Clinical and translational discovery最新文献_第9页

Recent advances in mitochondrial replacement therapy and its future expectations 线粒体替代疗法的最新进展及其未来展望

Clinical and translational discovery

Pub Date : 2025-01-06 DOI: 10.1002/ctd2.70010

Qifeng Lyu, Weiwei Zou, Taosheng Huang

The prevention of mitochondrial diseases is particularly important due to the lack of specific therapies. Therefore, mitochondrial replacement therapy (MRT) is expected to be a technology to prevent mitochondrial diseases. Admittedly, this technology sparked a lot of controversy and discussion. In this article, we review the recent advances in MRT, discuss its safety and ethical issues, and finally explore its potential to completely block the inheritance of mitochondrial diseases.

由于缺乏特异性治疗方法，线粒体疾病的预防尤为重要。因此，线粒体替代疗法（MRT）有望成为预防线粒体疾病的技术。诚然，这项技术引发了很多争议和讨论。在本文中，我们回顾了MRT的最新进展，讨论了其安全性和伦理问题，并最终探讨了其完全阻断线粒体疾病遗传的潜力。

引用次数: 0

Roads diverged in a wood: Proteins and RNAs encoded by cytochrome b (CYTB) gene in health and disease 森林中的道路分叉：细胞色素b （CYTB）基因编码的蛋白质和rna在健康和疾病中的作用

Clinical and translational discovery

Pub Date : 2025-01-03 DOI: 10.1002/ctd2.70026

Cijie Du, Baodan Chen, Yile Huang, Wenxi Liang, Ying Hua Su, Xingguo Liu

Background

The cytochrome b (CYTB) gene, a crucial component of the mitochondrial genome, plays a multifaceted role in cellular metabolism, energy production and various biological processes.

Main body

It is well known that the CYTB gene encodes a subunit of complex III in the electron transport chain, which is vital for the oxidative phosphorylation process and ATP generation. Various studies report that the CYTB gene not only encodes a core protein in the mitochondrial respiratory chain but also produces a long non-coding RNA called lncCYTB, which participates in a variety of physiological and pathological processes. Inspiringly, a study has recently revealed that the CYTB gene also encodes a novel 187 amino acid long polypeptide, CYTB-187AA, a mitochondrial DNA-encoded protein produced by cytosolic translation and important for early mammalian development.

Conclusion

This review will provide insight into the functional and expression properties of the CYTB gene, as well as its unique non-coding RNA signature, and describe the diseases associated with the CYTB gene, ranging from mitochondrial dysfunction to more complex genetic disorders.

细胞色素b （CYTB）基因是线粒体基因组的重要组成部分，在细胞代谢、能量产生和各种生物过程中起着多方面的作用。众所周知，CYTB基因在电子传递链中编码复合物III的一个亚基，该亚基对氧化磷酸化过程和ATP生成至关重要。各种研究报道，CYTB基因不仅编码线粒体呼吸链的核心蛋白，还产生一种名为lncCYTB的长链非编码RNA，参与多种生理和病理过程。令人鼓舞的是，最近的一项研究表明，CYTB基因还编码一种新的187个氨基酸的长多肽CYTB- 187aa，这是一种线粒体dna编码的蛋白质，由细胞质翻译产生，对早期哺乳动物的发育很重要。结论本综述将深入了解CYTB基因的功能和表达特性，以及其独特的非编码RNA特征，并描述与CYTB基因相关的疾病，从线粒体功能障碍到更复杂的遗传疾病。

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引用次数: 0

The FACTs trial for Fabry disease highlights the promise and challenges of gene therapy 法布里病的FACTs试验凸显了基因治疗的希望和挑战

Clinical and translational discovery

Pub Date : 2025-01-02 DOI: 10.1002/ctd2.70028

Jeffrey A. Medin, Michael L. West

Gene therapy studies in Fabry disease (FD) are proceeding utilising either lentivirus (LV) or adeno-associated virus (AAV) vectors with either ex vivo or in vivo transductions, respectively. In the FACTs (Fabry Disease Clinical Research and Therapeutics) gene therapy trial,1, 2 five male patients with classical FD (aged 29–48 years) received autologous LV-transduced CD34+ haematopoietic stem/progenitor cells (HSPCs). Cells were transduced ex vivo with a recombinant LV harbouring the cDNA for human α-galactosidase A (α-gal A) and returned to non-myeloablated hosts who had received low-dose melphalan. Cells engrafted well and polyclonal haematopoiesis was observed.3 In FD, as with a number of lysosomal storage disorders (LSDs), the overexpressed hydrolase can be used by primary corrected cells and can also be secreted, enabling uptake via a mannose-6-phosphate receptor into bystander cells. This was the rationale for targeting HSPCs as they, and their progeny, can circulate and thereby deliver the corrective enzyme systemically. In contrast to enzyme therapy (ET), this approach utilised a single infusion rather than continual biweekly treatments. This single infusion of LV-transduced cells led to continuous production of the α-gal A1 rather than variable peaks and troughs of activity as is seen with ET. The promise and challenges in gene therapy for amelioration of single-gene defects are highlighted by this study (See Figure 1).The 5-year data show that this LV-based gene therapy was safe and impactful.1 Four of the five patients went home the same day as their cell infusions. Febrile neutropenia was observed in one patient; another developed a PICC line infection. These were the only two severe adverse events. All patients achieved sufficient α-gal A activity that they technically did not have FD and were eligible to pause their ET. Three patients stopped ET and remained off for between 3 and 5 years duration. Other benefits were also observed: three of the patients had IgG-based antibody titres against α-gal A. In each case, these titres were reduced to background following the gene therapy and remained there for all 5 years. This was likely due to the conditioning regimen or to tolerisation generated by continual production of low levels of α-gal A from LV-transduced cells. Plasma globotriaosylsphingosine, an important biomarker, was also decreased in four of five patients. Further, estimated glomerular filtration rate, proteinuria and left ventricular mass index stabilised in most patients.After 5 years, no haematopoietic (or any other) malignancies have been seen in our study. This mirrors data to March 2022 in the entire gene therapy field when recombinant LV were employed.4 However, three recent trials contrast this situation.5 Haematological cancers developed in seven out of 67 pat

