较低强度治疗下获得高治愈率的患者。肿瘤浸润淋巴细胞（TIL）是天然存在的免疫系统细胞，可以从血液中进入肿瘤，并可以识别和破坏癌细胞。对于未接受辅助或新辅助化疗的早期TNBC患者，乳腺癌组织中TIL水平与癌症复发和死亡的关系尚不清楚。发表于JAMA的一项研究结果显示，具有肿瘤内高水平TIL的早期TNBC患者即使不接受化疗，也可能具有较低的复发风险和较高的生存率。在没有采用化疗的情况下，使用TIL水平≥50%可识别5年无复发生存率、远端无复发生存率和总生存率接近或超过90%的患者：在TIL水平≥50%的TNBC患者中，5年无复发生存率、远端无复发生存率和总生存率分别为83%、88%、90%。此外，TIL水平每升高10%，无浸润性疾病生存事件、无复发生存事件、远端无病生存事件、远端无复发生存事件和死亡风险分别降低8%、10%、13%、13%和12%。约2/3人有应答！新辅助治疗新星，使30%患者获病理完全缓解近年来，新辅助疗法的应用愈发广泛，其用于TNBC可改善治疗效果。此外，新辅助治疗后，病理完全缓解（pCR）是改善TNBC长期治疗效果的既定预后生物标志物。Sacituzumab govitecan（SG）是一种靶向TROP2的新型抗体偶联药物（ADC），已获美国FDA批准用于既往已接受过治疗的转移性三阴性乳腺癌（mTNBC）。发表于Annals of Oncology的一项研究（由研究者发起的临床试验）旨在评估新辅助SG用于局部TNBC患者的初步治疗效果。研究结果显示， 单用SG的pCR率为30%（n=15/50，95% CI 18%~45%）。单用SG的总有效率（ORR）为64%（n=32/50，95% CI 77%~98%）。中位随访18.9个月，所有受试者的2年无事件生存率为95%（95% CI 88%~100%）。HER2阳性乳腺癌前沿进展 HER2阳性乳腺癌占所有乳腺癌的15%~20%，相比于HER2阴性乳腺癌，其更具有侵袭性，患者预后更差。多种新型疗法的发展，给这类患者带来了显著生存获益。不用化疗，疗效不减！99%乳腺癌患者术后3年未复发目前，新辅助曲妥珠单抗和帕妥珠单抗（简称“双靶”）联合化疗是许多早期HER2阳性乳腺癌患者的标准治疗策略，而精准医疗的发展使得免去化疗成为关注焦点。此外，新辅助治疗后，手术时pCR是预测长期结局的良好指标。对于HER2阳性乳腺癌患者来说，采用双靶策略以获得高比例的pCR、同时减轻化疗反应，并提高预后效果是临床研究的重点。发表于《柳叶刀》的一项研究（PHERGain）将356例患者随机分配至A组（多西他赛+卡铂+曲妥珠单抗+帕妥珠单抗，TCHP治疗，71例）和B组（曲妥珠单抗和帕妥珠单抗联合或不联合内分泌治疗，285例）。患者分别在基线和2个治疗周期后接受PET检查。根据PET结果调整治疗策略，进行降阶治疗，若PET检查有应答则继续接受原方案治疗6个周期，若PET检查无应答则改为接受6个周期的TCHP治疗。研究结果显示，基于18F-脱氧葡萄糖正电子发射计算机断层扫描（18F-FDG-PET）的pCR适应性策略，B组患者3年无浸润性疾病生存率为94.8%。此外，B组PET应答且达到pCR的患者（86例，约占B组的1/3）3年无浸润性疾病生存率预估为96.4%，术后3年99%（85例）患者未出现疾病复发。这一策略明确了约1/3的HER2阳性乳腺癌患者在不影响治疗效果的前提下，可安全的免于化疗。超60%患者客观缓解！乳腺癌创新疗法具有持久抗肿瘤活性 德曲妥珠单抗是一种靶向HER2的ADC。2期DESTINY-Breast01试验（中位随访11.1个月）初步分析显示，在既往接受过恩美曲妥珠单抗治疗的HER2阳性转移性乳腺癌（mBC）患者中，德曲妥珠单抗治疗具有持久的抗肿瘤活性（客观缓解率[ORR]为60.9%），不过研究未达到中位总生存期（OS）。发表于Annals of Oncology的一项研究，报告了DESTINY-Breast01试验的更新累积生存结果（中位随访26.5个月）。该结果进一步证明：在既往接受过大量治疗的HER2阳性mBC患者中，德曲妥珠单抗具有持续的抗肿瘤活性：经独立中心审评证实的ORR为62.0%（95% CI，54.5%~69.0%），其中分别有54.9%和7.1%的患者达到部分缓解和完全缓解。“最常见”乳腺癌前沿进展 无浸润性疾病生存率90.4%！这种疗法可显著降低复发或死亡风险HR阳性/HER2阴性乳腺癌占乳腺癌病例的70%~75%。这类患者中大部分在早期（1期至3期）被诊断，辅助内分泌治疗可改善其预后，但仍有部分晚期患者复发。瑞波西利（ribociclib）是一种选择性细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂，有研究表明，瑞波西利能显著提高此类晚期乳腺癌患者的生存率，但其对早期乳腺癌的影响尚不清楚。NEJM发表了NATALEE试验的预先指定的中期疗效分析结果，研究分析显示，3年时，瑞波西利+非甾体芳香化酶抑制剂[NSAI]治疗显著改善了HR阳性/HER2阴性的2期或3期早期乳腺癌患者的无浸润性疾病生存期（iDFS）（瑞波西利+NSAI组 vs. 单独NSAI组=90.4% vs. 87.1%）。与单独使用NSAI相比，瑞波西利+NSAI治疗的无浸润性疾病生存率更高，患者复发或死亡风险降低25.2%（浸润性疾病、复发或死亡的风险比为0.75；95% CI 0.62~0.91）。参考资料（可上下滑动查看）[1] Leon-Ferre RA, et al., (2024). Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer. JAMA, doi: 10.1001/jama.2024.3056. [2] Spring LM, et al., (2024). Response-guided neoadjuvant sacituzumab govitecan for localized triple-negative breast cancer: results from the NeoSTAR trial. Ann Oncol, doi: 10.1016/j.annonc.2023.11.018. [3] Pérez-García JM, et al., (2024). 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): a randomised, open-label, phase 2 trial. Lancet, doi: 10.1016/S0140-6736(24)00054-0. [4] Saura C, et al., (2024). Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01). Ann Oncol, doi: 10.1016/j.annonc.2023.12.001.[5] Slamon D, et al., (2024). Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med, doi: 10.1056/NEJMoa2305488. 来源 | 医学新视点编辑 | Swagpp● 震撼！医生太拼了！90后医生白天给患者看病，夜晚摆摊兼职一天挣1500！超70%医生表示今年想有一份兼职，大三甲医生没时间咋办？● 2024年最新医生收入报告出炉！“最香”科室大换血？最高和最低年收入的科室竟相差218万?!● 震惊！三盒药2.52元，竟引发投诉，被指控想挣患者钱！集采后出现新情况，43%网友表示药太便宜了，我反而不敢吃！如何看待？版权说明：梅斯医学（MedSci）是国内领先的医学科研与学术服务平台，致力于医疗质量的改进，为临床实践提供智慧、精准的决策支持，让医生与患者受益。欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。点击下方「阅读原文」 立刻下载梅斯医学APP！

2024年1月25日，乳腺癌 NCCN 指南更新至2024.V1版，此次药物治疗方面的更新主要涉及化疗药物的选择和剂量的调整，具体更新内容如下。并且本文汇总了最新版乳腺癌NCCN指南推荐的靶向、免疫药及方案选择，仅供参考。01术前/辅助治疗方案HER2阴性的三阴性乳腺癌（TNBC）其他推荐方案调整：● 紫杉醇+卡铂（不同给药方式）调整为2A类证据● 多西他赛+卡铂删除“仅用于新辅助治疗”，调整为2A类证据HER2 阳性乳腺癌其他推荐方案调整：● 新增紫杉醇/卡铂+曲妥珠单抗+帕妥珠单抗HER2 阴性乳腺癌其他推荐方案给药剂量调整：● 多西他赛＋卡铂（4～6个周期），删除“仅限术前”HER2 阳性乳腺癌首选方案调整：● 新增TDM-1方案，剂量每日3.6mg/kg，21天一个疗程，共14个疗程02全身治疗方案ER和/或PR阳性复发不可切除（局部或区域）或IV期（M1）乳腺癌其他推荐治疗方案调整：● 修改第二条：选择性ER下调剂（氟维司群）＋非甾体芳香化酶抑制剂（阿那曲唑、来曲唑）（1 类），删除氟维司群的“1类推荐”复发性不可切除（局部或区域）或Ⅳ期（M1）疾病靶向治疗和相关生物标志物检测调整：● 新增任何亚型的生物标志物检测：胚系BRCA1或BRCA2突变，胚系测序，FDA批准用药为奥拉帕利、他拉唑帕利，NCCN指南的证据类别为1类，NCCN指南推荐为首选方案● HR阳性/HER2阴性的生物标志物检测修订为：PIK3CA或AKT1激活突变或PTEN突变；NGS检测的样本类型修改为：血液或如果血液阴性则使用肿瘤组织● 其他检测的样本类型修改HER2阴性方案化疗药物调整：● 新增抗代谢药物：卡培他滨1500mg口服，每日两次，第1-7天和第15-21天，每28天循环现将2024.V1版乳腺癌NCCN指南推荐的靶向、免疫药物及使用方案汇总如下：01术前/辅助治疗方案HER2阴性首选方案：① 奥拉帕利, 如果基因检测为胚系BRCA1/2 突变② 高危的三阴性乳腺癌 （TNBC）：术前帕博利珠单抗+卡铂+紫杉醇，随后术前帕博利珠单抗+环磷酰胺+阿霉素或表柔比星，随后辅助帕博利珠单抗脚注：c.以下情况考虑加用奥拉帕利辅助治疗1年，胚系BRCA1/2突变且：● 三阴性乳腺癌（TNBC），如果1）≥pT2或≥pN1辅助化疗后，或2）新辅助化疗后残留病灶。● HR阳性，HER2阴性，如果1）辅助化疗后≥4个阳性淋巴结（2A类），或2）术前治疗后残留病变和临床分期、病理分期、雌激素受体状态和肿瘤分级（CPS+EG） 评分≥3。辅助奥拉帕利可与内分泌治疗同时使用。d.OlympiA 研究中的患者未接受卡培他滨治疗，因此没有先后顺序或一种方案优于另一种的证据。e.High-risk 高危标准包括II～III期TNBC。辅助帕博利珠单抗（2A类）的使用可能需要个体化。HER2阳性首选方案：① 紫杉醇+曲妥珠单抗② TCH（多西他赛/卡铂/曲妥珠单抗）③ TCHP（多西他赛/卡铂/曲妥珠单抗/帕妥珠单抗）④ 如果术前治疗后无残留病灶或未接受术前治疗：使用曲妥珠单抗（1类）±帕妥珠单抗完成长达一年的抗HER2靶向治疗⑤ 如果术前治疗后残留病灶：单独使用恩美曲妥珠单抗 (T-DM1)（1类）。