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Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation. 喉癌伴肺部转移在停用 Nivolumab 后出现长期完全应答和延迟免疫相关不良事件
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2021-07-19 DOI: 10.1177/01455613211031025
Takahito Kondo, Munehide Nakatsugawa, Mitsuru Okubo, Hironori Nakamura, Daisuke Yunaiyama, Midori Wakiya, Atsuo Takeda, Naiue Kikawada, Takuma Kishida, Miwako Someya, Shigekazu Yoshida, Yasuo Ogawa, Kiyoaki Tsukahara

We report a case of laryngeal cancer with multiple lung metastases that maintained a complete response (CR) for 18 months after discontinuing nivolumab treatment, with colitis developing 5 months after drug discontinuation. A 65-year-old man was diagnosed with T3N2cM0 stage IVA right supraglottic squamous cell carcinoma that progressed after 1 course of TPF (cisplatin, docetaxel, and 5-fluorouracil) as induction chemotherapy. He underwent total laryngectomy, bilateral neck dissection, pharyngeal reconstruction with anterolateral thigh flap, and creation of a permanent tracheostoma; extranodal extension was detected in the right cervical lymph node metastasis, and the patient underwent adjuvant radiotherapy. Multiple lung metastases occurred during radiotherapy, and the patient was deemed platinum refractory; nivolumab treatment was thus initiated. The tumor proportion score for programmed death-ligand 1-evaluated via antibody testing of the laryngeal tumor-was <1. The patient received 240 mg/body nivolumab every 2 weeks; a computed tomography performed after course 16 of nivolumab treatment confirmed a CR. He exhibited grade 2 thyroid dysfunction, grade 1 interstitial pneumonia, and grade 2 colitis after 6, 7, and 14 months of receiving nivolumab, respectively; treatment was discontinued as despite maintaining a CR, interstitial pneumonia occurred twice. Colitis appeared 5 months after nivolumab discontinuation; nevertheless, a CR was maintained after 18 months.

我们报告了一例喉癌伴多发性肺转移的病例,患者在停用 nivolumab 治疗 18 个月后仍保持完全应答(CR),但在停药 5 个月后出现结肠炎。一名 65 岁的男性被诊断为 T3N2cM0 右声门上鳞癌 IVA 期,在接受一个疗程的 TPF(顺铂、多西他赛和 5-氟尿嘧啶)诱导化疗后病情出现进展。他接受了全喉切除术、双侧颈部切除术、大腿前外侧皮瓣咽部重建术和永久性气管造口术;在右颈淋巴结转移处发现了结节外扩展,患者接受了辅助放疗。放疗期间出现多处肺转移,患者被认为是铂类难治性患者,因此开始接受尼伐单抗治疗。通过喉部肿瘤抗体检测评估的程序性死亡配体 1 肿瘤比例评分为
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引用次数: 0
Reimagining Dearomatization: Arenophile-Mediated Single-Atom Insertions and π-Extensions.
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2025-03-11 DOI: 10.1021/acs.accounts.5c00035
Zohaib Siddiqi, David Sarlah
<p><p>ConspectusDearomatization of simple aromatics serves as one of the most direct strategies for converting abundant chemical feedstocks into three-dimensional value-added products. Among such transformations, cycloadditions between arenes and alkenes have historically offered effective means to construct complex polycyclic architectures. However, traditionally harsh conditions, such as high-energy UV light irradiation, have greatly limited the scope of this transformation. Nevertheless, recent progress has led to the development of visible-light-promoted dearomative photocycloadditions with expanded scope capable of preparing complex bicyclic structures.A fundamentally distinct approach to dearomative photocycloadditions involves the visible-light activation of arenophiles, which undergo <i>para</i>-photocycloaddition with various aromatic compounds to produce arene-arenophile cycloadducts. While only transiently stable and subject to retro-cycloaddition, further functionalization of the photocycloadducts has allowed for the development of a wide collection of dearomatization methodologies that access products orthogonal to existing chemical and biological processes. Central to this strategy was the observation that arene-arenophile photocycloaddition reveals a π-system that can be functionalized through traditional olefin chemistry. Coupled with subsequent [4 + 2]-cycloreversion of the arenophile, this process acts to effectively isolate a single π-system from an aromatic ring. We have developed several transformations that bias this methodology to perform dearomative single-atom insertion and π-extension reactions to prepare unique products that cannot be prepared easily through traditional means.Through the application of a dearomative epoxidation, we were able to develop a method for the epoxidation of arenes and pyridines to arene-oxides and pyridine-oxides, respectively. Notably, when this arenophile chemistry is applied to polycyclic arenes, photocycloaddition reveals a π-system transposed from the site of native olefinic reactivity, enabling unique site-selectivity for dearomative functionalization. As a result, we were able to perform a single-atom insertion of oxygen into polycyclic (aza)arenes to prepare 3-benzoxepines. When applying this strategy in the context of cyclopropanations, we were able to accomplish a dearomative cyclopropanation of polycyclic (aza)arenes which yield benzocycloheptatrienes upon cycloreversion. Notably, while the Buchner ring expansion is a powerful method for the direct single-atom insertion of carbon into arenes, the corresponding cyclopropanation of polycyclic arenes does not yield ring-expanded products. Furthermore, this strategy could be utilized for the synthesis of novel nanographenes through the development of an M-region annulative π-extension (M-APEX) reaction. Traditionally, methods for π-extension rely on the native reactivity of polycyclic aromatics at the K- and bay-region. However, photocy
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引用次数: 0
An Open Source Replication of a Winning Recidivism Prediction Model. 一个成功的累犯预测模型的开源复制。
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2022-11-03 DOI: 10.1177/0306624X221133004
Giovanni M Circo, Andrew P Wheeler