法布里病（FD）的基因治疗研究正在分别利用慢病毒（LV）或腺相关病毒（AAV）载体进行体外或体内转导。在FACTs （Fabry Disease Clinical Research and Therapeutics）基因治疗试验中，5名男性经典FD患者（29-48岁）接受了自体lv转导的CD34+造血干细胞/祖细胞（HSPCs）治疗。在体外用含有人α-半乳糖苷酶a (α-gal a) cDNA的重组LV转导细胞，并将其返回给接受低剂量melphalan的非清髓宿主。细胞植入良好，观察到多克隆造血在FD中，与许多溶酶体储存障碍（lsd）一样，过表达的水解酶可以被原代校正细胞使用，也可以被分泌，使甘露糖-6-磷酸受体能够被吸收到旁细胞中。这就是靶向HSPCs的基本原理，因为它们及其后代可以循环，从而在系统中传递纠正酶。与酶疗法（ET）相比，这种方法采用单次输注而不是连续的双周治疗。单次输注lv转导的细胞导致α-gal A1的持续产生，而不是像ET那样出现活性的起伏。本研究强调了改善单基因缺陷的基因治疗的前景和挑战（见图1）。5年的数据表明，这种基于lv的基因治疗是安全有效的5名患者中有4名在接受细胞输注的当天就回家了。发热性中性粒细胞减少1例；另一人出现PICC系感染。这是仅有的两个严重的不良事件。所有患者均达到足够的α-gal A活性，因此从技术上讲，他们没有FD，有资格暂停ET治疗。有3名患者停止了ET治疗，并持续了3至5年。其他益处也被观察到：3名患者具有针对α-gal a的基于igg的抗体滴度，在每个病例中，这些滴度在基因治疗后降低到背景水平，并保持了5年。这可能是由于调理方案或由lv转导细胞持续产生低水平α-半乳糖A所产生的耐受性。血浆globotriaosylsphingosin（一种重要的生物标志物）在5名患者中也有所下降。此外，大多数患者的肾小球滤过率、蛋白尿和左心室质量指数均趋于稳定。5年后，在我们的研究中没有发现造血（或任何其他）恶性肿瘤。这反映了到2022年3月整个基因治疗领域使用重组LV时的数据然而，最近的三项试验却与此相反在67例脑白质营养不良患者中，有7例接受了重组LV介导的自体CD34+ HSPCs，其中重组LV介导了ABCD1 cDNA的表达。LV含有一个内部MNDU3启动子增强子；事实研究LV没有。这些看似异常的结果加强了在实施之前，在许多体外和体内试验中对临床指导的左室结构进行深入测试的必要性。虽然这种自体方法是“个性化医疗”的缩影，但它也表明，考虑到所涉及的复杂物流，源自不同临床地点并使用集中载体生产和转导场所的个性化细胞疗法仍然可能有效。另一个重要的考虑因素是成本。FACTs研究中的基因治疗比FD的其他治疗费用低得多。三名法布里病人的体外循环治疗退出在5年内为加拿大医疗保健系统节省了400多万美元的体外循环治疗费用。转导细胞也输注在门诊设置，只有一个病人需要过夜住院。例如，这与接受全剂量丁硫丹清髓调节的基因治疗患者的临床和费用轨迹形成对比。总之，FACTs研究的安全性结果，以及持久和有效的结果，为其他涉及可溶性溶酶体水解酶的lsd的治疗打开了大门。这些结果也为扩大lv介导治疗更多FD患者（包括女性和“非经典”疾病患者）提供了令人信服的理由。像这样的基因疗法面临的一个挑战是扩大规模。您是如何从一项涉及五名患者的试验，发展到对许多FD患者进行如此努力的“个性化医疗”适应？在这里，也许嵌合抗原受体修饰细胞的免疫疗法将是一个很好的模型。正如我们所展示的，lv转导的T细胞也可以用来递送溶酶体水解酶。如果能够用一种“现成”的方法治疗许多法布里患者，也会很有吸引力。

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Exosomes and machine perfusion as a therapy to improve organ transplantation 外泌体和机器灌注作为改善器官移植的治疗方法

Clinical and translational discovery

Pub Date : 2024-12-22 DOI: 10.1002/ctd2.70025

Wayne J. Hawthorne, Rajith Amaratunga, Ahmer Hameed

Cellular therapies are cutting-edge technologies that are now expanding into all spheres of medicine including transplantation. We are increasingly reliant upon marginal or less optimal donor organs for transplantation, however, to close the ever-widening gap between organ demand and supply. Such organs have higher discard rates and less ideal short and longer-term outcomes and ideally require improved organ preservation and resuscitation methods which can be utilised regardless of the jurisdiction.1 Various cellular therapies are gaining significant momentum as a novel approach to reducing transplant organ ischemia/reperfusion injury (IRI), and potential improvement in graft outcomes. As seen in Figure 1, machine perfusion of organs provides the ideal setting to specifically deliver many targeted therapies to individual grafts, including therapies such as; stem cells, organoids, viral transduction, nanoparticles, and the use of exosome-based treatments.2Exosomes are small extracellular vesicles (30–150 nm in diameter), that play a unique role in cellular communication, derived from the endosomal pathway, with intraluminal vesicles being formed in multivesicular bodies and subsequently released with fusion of the plasma membrane. Unlike traditional cell-based therapies, exosomes do not contain live cells, reducing concerns about immune interaction in both the organ and subsequently recipient. In the study by Burdeyron et al.3 innovatively delivered exosomes derived from porcine urine progenitor cells (UPCs) to kidneys using hypothermic and normothermic machine perfusion (HMP and NMP).IRI is a critical challenge in transplantation, particularly impacting organs from extended criteria donors and those from donors after circulatory death. These types of organs are generally more sensitive to ischemia, with attendant magnification of injury during reperfusion, and a subsequent higher incidence of graft dysfunction/rejection.4 Technologies such as HMP and NMP are variably employed by different centres to improve organ quality prior to transplantation. HMP involves the continuous circulation of a cold preservation solution through the kidney, whilst NMP involves perfusing the kidney with a warm, oxygenated solution to simulate physiological conditions. While these methods offer some protective effects, they do not completely ameliorate IRI, and significant further work is required to enhance their efficacy.5Exosomes carry bioactive molecules, including microRNAs (miRNAs), mRNAs, and proteins, which can influence cellular interaction and regulate immune activity. Exosome-based therapy can leverage the potential for intercellular communication, signalling cascades, and other physiological effects without the complexity and risks associated with administering whole cells. Studies have shown that exosomes derived f