如果因毒性停用恩美曲妥珠单抗 (T-DM1)，则使用曲妥珠单抗（1类）±帕妥珠单抗完成一年的治疗。如果初始淋巴结阳性，采用曲妥珠单抗+帕妥珠单抗（1类）在某些情况下使用：① 多西他赛+环磷酰胺+曲妥珠单抗② AC序贯T+曲妥珠单抗（阿霉素/环磷酰胺序贯紫杉醇+曲妥珠单抗，多种方案）③ AC序贯T+曲妥珠单抗+帕妥珠单抗（阿霉素/环磷酰胺序贯紫杉醇+曲妥珠单抗+帕妥珠单抗，多种方案）④ 来那替尼（仅辅助治疗）⑤ 紫杉醇+曲妥珠单抗+帕妥珠单抗⑥ 恩美曲妥珠单抗 (T-DM1)（仅辅助治疗）其他推荐方案：① AC序贯多西他赛+曲妥珠单抗（阿霉素+环磷酰胺序贯多西他赛+曲妥珠单抗）② AC序贯多西他赛+曲妥珠单抗+帕妥珠单抗（阿霉素/环磷酰胺序贯多西他赛+曲妥珠单抗+帕妥珠单抗）③ 紫杉醇/卡铂+曲妥珠单抗+帕妥珠单抗02全身治疗方案ER和/或PR阳性复发不可切除（局部或区域）或IV期（M1）乳腺癌HER2阴性，绝经后或绝经前接受卵巢切除或抑制首选方案：ⅰ 一线治疗① 芳香化酶抑制剂+CDK4/6抑制剂（瑞博西尼（1类），阿贝西利，帕博西尼）② 氟维司群+CDK4/6抑制剂（瑞博西尼（1类），阿贝西利（1类），帕博西尼）ⅱ 二线及后续治疗① 如果既往未使用过CDK4/6抑制剂，则使用氟维司群+CDK4/6抑制剂（阿贝西利，帕博西尼，瑞博西尼）（1类）② 针对PIK3CA激活突变患者，使用阿培利司+氟维司群（1类）、卡帕塞替尼+氟维司群（1类）针对AKT1激活突变或PTEN突变患者，使用卡帕塞替尼+氟维司群（1类）③ 依维莫司+内分泌治疗（依西美坦、氟维司群、他莫昔芬）其他推荐方案：ⅰ 一线和/或后续治疗① 选择性 ER 下调剂（氟维司群、ESR1突变：依拉司群（2A类，其他推荐））② 选择性ER下调调节剂（氟维司特）+非甾体芳香化酶抑制剂（阿那曲唑，来曲唑）（1类）③ 非甾体芳香化酶抑制剂（阿那曲唑、来曲唑）④ 选择性雌激素受体调节剂（他莫昔芬）⑤ 甾体芳香化酶抑制剂（依西美坦）在某些情况下有用：ⅰ后续治疗① 阿贝西利HER2阳性，绝经后或绝经前接受卵巢切除或抑制① 芳香化酶抑制剂±曲妥珠单抗 ② 芳香化酶抑制剂±拉帕替尼 ③ 芳香化酶抑制剂±拉帕替尼 + 曲妥珠单抗 ④ 氟维司群±曲妥珠单抗 ⑤ 他莫昔芬±曲妥珠单抗HR阳性和HER2阴性的伴有内脏危机或内分泌难治性的复发性不可切除（局部或区域）或IV期（M1）乳腺癌ⅰ 一线治疗胚系BRCA1/2突变：PARP抑制剂（奥拉帕利，他拉唑帕尼）（1类，首选）ⅱ 二线治疗HER2 IHC 1+或2+/ISH阴性：德曲妥珠单抗（1类，首选）ⅲ 三线或后线治疗① MSI-H/dMMR ：多塔利单抗、帕博利珠单抗（2A类，在某些情况下使用）② NTRK融合：拉罗替尼、恩曲替尼（2A类，在某些情况下使用）③ RET融合：塞尔帕替尼（2A类，在某些情况下使用）④ TMB-H(≥10 mut/Mb)：帕博利珠单抗（2A类，在某些情况下使用）HR阴性和HER2阴性的复发性不可切除（局部或区域）或IV期（M1）的三阴性乳腺癌ⅰ 一线治疗① PD-L1 CPS≥10且无论是否具有BRCA1/2胚系突变：帕博利珠单抗+化疗（白蛋白紫杉醇、紫杉醇、或吉西他滨和卡铂）（1类，首选）② PD-L1 CPS＜10且BRCA1/2胚系突变：PARP抑制剂（奥拉帕利，他拉唑帕尼）（1类，首选）或铂类（顺铂或卡铂）（1类，首选）ⅱ 二线治疗① BRCA1/2胚系突变：PARP抑制剂（奥拉帕利，他拉唑帕尼）（1类，首选）② 无BRCA1/2胚系突变且HER2 IHC1+或2+/ISH阴性：德曲妥珠单抗（1类，首选）ⅲ 三线或后线治疗① MSI-H/dMMR ：多塔利单抗、帕博利珠单抗（2A类，在某些情况下使用）② NTRK融合：拉罗替尼、恩曲替尼（2A类，在某些情况下使用）③ RET融合：塞尔帕替尼（2A类，在某些情况下使用）④ TMB-H(≥10 mut/Mb)：帕博利珠单抗（2A类，在某些情况下使用）HR+/-、HER2阳性的复发性不可切除（局部或区域）或IV期（M1）的乳腺癌ⅰ 一线治疗① 帕妥珠单抗+曲妥珠单抗+多西他赛(1类，首选方案）② 帕妥珠单抗+曲妥珠单抗+紫杉醇(2A类，首选方案）  ⅱ 二线治疗① 德曲妥珠单抗(1类，首选方案）  ⅲ 三线治疗① 图卡替尼+曲妥珠单抗+卡培他滨(1类，首选方案）② 恩美曲妥珠单抗(T-DM1)ⅳ 四线及以上治疗(最佳顺序未知)：① 曲妥珠单抗+多西他赛/长春瑞滨② 曲妥珠单抗+紫杉醇±卡铂③ 卡培他滨+曲妥珠单抗/拉帕替尼④ 曲妥珠单抗+拉帕替尼（无细胞毒性治疗）⑤ 曲妥珠单抗+其他化疗药物⑥ 来那替尼+卡培他滨⑦ 玛格妥昔单抗+化疗（卡培他滨、艾日布林、吉西他滨或长春瑞滨）新兴的生物标志物，用于识别iv期（M1）疾病患者的新的治疗方法① HER2激活突变：来那替尼±氟维司群（2B类，在某些情况下使用：ER+/HER2-且已接受CDK4/6抑制剂治疗的患者）、来那替尼±曲妥珠单抗/氟维司群（2B类，在某些情况下使用：ER+/HER2-且已接受CDK4/6抑制剂治疗的患者）② 体系BRCA1/2突变：奥拉帕尼（2B类，在某些情况下使用）③ 胚系PALB2突变：奥拉帕尼（2B类，在某些情况下使用）（注：NCCN指南中，所有建议均属2A类，除非另有说明）参考资料：2024.v1版乳腺癌NCCN指南编辑：momo声明：本文仅供医疗卫生专业人士为了解资讯使用，不代表本平台观点。该信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议。如该信息被用于了解资讯以外的目的，平台及作者不承担相关责任。