We present results of our winning solution to the National Institute of Justice recidivism forecasting challenge. Our team, "MCHawks," placed highly in both terms of accuracy (as measured via the Brier score), as well as the fairness criteria (weighted by differences in false positive rates between White and Black parolees). We used a non-linear machine learning model, XGBoost, although we detail our search of different model specifications, as many different models' predictive performance is very similar. Our solution to balancing false positive rates is trivial; we bias predictions to always be "low risk" so false positive rates for each racial group are zero. We discuss changes to the fairness metric to promote non-trivial solutions. By providing open-source replication materials, it is within the capabilities of others to build just as accurate models without extensive statistical expertise or computational resources.

我们介绍了我们在国家司法研究所累犯预测挑战赛中获胜的解决方案的结果。我们的团队 "MCHawks "在准确性(通过布赖尔得分衡量)和公平性标准(根据白人假释犯和黑人假释犯之间的误判率差异加权)方面都取得了优异成绩。我们使用了非线性机器学习模型 XGBoost,尽管我们详细说明了我们对不同模型规格的搜索,因为许多不同模型的预测性能非常相似。我们平衡假阳性率的方法很简单:我们将预测偏向于 "低风险",因此每个种族群体的假阳性率为零。我们讨论了公平性指标的变化,以促进非微不足道的解决方案。通过提供开源的复制材料,其他人无需丰富的统计专业知识或计算资源,也能建立同样精确的模型。
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引用次数: 0
Effects of Hyaluronic Acid/Collagen Resorbable Gel Use in Endoscopic Dacryocystorhinostomy. 透明质酸/胶原可吸收凝胶用于内窥镜泪囊鼻腔造口术的效果
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2022-06-21 DOI: 10.1177/01455613221104438
Hyunkyu Lee, Sumin Yoon, Sehyun Baek

The purpose of this study was to investigate whether the use of hyaluronic acid/collagen resorbable gel (Regenwel®) has an inhibitory effect on rhinostomy obstruction during endoscopic dacryocystorhinostomy (Endo DCR). A total of 298 patients diagnosed with unilateral primary acquired nasolacrimal duct obstruction from May 2017 to June 2021 who underwent Endo DCR were enrolled. The patients were divided into the Regenwel group (152 patients) and the Control group (146 patients) that did not use Regenwel during surgery, and the medical records were compared and analyzed retrospectively. The mean age of the Regenwel group was 65.8 years, and that of the Control group was 63.2 years. Regarding anatomical success as the primary outcome, the Regenwel group had a higher success rate than the Control group (96.7% vs 86.3%, P = .012), and the functional success result confirmed that the Regenwel group had a higher success rate than the Control group (94.1% vs 84.3%, P = .024). Among secondary outcomes, granulation formation occurred less frequently in the Regenwel group than in the Control group (9.2% vs 32.2%, P < .001), and there was no statistically significant difference in postoperative bleeding between the 2 groups (0% vs 1.4%, P = .478). The Regenwel group had fewer infections after surgery than the Control group (5.3% vs 8.9%, P = .012) and required less frequent revision surgery (2.0% vs 15.8%, P < .001). In conclusion, Regenwel is a resorbable gel containing hyaluronic acid and collagen that is used during Endo DCR and is thought to contribute to the improvement of surgical success rate by preventing complications such as rhinostomy obstruction and bleeding after surgery.