细胞疗法是一种尖端技术，目前正在扩展到包括移植在内的所有医学领域。然而，我们越来越依赖边缘或不太理想的供体器官进行移植，以缩小器官需求和供应之间日益扩大的差距。这样的器官丢弃率较高，短期和长期结果不太理想，理想情况下需要改进器官保存和复苏方法，这些方法可以在任何司法管辖区使用各种细胞疗法作为减少移植器官缺血/再灌注损伤（IRI）和潜在改善移植结果的新方法正获得显著的发展势头。如图1所示，器官的机器灌注为特异性地向单个移植物提供许多靶向治疗提供了理想的环境，包括诸如；干细胞，类器官，病毒转导，纳米颗粒，以及基于外泌体治疗的使用。2外泌体是细胞外小泡（直径30 - 150nm），在细胞通讯中起独特作用，起源于内体途径，在多泡体中形成腔内小泡，随后随着质膜融合释放。与传统的基于细胞的疗法不同，外泌体不含活细胞，减少了对器官和随后的受体免疫相互作用的担忧。在Burdeyron等人的研究中，他们创新性地使用低温和恒温机器灌注（HMP和NMP）将猪尿祖细胞（UPCs）衍生的外泌体输送到肾脏。IRI是移植中的一个关键挑战，特别是影响来自延长标准供体和循环性死亡后供体的器官。这些类型的器官通常对缺血更敏感，在再灌注时损伤会随之放大，随后移植物功能障碍/排斥反应的发生率更高不同的中心采用不同的技术，如HMP和NMP，以改善移植前的器官质量。HMP涉及冷保存溶液通过肾脏的连续循环，而NMP涉及用温暖的含氧溶液灌注肾脏以模拟生理条件。虽然这些方法提供了一些保护作用，但它们并不能完全改善IRI，需要进一步的大量工作来提高其功效。外泌体携带生物活性分子，包括microrna （miRNAs）、mrna和蛋白质，它们可以影响细胞相互作用并调节免疫活性。基于外泌体的治疗可以利用细胞间通讯、信号级联和其他生理效应的潜力，而不需要与全细胞治疗相关的复杂性和风险。研究表明，来自各种细胞类型的外泌体，包括间充质干细胞（MSCs）和UPCs，具有抗炎、抗凋亡和促血管生成的特性，使其成为减轻IRI的有希望的药物。这可能包括某些mirna，它们可以减少促炎细胞因子的表达，如白细胞介素-6和肿瘤坏死因子- α，它们是IRI和器官损伤的主要原因。mscs通常用于再生医学，其外泌体在临床前和临床研究中都显示出保护器官免受IRI的希望。例如，在不同的IRI模型/研究中，msc衍生的外泌体被证明可以保护大鼠的肾脏和肝脏，保持细胞活力并调节炎症反应。upcs作为外泌体的来源具有独特的优势，因为它们可以非侵入性地从尿液中收集，不像MSCs具有抗炎/再生能力，而且它们的肾脏来源可能使它们更适合肾脏靶向移植治疗。在Burdeyron等人的研究中，分离并鉴定了3个猪upc衍生的外泌体，然后将其用于离体肾脏模型。通过使用HMP和NMP递送外泌体，研究人员观察到肾脏组织完整性的显著改善，炎症减少，细胞损伤标志物水平降低。这种作用可能是由于外泌体中的生物活性分子在细胞水平上调节免疫和炎症反应，最终减少损伤并促进组织修复。NMP模拟生理条件的能力意味着它可以支持外泌体的摄取和与组织的相互作用，这是目前静态冷藏方法所不能做到的Rigo和他的同事证明，人肝干细胞来源的细胞外囊泡（HLSC-EVs）治疗4小时有效地减少了缺氧nmp期间的肝损伤。尽管基于外泌体的治疗为减少IRI和改善移植结果提供了令人兴奋的途径，但仍有一些挑战需要解决。外泌体分离、组成和表征的标准化对于确保移植使用的一致治疗质量、安全性和有效性至关重要。还需要更深入地了解外泌体中负责其保护作用的特定生物活性分子。鉴定最有效的外泌体衍生的mirna、蛋白质和其他分子可能导致靶向外泌体修饰，从而增强其治疗潜力。例如，外泌体可以被设计成携带更高水平的特定抗炎或再生mirna，使它们适应特定移植应用的需要。此外，临床转化将需要在应用于患者之前，在大型动物模型中进行全面的测试，以确认外泌体治疗的安全性和有效性。还需要进行人体研究，以验证这些疗法能够提供一致的结果，而不会产生意想不到的副作用。根据Burdeyron等人的详细研究，从尿祖细胞中提取的外泌体，通过HMP和NMP给药，可以增强猪肾模型中缺血/再灌注损伤的缓解。外泌体治疗的潜力超出了肾脏，其他器官的研究也证明了这一点。通过利用外泌体的保护和再生能力，研究人员可以改善边缘供体移植的结果，并解决目前移植器官严重短缺的问题。基于外泌体的疗法代表了移植医学的一种创新方法，提供了一种潜在的更安全、更可控的替代全细胞疗法。这种方法利用了干细胞信号的治疗益处，而不引入活细胞，潜在地降低了与免疫排斥相关的风险。未来对外泌体分离、表征和工程的研究将是使这种疗法在临床环境中成为一种实用、安全和有效的解决方案的关键。韦恩·霍桑设计、撰写并修改了手稿和图。Rajith Amaratunga修改了这个数字。Ahmer Hameed修改了手稿。作者声明无利益冲突。