KANAZAWA, Japan, Jan. 10, 2024 /PRNewswire/ -- Researchers at Nano Life Science Institute (WPI-NanoLSI), Kanazawa University report in Nano Letters how the flexibility of a protein hinge plays a crucial role in the transfer of proteins in key cell processes. Ubiquitination – the addition of the protein ubiquitin - is a key stage in many cell processes, such as protein degradation, DNA repairs, and signal transduction. Using high-speed atomic force microscopy (HS-AFM) and molecular modelling, researchers led by Hiroki Konno and Holger Flechsig at WPI-NanoLSI, Kanazawa University have identified how the mobility of a ubiquitination related enzyme hinge allows ubiquitination to take place. Previous studies have identified a number of enzymes that facilitate ubiquitination, including an enzyme that activates ubiquitin (E1), an enzyme that conjugates it (E2), and an enzyme that catalyzes ubiquitin protein joining (i.e. a ligase, E3) to target protein (Fig. 1). The HECT-type E3 ligase is characterized by a HECT domain that comprises an N lobe with the E2-binding site and a C lobe with a catalytic Cys residue, a flexible hinge connects the two lobes, leading to the hypothesis that ubiquitination is facilitated by the rearrangement of the protein around this hinge. Konno and their collaborators deployed their high-speed atomic force microscope to hunt for evidence that this was the case. The researchers noted that when the HECT domain was crystallized with a type of E2 enzyme, it formed an L shape such that the distance between the catalytic Cys residue of the HECT domain and the catalytic Cys of the E2 enzyme was 41 Å – too far for the transfer of ubiquitin. However, in its catalytic conformation the HECT domain has a different shape where the distance between the two catalytic Cys residues is much closer – just 8 Å – so this is thought to be a 'catalytic conformation'. Analysis of HS-AFM images of a wild-type HECT domain of E6AP revealed two conformations – one of which looked spherical and the other oval (Fig. 2). Using AFM simulations they attributed the oval shapes to the L conformation and spherical shapes are either the catalytic conformation or the so called inverted T conformation, which had been observed in the another type of HECT domain where the distance between the Cys residues is 16 Å (Fig. 2). To overcome the spatio-temporal resolution limitations of