本研究旨在探讨使用透明质酸/胶原可吸收凝胶(Regenwel®)是否对内窥镜泪囊鼻腔造口术(Endo DCR)期间的鼻腔造口阻塞有抑制作用。2017年5月至2021年6月期间,共有298名确诊为单侧原发性获得性鼻泪管阻塞的患者接受了内镜下泪囊鼻腔造口术(Endo DCR)。这些患者被分为雷根韦尔组(152例)和手术中未使用雷根韦尔的对照组(146例),并对病历进行比较和回顾性分析。Regenwel 组的平均年龄为 65.8 岁,对照组的平均年龄为 63.2 岁。解剖学成功率是主要结果,Regenwel 组的成功率高于对照组(96.7% vs 86.3%,P = .012);功能成功率结果证实,Regenwel 组的成功率高于对照组(94.1% vs 84.3%,P = .024)。在次要结果中,Regenwel 组肉芽形成发生率低于对照组(9.2% vs 32.2%,P < .001),两组术后出血量差异无统计学意义(0% vs 1.4%,P = .478)。与对照组相比,Regenwel 组术后感染较少(5.3% vs 8.9%,P = .012),需要翻修手术的次数也较少(2.0% vs 15.8%,P < .001)。总之,Regenwel 是一种含有透明质酸和胶原蛋白的可吸收凝胶,可用于 Endo DCR,通过预防鼻腔造口阻塞和术后出血等并发症,有助于提高手术成功率。
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引用次数: 0
Prognostic significance of cystic nodal metastasis in HPV-positive oropharyngeal cancer. HPV 阳性口咽癌囊性结节转移的预后意义。
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2022-07-04 DOI: 10.1177/01455613221112340
Jure Pupić-Bakrač, Mario Rašić

This is a brief communication stressing some critical points associated with cystic nodal metastasis (CNM) in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) and its implication on treatment protocols and outcomes.