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引用次数: 0

Molecular mechanisms underlying oesophageal cancer development triggered by chronic alcohol consumption 长期饮酒引发食道癌的分子机制

Clinical and translational discovery

Pub Date : 2024-12-05 DOI: 10.1002/ctd2.70021

Huai Yi Chen, Chia Rou Por, Yong Kai Hong, Eason Qi Zheng Kong, Vetriselvan Subramaniyan

This review explores the mechanisms underlying alcohol-induced oesophageal carcinogenesis, including DNA damage, oxidative stress, and nutritional deficiencies. Alcohol metabolism primarily involves alcohol dehydrogenase (ADH) converting ethanol to acetaldehyde, which can cause DNA damage, inhibit repair mechanisms, and form DNA adducts thus inhibiting DNA replication. Plus, it delves into the epidemiological evidence, genetic susceptibility, epigenetic modifications, biomarkers, and preventive strategies associated with alcohol-related oesophageal cancers. Consumption of alcohol increases the risk of gastroesophageal reflux disease thus compromising mucosal integrity of the oesophagus as dysregulation of cytokines such as IL-18, TNFA, GATA3, TLR4, and CD68 expands the intercellular spaces of epithelial cells. Genetic variants, such as ADH1B rs1229984 and ALDH2 rs671, significantly influence susceptibility to alcohol-related oesophageal cancers, with these variations affecting acetaldehyde metabolism and cancer risk. Understanding these factors is crucial for early detection, effective treatment, and the development of targeted prevention strategies. Biomarkers, such as miRNA and metabolite markers, offer non-invasive methods for early detection, while advanced endoscopic techniques provide better diagnostic accuracy. Pharmacological interventions, such as statins and proton pump inhibitors, also show potential for reducing cancer progression in high-risk individuals. Despite advances, late-stage oesophageal cancer diagnoses are still common, highlighting the need for better screening and prevention. Further research, including this study, should aim to improve early detection, personalise prevention, and explore new treatments to reduce cases and enhance outcomes in alcohol-related oesophageal cancers.

本文综述了酒精诱导食管癌发生的机制，包括DNA损伤、氧化应激和营养缺乏。酒精代谢主要涉及酒精脱氢酶（ADH）将乙醇转化为乙醛，这会导致DNA损伤，抑制修复机制，形成DNA加合物，从而抑制DNA复制。此外，它还深入研究了与酒精相关的食道癌相关的流行病学证据、遗传易感性、表观遗传修饰、生物标志物和预防策略。饮酒会增加胃食管反流病的风险，从而损害食管粘膜的完整性，因为IL-18、TNFA、GATA3、TLR4和CD68等细胞因子的失调会扩大上皮细胞的细胞间隙。遗传变异，如ADH1B rs1229984和ALDH2 rs671，显著影响酒精相关食管癌的易感性，这些变异影响乙醛代谢和癌症风险。了解这些因素对于早期发现、有效治疗和制定有针对性的预防策略至关重要。生物标记物，如miRNA和代谢物标记物，为早期检测提供了非侵入性方法，而先进的内窥镜技术提供了更好的诊断准确性。药物干预，如他汀类药物和质子泵抑制剂，也显示出在高危人群中减少癌症进展的潜力。尽管取得了进展，但晚期食管癌诊断仍然很常见，这突出了更好的筛查和预防的必要性。包括本研究在内的进一步研究应致力于改善早期发现，个性化预防，并探索新的治疗方法，以减少酒精相关食管癌的病例并提高预后。

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引用次数: 0

An auxiliary diagnostic approach based on traditional Chinese medicine constitutions for older patients with frailty 基于中医体质的老年虚弱患者辅助诊断方法

Clinical and translational discovery

Pub Date : 2024-11-25 DOI: 10.1002/ctd2.70019

Xuchao Gu, Xiaojun Wang, Yijing Yang, Kangwei Guan, Hung-Chen Chang, Dehua Liu, Wenhao Wang, Tao Wu, Peiqing He, Jiaofeng Wang, Jie Chen, Zhijun Bao

Introduction

As global population ages, frailty has surfaced as a major public health challenge. Given the heterogeneity of frailty in the clinical presentation, it is imperative to develop personalised diagnostic and treatment strategies. The traditional Chinese medicine (TCM) constitution offers notable advantages in discerning individual differences. This study aims to elucidate the association between TCM constitutions and frailty, providing insights into the application of TCM for the frailty management.

Methods

An observational study was conducted at Huadong hospital from July 2022 to November 2023. A total of 241 older patients were recruited. Each patient underwent assessments for the TCM constitution and frailty status. Comprehensive data collection encompassed medical history, biochemical indicators, bone mineral density (BMD), body composition and physical performance metrics. Plasma samples were also collected to detect levels of inflammatory factors and lymphogenesis-related factors, including IL-1β, TNF-α, VEGF-C, ANGPTL4 and ACV-A. Multi-level statistical analysis was used to establish the relationship of TCM constitutions with frailty.

Results

Amongst all participants, 54 individuals were classified as non-frail, 90 individuals as pre-frail and 97 individuals as frail. Regression analysis indicated that frailty was closely associated with four imbalanced TCM constitutions: Qi deficiency, phlegm dampness, blood stasis and Qi depression. Subsequent analysis demonstrated that Qi deficiency was associated with decreased BMD, phlegm dampness with elevated high-density lipoprotein levels, Blood stasis with elevated blood glucose levels, and Qi depression with both decreased BMD and elevated low-density lipoprotein levels. Furthermore, individuals characterised by imbalanced TCM constitutions exhibited inferior handgrip strength, walking pace, lower limb strength and higher levels of inflammatory factors and lymphogenesis-related factors compared to those with balanced TCM constitution.

Conclusion

Frailty is independently associated with Qi deficiency, phlegm dampness, blood stasis and Qi depression. Personalised diagnostic approaches based on the TCM constitution may offer valuable insights for directing treatment for older patients with frailty.