imaging, the experiments were complemented by molecular modelling to visualize HECT domain conformational motions at the atomistic level. Simulation AFM was used to generate a corresponding pseudo AFM movie, which clearly showed the change from spherical to the oval shaped topography (Fig. 2). "Although experimental limitations do not allow us to resolve the intermediate conformations," explain the researchers in their report of the work. "The performed modeling provides evidence that the transitions between spherical and oval HECT domain shapes observed under HS-AFM correspond to functional conformational motions under which the C-lobe rotates relative to the N-lobe, thereby allowing the change between catalytic and L-shape HECT conformations." Further experiments with mutant HECT domains with less flexibility in the hinge revealed no flipping between conformations – the mutant HECT domains were locked in the catalytic conformation. They also found that while these mutant HECT domains could form two ubiquitin proteins joined together more efficiently than the wild type. E6AP, the HECT-type E3 in this study, interacts with E6 protein derived from human papillomavirus (HPV) and ubiquitinates p53, a tumor suppressor protein. It is also known that ubiquitination of p53 by E6AP and E6 is a major cause of cervical cancer. However, the mechanism of p53 ubiquitination by the interaction of E6AP and E6 proteins remains unclear. In the future, we will elucidate the structural dynamics of E6AP/E6, and the E6AP/E6/p53 complex with HS-AFM, and clarify how E6 increases the activity of p53 ubiquitination by E6AP. Figure 1 link: Fig 1 caption: Ubiquitination and degradation of protein by the ubiquitin-proteasome system. © 2023 Takeda, et al., Published by American Chemical Society Fig. 2 link: Fig 2 caption: High-speed AFM observation and simulation of the structural dynamics of the HECT domain of E6AP. (A) HS-AFM image of the HECT domain. Spherical (white dotted line) and oval (blue dotted line) conformational states were observed. (B) Simulated transition process of the structural state of the HECT domain and its pseudo AFM image. (C) Ubiquitin (Ub) is transferred from E2 to E3 (HECT domain). After the addition of ubiquitin-containing E2 (E2-Ub), E2-Ub (white arrow) binds to the HECT domain, and after E2 dissociates, a small particle (blue arrow) that appears to be