引言随着全球人口老龄化的加剧，体弱已成为公共卫生领域的一大挑战。鉴于体弱在临床表现上的异质性，制定个性化的诊断和治疗策略势在必行。传统中医体质在辨别个体差异方面具有显著优势。本研究旨在阐明中医体质与虚弱之间的关系，为应用中医治疗虚弱提供见解。方法 2022年7月至2023年11月在华东医院进行了一项观察性研究。共招募了 241 名老年患者。每位患者都接受了中医体质和虚弱状态评估。全面的数据收集包括病史、生化指标、骨质密度（BMD）、身体成分和体能指标。此外，还采集了血浆样本，以检测炎症因子和淋巴生成相关因子的水平，包括 IL-1β、TNF-α、VEGF-C、ANGPTL4 和 ACV-A。采用多层次统计分析确定中医体质与虚弱的关系。结果在所有参与者中，54 人被归类为非虚弱，90 人被归类为前期虚弱，97 人被归类为虚弱。回归分析表明，体弱与四种失衡的中医体质密切相关：气虚、痰湿、血瘀和气郁。随后的分析表明，气虚与骨密度降低有关，痰湿与高密度脂蛋白水平升高有关，血瘀与血糖水平升高有关，而气郁则与骨密度降低和低密度脂蛋白水平升高有关。此外，与中医体质平衡者相比，中医体质失衡者的手握力、步行速度、下肢力量较差，炎症因子和淋巴生成相关因子水平较高。结论虚弱与气虚、痰湿、血瘀和气郁有独立关联。基于中医体质的个性化诊断方法可为指导老年体弱患者的治疗提供有价值的见解。

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引用次数: 0

Application of machine learning-based phenotyping in individualized fluid management in critically ill patients with heart failure 基于机器学习的表型分析在心力衰竭重症患者个体化输液管理中的应用

Clinical and translational discovery

Pub Date : 2024-11-25 DOI: 10.1002/ctd2.70020

Chengjian Guan, Bing Xiao

Heart failure (HF) is a major public health challenge, with fluid management being one of the most critical aspects of treatment. Fluid management is particularly a complex and challenging issue in critically ill patients, especially when cardiac pump function fails to meet the body's needs.1-3 Clinicians often face multiple challenges when formulating fluid management strategies, including significant individual variations, complex dynamic changes, and diverse monitoring indicators. Most current intervention studies targeting fixed fluid management in HF patients have reported negative outcomes,4, 5 reflecting the heterogeneity of severe HF patients and highlighting the urgent need for precision medicine. Therefore, our study aims to identify distinct characteristics of critically ill HF patients through retrospective analyses and develop targeted treatment strategies based on the optimal fluid balance ranges identified by longitudinal infusion data for each patient phenotype (Figure 1).6The advancement of artificial intelligence and machine learning (ML) technology offers innovative solutions to these challenges. Unsupervised ML has emerged as a powerful tool in medical research, capable of identifying patterns in complex, high-dimensional data without explicit labelling. The patient data were extracted from two intensive care unit databases, integrating both numerical and categorical variables to maintain comprehensive clinical characteristics. The K-Prototypes algorithm was selected for its ability to effectively combine the principles of K-Means and K-Modes principles, thereby enhancing clustering quality by considering the differential contributions of various variable types to the total distance between samples.7 Furthermore, fluid management is a dynamic process, where daily interventions and test results can affect subsequent outcomes. To address this, we analyzed 7-day fluid balance records using the G-formula parameter.8 a sophisticated statistical approach to eliminate confounding effects between time-varying exposures and outcomes, thus providing more reliable clinical guidance.Our analysis identified four distinct phenotypes of HF patients, each exhibiting significant differences in clinical characteristics and prognosis. The optimal fluid balance ranges for each phenotype aligned closely with their distinct clinical features. Phenotype A, characterized by severe inflammation and aggressive interventions including high rates of vasoactive drug use and mechanical ventilation, showed optimal outcomes with a moderate fluid balance of between –1000 and 500 mL per day. This finding indicates that a positive fluid balance is associated with adverse effects on mechanical ventilation duration and mortality. Phenotype C, despite having milder clinical parameters but combined with advanced age and multiple c

心力衰竭（HF）是一项重大的公共卫生挑战，而体液管理是治疗中最关键的环节之一。1-3 临床医生在制定液体管理策略时往往面临多重挑战，包括显著的个体差异、复杂的动态变化和多样的监测指标。目前大多数针对高血压患者固定液体管理的干预研究都报告了负面结果，4、5 反映了严重高血压患者的异质性，并突出了对精准医疗的迫切需求。因此，我们的研究旨在通过回顾性分析确定重症 HF 患者的不同特征，并根据纵向输液数据为每种患者表型确定的最佳液体平衡范围（图 1）制定有针对性的治疗策略6。6 人工智能和机器学习（ML）技术的发展为这些挑战提供了创新性的解决方案。无监督 ML 已成为医学研究的强大工具，它能够在没有明确标签的情况下识别复杂的高维数据中的模式。患者数据是从两个重症监护室数据库中提取的，整合了数字变量和分类变量，以保持全面的临床特征。之所以选择 K-Prototypes 算法，是因为该算法能够有效结合 K-Means 和 K-Modes 原理，从而通过考虑各种变量类型对样本间总距离的不同贡献来提高聚类质量。我们的分析确定了四种不同的高血压患者表型，每种表型在临床特征和预后方面都有显著差异。每种表型的最佳体液平衡范围与其不同的临床特征密切相关。表型 A 以严重炎症和积极干预（包括大量使用血管活性药物和机械通气）为特征，其最佳预后为每天-1000 至 500 毫升的中度体液平衡。这一发现表明，正的体液平衡与机械通气持续时间和死亡率的不利影响相关。表型 C 虽然临床指标较轻，但合并高龄和多种并发症，死亡率较高，需要严格限制液体摄入（每天-1500 至 500 毫升），这突出表明了年龄和体弱对高频预后的重要影响。为了便于临床应用，我们开发了一种简化的分类方法，使用通过特征筛选确定的九个临床指标：年龄、血尿素氮、血细胞比容、血管活性药物使用、肾脏疾病、肌酐、舒张压、机械通气状态和阴离子间隙。XGBoost 模型在内部和外部验证中均表现出良好的预测效果，曲线下面积值分别为 0.918 至 0.943 和 0.802 至 0.907。我们开发了一种基于网络的分型工具，以方便床旁快速识别表型，从而为液体管理的及时决策提供支持。虽然我们目前的研究结果显示出了良好的前景，但仍有必要在几个关键领域开展进一步的研究和技术进步。首先，前瞻性验证研究至关重要，应包括不同的患者群体和医疗环境，以确保研究结果的广泛适用性。其次，新型生物标记物的整合为提高表型分类的准确性提供了机会。除了传统的临床参数外，新型分子标记物、遗传特征和复杂的成像指标可以让人们更深入地了解疾病机制和治疗反应。从技术角度来看，不断完善预测模型仍然至关重要。应用先进的 ML 架构，包括深度学习和集合方法，有可能提高预测的准确性和模型的稳健性。

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引用次数: 0

Use of short-term cervical collars is associated with emotional discomfort 使用短期颈椎项圈与情绪不适有关

Clinical and translational discovery

Pub Date : 2024-11-08 DOI: 10.1002/ctd2.70016

Abha Somesh, Jackson Catalano, Andrew Underhill, Jessica Hocking, Evan Symons, Biswadev Mitra

We read with interest the manuscript on the topic of cervical collars for the management of spinal cord injuries.¹ Kolli et al. provide compelling evidence on the low levels of evidence for cervical collars to restrict movement and prevent worsening injury. On the contrary, evidence towards delayed recovery and worse pain profiles suggest adverse effects from collar use.¹

The association of long-term collar use with poorer quality of life was highlighted.¹ especially in older adults.^{2, 3} However, patient experiences of wearing cervical collars for shorter times in an emergency department (ED) setting have not been previously evaluated. The current standard of care in Victoria, Australia is the use of rigid foam cervical collars for spinal immobilisation in a patient with suspected cervical spine injury.⁴

We conducted a pilot prospective cohort study at an adult major trauma centre in Australia which records approximately 10 000 trauma presentations a year. The aim of this study was to evaluate patients’ experiences in a short-term cervical collar and the purpose of the study was to generate a hypothesis of harm. Short-term was defined as the period between application of the collar and until being cleared of any cervical spine injuries, which is less than 12 h.

A total of 20 participants enrolled by convenience sampling who were managed in cervical collars awaiting clearance with a Glasgow Coma Scale rating of 15, and who could converse in English formed the exposure group. A non-exposure group of 20 participants included adult patients not in cervical collars awaiting the results of investigations in the ED. All 40 participants were admitted to the short-stay unit in the ED with an aim to be discharged home in 24 h which suggests they all had low disease severity. The groups were matched for age (± 2 years) and gender. All 40 participants were assessed at a single time point using the Patient Evaluation of Emotional Comfort Experience (PEECE) questionnaire.⁵ This tool evaluates positive mental well-being elements like emotional comfort rather than negative health outcomes.

Each component of the PEECE score and the total were summarised using medians (inter-quartile range) and differences were compared using the Wilcoxon Rank Sum test. A p-value of <.05 was defined to be statistically significant. All analyses were conducted using Stata v18.0.

The total PEECE score among patients with a collar was 30.5 (interquartile range [IQR] 21–39.5), significantly lower than patients without a collar (total score 38.5; IQR 32–41.5, p = .016) (Figure 1). With a collar in place, patients reported significantly lower scores for positive emotions of being at ease, relaxed or wanting to smile. In addition, they also scored significantly lower perceptions of being valued, f

我们饶有兴趣地阅读了有关颈椎项圈治疗脊髓损伤的手稿。1 Kolli 等人提供了令人信服的证据，证明颈椎项圈在限制活动和防止损伤恶化方面作用不大。相反，有证据表明颈圈的使用会导致恢复延迟和疼痛状况恶化。1 长期使用颈圈会导致生活质量下降，1 尤其是对老年人而言。2, 3 然而，此前尚未对急诊科（ED）环境中较短时间佩戴颈圈的患者体验进行评估。在澳大利亚维多利亚州，目前的护理标准是对疑似颈椎损伤患者使用硬质泡沫颈圈进行脊柱固定。4 我们在澳大利亚的一家成人主要创伤中心开展了一项试点前瞻性队列研究，该中心每年约有 10,000 例创伤病例。这项研究的目的是评估患者在短期颈椎项圈中的体验，并提出伤害假设。短期颈圈的定义是：从戴上颈圈到颈椎损伤痊愈的时间，不超过12小时。通过方便抽样，共有20名患者加入了接触组，他们都是戴着颈圈等待痊愈的患者，格拉斯哥昏迷量表评分为15分，能用英语交谈。非暴露组有 20 人，包括在急诊室等待检查结果的未佩戴颈椎吊环的成年患者。所有40名参与者都在急诊室短期住院，目的是在24小时内出院回家，这表明他们的疾病严重程度都不高。各组的年龄（± 2 岁）和性别匹配。所有 40 名参与者均在一个时间点接受了 "患者情绪舒适体验评估"（PEECE）问卷5 的评估。该工具评估的是积极的心理健康要素，如情绪舒适度，而不是消极的健康结果。P值为 <.05为具有统计学意义。带项圈患者的 PEECE 总分为 30.5（四分位数间距 [IQR] 21-39.5），明显低于不带项圈的患者（总分 38.5；IQR 32-41.5，p = .016）（图 1）。戴上项圈后，患者在自在、放松或想笑等积极情绪方面的得分明显降低。此外，他们在被重视感、安全感或感恩感方面的得分也明显较低（表 1）。我们认识到样本量小和存在未知混杂因素的局限性。戴颈圈的患者视野有限，因为大多数患者被要求平躺，颈部不能活动。因此，除非他们对治疗有充分的了解和认识，否则可能无法理解为他们提供的所有护理。6, 7 颈椎项圈患者的控制感得分较低，而知情感和被照顾感得分较高，这表明颈椎项圈患者有特殊和独特的需求。必要时，医院对颈圈的管理需要特别关注舒适度，并经常更新进展情况。在患者卧床仰卧时，可以通过视听刺激提供情感支持。Kolli 等人1 认为，颈圈的使用可能会对某些患者群体造成伤害，不恰当的使用也可能会增加患者出现不良后果的可能性。结合我们的研究结果来看，显然有必要采取创新策略来改善对疑似或实际颈椎损伤患者的护理。由 AS 和 JC 修改想法并收集数据。手稿撰写由 AS、JC、BM 和 JH 完成。稿件由所有作者审阅和编辑。作者声明无利益冲突。本研究未获得任何资助。伦理批准由阿尔弗雷德人类研究和伦理委员会提供（项目编号 487/18）。