ubiquitin is added to the HECT domain. © 2023 Takeda, et al., Published by American Chemical Society Glossary Ubiquitin The protein takes its name from the term 'ubiquitous' because it is found in almost all tissues. It can be added as a single protein or further proteins added into a chain. This 'ubiquitination' is an essential step in many cell processes. High-speed atomic force microscopy This imaging technique uses a nanosized tip at the end of a cantilever that is scanned over a sample. It can be used to determine the topography of a sample surface from the change in the strength of forces between the tip and the sample with distance, and the resulting deflection of the cantilever. It was first developed in the 1980s but a number of modifications have augmented the functionality of the technique since. It is better suited to imaging biological samples than the scanning tunnelling microscope developed that had been developed because it does not require a conducting sample. In the 2000s Toshio Ando at Kanazawa University was able to improve the scanning speed to such an extent that moving images could be captured. This allowed people to use the technique to visualize molecular processes for the first time. Reference Kazusa Takeda†, Holger Flechsig†, Ikumi Muro†, Romain Amyot, Fuminori Kobayashi, Noriyuki Kodera, Toshio Ando and Hiroki Konno, Structural Dynamics of E6AP E3 Ligase HECT Domain and Involvement of a Flexible Hinge Loop in the Ubiquitin Chain Synthesis Mechanism, Nano Letters, 2023, 23, 24, 11940–11948. †These authors contributed equally to this work DOI：10.1021/acs.nanolett.3c04150 URL: Contact Hiroe Yoneda Senior Specialist in Project Planning and Outreach NanoLSI Administration OfficeNano Life Science Institute (WPI-NanoLSI) Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan Email: [email protected] Tel: +81 (76) 234-4555 About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University Understanding nanoscale mechanisms of life phenomena by exploring 'uncharted nano-realms'. Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale. About the World Premier International Research Center Initiative (WPI) The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS). About Kanazawa University As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities. The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas. SOURCE Kanazawa University