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引用次数: 0

Challenges and advances of immune checkpoint therapy 免疫检查点疗法的挑战与进步

Clinical and translational discovery

Pub Date : 2024-11-04 DOI: 10.1002/ctd2.70001

Lingyu Li, Yingli Sun

Background and Objectives

Immuno-checkpoint therapy (ICT) significantly alters the clinical course of cancer patients, providing long-lasting clinical benefits and offering the potential for cure to some patients. However, response rates for different tumour types vary, and predictive biomarkers are needed to enhance patient selection for the purpose of optimising effectiveness and reducing toxicity. This has driven efforts to decipher the immune and non-immune factors that regulate ICT response.

Main Content

This review offers a thorough examination of the advantages and future challenges of immune checkpoint inhibitors in cancer therapy. Additionally, we explore ongoing efforts to address current challenges, such as guiding subsequent clinical trials, developing ICT combination therapy strategies and utilising epigenetics to enhance clinical efficacy.

Conclusion and Perspectives

Despite significant progress, ICT faces challenges including immune-related adverse events (irAEs) and resistance mechanisms. Ongoing research focuses on developing novel biomarkers, combination therapies, and epigenetic strategies to improve the efficacy and safety of ICT for cancer patients worldwide. Future studies are required to validate these findings across different tumor types and treatment settings.

背景和目的免疫检查点疗法（ICT）可显著改变癌症患者的临床病程，提供持久的临床疗效，并为某些患者提供治愈的可能。然而，不同肿瘤类型的反应率各不相同，因此需要预测性生物标志物来加强对患者的选择，以达到优化疗效和减少毒性的目的。这促使人们努力破解调节信息和通信技术反应的免疫和非免疫因素。主要内容本综述深入探讨了免疫检查点抑制剂在癌症治疗中的优势和未来挑战。此外，我们还探讨了当前为应对挑战所做的努力，如指导后续临床试验、开发 ICT 联合治疗策略以及利用表观遗传学提高临床疗效。结论与展望尽管取得了重大进展，但 ICT 仍面临着免疫相关不良事件 (irAE) 和耐药机制等挑战。目前的研究重点是开发新型生物标记物、联合疗法和表观遗传学策略，以提高全球癌症患者使用信息和通信技术的疗效和安全性。未来的研究需要在不同的肿瘤类型和治疗环境中验证这些发现。

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引用次数: 0

Drug repurposing: Bortezomib in the treatment of PTEN-deficient iCCA 药物再利用：硼替佐米治疗PTEN缺陷的iCCA

Clinical and translational discovery

Pub Date : 2024-10-29 DOI: 10.1002/ctd2.70004

Shi-jia Dai, Tian-yi Jiang, Zhen-gang Yuan

Intrahepatic cholangiocarcinoma (iCCA) is an epithelial malignancy arising from intrahepatic biliary tract, characterised by a dismal prognosis with limited therapeutic alternatives.¹ The standard first-line treatment for patients with unresectable iCCA includes gemcitabine-based chemotherapy and immunotherapy. However, the objective response rate (ORR) of first-line treatment is below 30%, and there is currently insufficient evidence to support the use of second-line chemotherapy.^{2, 3} This underscores an urgent need to identify novel therapeutic targets and effective drugs for iCCA.

Our previous research has demonstrated that phosphatase and tension homolog (PTEN), a tumour suppressor which counteracts phosphatidylinositol 3-kinase (PI3K)–AKT signalling, is frequently mutated or deleted in iCCA.⁴ We established a spontaneous iCCA model in mice through liver-specific PTEN disruption and Kras activation, highlighting the crucial role of PTEN in iCCA tumourigenesis.⁵ Importantly, we identified PTEN as a pivotal regulator of both the lysosomal and proteasomal systems, which are essential for maintaining cellular proteostasis in CCA cells. PTEN drives lysosome biogenesis and acidification through its protein phosphatase activity, which dephosphorylates transcription factor EB (TFEB) at Ser211, thereby regulating exosome secretion and iCCA metastasis.⁶ Simultaneously, PTEN inhibits proteasomal transcription via its lipid phosphatase activity in a BACH1/MAFF-dependent manner.⁷ Consequently, PTEN deficiency enhances protein synthesis and proteasomal activity, creating a dependency on the proteasome for iCCA cell growth and survival. Therefore, targeting the proteasome machinery by inhibitor bortezomib induces more apoptosis in PTEN-deficient iCCA cells.

We subsequently conducted a clinical trial (NCT03345303) to assess whether PTEN-deficient iCCA patients could benefit from bortezomib treatment after failure of first-line chemotherapy, investigating PTEN as a potential biomarker for proteasome inhibition. This open-label, single-arm, phase II clinical trial was conducted at the Eastern Hepatobiliary Surgery Hospital, Shanghai. A total of 130 advanced iCCA patients were screened for PTEN expression and 16 were enrolled and treated with single-agent bortezomib. Among the intent-to-treat cohort (n = 16), the ORR was 18.75% (three out of 16), and the disease control rate (DCR) was 43.75% (seven out of 16). Notably, three patients did not undergo efficacy assessment, resulting in more favourable outcomes in the per-protocol (PP) cohort (n = 13), which demonstrated an ORR of 23.08% and a DCR of 53.85%. The median progression-free survival (PFS) was 3.6 months, and median overall survival (OS) was 9.6 months in the PP cohort. To our knowledge, the primary efficacy endpoint of our trail, the

肝内胆管癌（iCCA）是一种发生于肝内胆道的上皮性恶性肿瘤，其特点是预后不佳且治疗手段有限1 。然而，一线治疗的客观反应率（ORR）低于 30%，目前也没有足够的证据支持二线化疗的使用。2, 3 这凸显了为 iCCA 寻找新的治疗靶点和有效药物的迫切需要。我们之前的研究表明，磷酸酶和张力同源物（PTEN）是一种肿瘤抑制因子，可对抗磷酸肌醇 3- 激酶（PI3K）-AKT 信号，在 iCCA 中经常发生突变或缺失。我们通过肝特异性 PTEN 干扰和 Kras 激活建立了小鼠自发性 iCCA 模型，突出了 PTEN 在 iCCA 肿瘤发生过程中的关键作用5。PTEN 通过其蛋白磷酸酶活性驱动溶酶体的生物生成和酸化，使转录因子 EB（TFEB）在 Ser211 处去磷酸化，从而调节外泌体的分泌和 iCCA 的转移。同时，PTEN 通过其脂质磷酸酶活性以 BACH1/MAFF 依赖性方式抑制蛋白酶体转录。7 因此，PTEN 缺乏会增强蛋白质合成和蛋白酶体活性，从而使 iCCA 细胞的生长和存活依赖于蛋白酶体。我们随后开展了一项临床试验（NCT03345303），以评估PTEN缺陷的iCCA患者在一线化疗失败后是否能从硼替佐米治疗中获益，并将PTEN作为蛋白酶体抑制的潜在生物标志物进行研究。这项开放标签、单臂、II期临床试验在上海东方肝胆外科医院进行。共对130名晚期iCCA患者进行了PTEN表达筛查，16名患者入组并接受了硼替佐米单药治疗。在意向治疗队列（n = 16）中，ORR为18.75%（16人中有3人），疾病控制率（DCR）为43.75%（16人中有7人）。值得注意的是，有三名患者没有接受疗效评估，因此按方案治疗队列（13 人）的结果更为理想，ORR 为 23.08%，DCR 为 53.85%。PP队列的中位无进展生存期（PFS）为3.6个月，中位总生存期（OS）为9.6个月。据我们所知，我们研究的主要疗效终点--PP队列的ORR仅低于之前有关FGFR抑制剂的报道，但与其他二线治疗方案相比，如FOLFOX（5%）、瑞戈非尼（11%）和乐伐替尼联合帕博利珠单抗（10%），ORR有了显著改善。此外，硼替佐米相关毒性被认为是可以接受的，没有治疗相关死亡病例，血小板计数下降是最常见的不良反应。这些结果表明，硼替佐米是治疗 PTEN 缺陷 iCCA 的一种很有前景的二线疗法。8 基于从二线单药治疗研究中获得的启示，我们正在推进一项 II 期介入临床试验（ChiCTR2000035916），旨在进一步评估吉西他滨类化疗联合硼替佐米治疗胆管癌（CCA）的疗效（见图 1）。该试验旨在招募200名晚期CCA患者，探讨PTEN和PIK3CA/B的改变是否会影响这种联合疗法的疗效，最终目标是为中国的CCA患者开发出分子定制的治疗方案。初步研究结果表明，PTEN缺乏的患者从联合治疗中获益更大，这也证实了我们在二线单药治疗研究中观察到的结果。在本研究中，我们重点关注硼替佐米。作为第一代蛋白酶体抑制剂，硼替佐米已在临床上应用了近 20 年10 ，对其安全性、耐受性和药代动力学特性进行了广泛的研究，使其更适于 "药物重新定位"。值得注意的是，之前一项评估硼替佐米对非选择性胆道癌（BTC）患者疗效的 II 期试验未能达到主要终点，但取得了令人鼓舞的疾病稳定性和中位 PFS。这表明，生物标志物驱动的患者选择和联合用药策略可能会带来显著疗效。我们之前的研究发现，PTEN缺陷的iCCA细胞表现出较高的蛋白酶体活性和增殖能力，从而在体外和体内对硼替佐米产生敏感性。从机理上讲，我们发现PTEN-AKT-FOXO1-BACH1/MAFF信号通路调节蛋白酶体基因的转录，并影响硼替佐米的敏感性。因此，我们启动了一项前瞻性临床试验，史无前例地评估了蛋白酶体抑制剂硼替佐米在选定的 PTEN 缺陷 ICC 患者群中的疗效。有效及时的筛查对于指导后续的二线治疗至关重要。在这项研究中，我们采用了多种技术来评估 PTEN 缺陷，包括免疫组化（IHC）、新一代测序（NGS）和 RNA 范围技术。我们的研究结果表明，PTEN 蛋白表达与基因改变密切相关。与我们之前对 50 例 ICC 患者进行 PTEN IHC 和基因测序的研究结果一致，PTEN 缺乏与基因改变显著相关。PTEN 同源缺失或框移突变通常会导致蛋白表达缺失；因此，我们主张将 IHC 作为初步筛查方法。此外，对 "癌症药物敏感性基因组学"（Genomics of Drug Sensitivity in Cancer）和 "癌症治疗反应门户网站"（Cancer Therapeutics Response Portal）数据库的分析表明，PTEN 缺失可提高各种肿瘤对蛋白酶体抑制剂的敏感性，这表明我们的发现可能具有广泛的适用性。在胆囊癌4和胶质母细胞瘤11中也观察到了类似的细胞和动物表型，这表明基于PTEN分子亚型的蛋白酶体抑制剂精准治疗方法可能会扩展到其他肿瘤，使更多PTEN缺失患者受益。总之，我们的研究表明，硼替佐米作为PTEN缺失型iCCA的二线疗法具有可控毒性和良好疗效，在PP队列中毒性可控，中位OS为9.6个月。这些结果支持蛋白酶体抑制剂在实体瘤中的广泛应用，并为PTEN缺陷型恶性肿瘤患者带来了新的希望。

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