这篇简讯强调了人乳头状瘤病毒(HPV)阳性口咽鳞癌(OPSCC)中与囊性结节转移(CNM)相关的一些关键点及其对治疗方案和结果的影响。
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引用次数: 0
Fluorescent Metallacycles via Coordination-Driven Self-Assembly: Preparation, Regulation, and Applications.
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2025-03-18 DOI: 10.1021/acs.accounts.5c00043
Wei-Tao Dou, Hai-Bo Yang, Lin Xu
<p><p>ConspectusFluorescence by small molecular dyes is renowned for its real-time, dynamic, and noninvasive nature. It has become indispensable across scientific domains, including information storage, optoelectronic materials, biosensing, and both diagnosing and treating diseases. Despite their widespread use, these molecular dyes suffer from several limitations due to the sensitivity of their photophysical properties to environmental factors, such as concentration, solvent composition, and polarity. These challenges become particularly prominent when assembling or aggregating fluorescent molecules; their optical characteristics often become unpredictable or uncontrollable. Alternative strategies to stabilize and tune fluorescence during preparation are therefore crucial.Metal coordination, a classical approach in supramolecular chemistry, offers a promising solution. Coordinating fluorescent dyes to metals precisely directs self-assembly, ensuring defined stoichiometries, geometries, and reversibility. The resulting multifunctional metallacycles combine the advantages inherent to molecular design and fluorescence, pushing the boundaries of fluorescence-based assemblies. We present a modular, directional, and controllable strategy for the self-assembly of supramolecular metallacycles with well-defined geometries, providing a new avenue to address the limitations of traditional small molecular dyes.A key innovation in this research lies in the incorporation of photochromic units into the metallacycles, tuning their photophysical properties reversibly under external illumination. Their emission wavelengths, chiralities, and circularly polarized luminescence (CPL) signals can all be modulated dynamically. These characteristics offer the potential for holographic imaging, where fine control of fluorescence behavior is crucial. We introduce a novel multistep Förster resonance energy transfer (FRET) strategy that enables real-time monitoring of the metallacycle assembly dynamics. Our FRET approach has been employed to develop photosensitized oxygenation reactions and highly efficient light-harvesting systems, highlighting its versatility. The unique photophysical properties of our fluorescent metallacycles have been applied successfully in several fields. They detect heparin quantitatively, showcasing their potential in biosensing. They have been integrated into nanoagents for photothermal, photodynamic, and chemotherapeutic therapies guided by imaging, offering a multimodal approach to therapeutic intervention. Such precise control over fluorescence, energy transfer, and assembly dynamics not only opens new avenues in materials design but also underscores supramolecular metallacycles' potential for advancing fluorescence technologies. Integrating metal coordination into fluorescence represents a significant step in the design and application of functional fluorescent metallacycles. This design strategy both advances fundamental supramolecular chemis
{"title":"Fluorescent Metallacycles via Coordination-Driven Self-Assembly: Preparation, Regulation, and Applications.","authors":"Wei-Tao Dou, Hai-Bo Yang, Lin Xu","doi":"10.1021/acs.accounts.5c00043","DOIUrl":"10.1021/acs.accounts.5c00043","url":null,"abstract":"&lt;p&gt;&lt;p&gt;ConspectusFluorescence by small molecular dyes is renowned for its real-time, dynamic, and noninvasive nature. It has become indispensable across scientific domains, including information storage, optoelectronic materials, biosensing, and both diagnosing and treating diseases. Despite their widespread use, these molecular dyes suffer from several limitations due to the sensitivity of their photophysical properties to environmental factors, such as concentration, solvent composition, and polarity. These challenges become particularly prominent when assembling or aggregating fluorescent molecules; their optical characteristics often become unpredictable or uncontrollable. Alternative strategies to stabilize and tune fluorescence during preparation are therefore crucial.Metal coordination, a classical approach in supramolecular chemistry, offers a promising solution. Coordinating fluorescent dyes to metals precisely directs self-assembly, ensuring defined stoichiometries, geometries, and reversibility. The resulting multifunctional metallacycles combine the advantages inherent to molecular design and fluorescence, pushing the boundaries of fluorescence-based assemblies. We present a modular, directional, and controllable strategy for the self-assembly of supramolecular metallacycles with well-defined geometries, providing a new avenue to address the limitations of traditional small molecular dyes.A key innovation in this research lies in the incorporation of photochromic units into the metallacycles, tuning their photophysical properties reversibly under external illumination. Their emission wavelengths, chiralities, and circularly polarized luminescence (CPL) signals can all be modulated dynamically. These characteristics offer the potential for holographic imaging, where fine control of fluorescence behavior is crucial. We introduce a novel multistep Förster resonance energy transfer (FRET) strategy that enables real-time monitoring of the metallacycle assembly dynamics. Our FRET approach has been employed to develop photosensitized oxygenation reactions and highly efficient light-harvesting systems, highlighting its versatility. The unique photophysical properties of our fluorescent metallacycles have been applied successfully in several fields. They detect heparin quantitatively, showcasing their potential in biosensing. They have been integrated into nanoagents for photothermal, photodynamic, and chemotherapeutic therapies guided by imaging, offering a multimodal approach to therapeutic intervention. Such precise control over fluorescence, energy transfer, and assembly dynamics not only opens new avenues in materials design but also underscores supramolecular metallacycles' potential for advancing fluorescence technologies. Integrating metal coordination into fluorescence represents a significant step in the design and application of functional fluorescent metallacycles. This design strategy both advances fundamental supramolecular chemis","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1151-1167"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The Photoactivated Depot (PAD): Light Triggered Control of Therapeutic Protein Solubility and Release.
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2025-03-03 DOI: 10.1021/acs.accounts.4c00718
Simon H Friedman
<p><p>ConspectusMany therapeutic proteins can benefit from controlling the timing and amount of their release. This is especially true for signaling molecules such as insulin, whose requirements vary continually throughout the day. Currently, the only way to provide this variable delivery is through a pump. Pumps, and their required cannulas/needles, introduce a wide range of problems, including cannula occlusion, infection, and biofouling. We have instead pursued the photoactivated depot or PAD approach, in which therapeutic proteins are released into the body through light activation of shallow, skin-based depots that are activated by small LED light sources ( <i>Angew. Chem.</i> 2013, 125(5), 1444-1449, <i>Mol. Pharmaceutics</i> 2016, 13(11), 3835-3841, <i>J. Am. Chem. Soc.</i> 2017, 139(49), 17861-17869, <i>ACS Biomater Sci. Eng.</i> 2021, 7(4), 1506-1514, and <i>ACS Biomater Sci. Eng.</i> 2024, 10(6), 3806-3812). By linking protein release to transcutaneous irradiation, we can control the amount and timing of therapeutic release by varying the amount and timing of irradiation. At the heart of this approach are PAD materials that contain three key elements: the therapeutic protein, a photocleavable (PC) group, and a solubility reducing moiety. This latter element is needed to allow the PAD material to stay at the site of injection, so that light can be effectively directed to it. The light causes the PC group to break its bond with the therapeutic protein, which can then diffuse into the capillary bed and be absorbed into systemic circulation. We have pursued four distinct methods of achieving solubility reduction prior to irradiation. The first approach is to use a highly insoluble polymer that is linked to the therapeutic protein via the PC group. This was the approach we used in our first attempt at making a PAD material and proved to be effective in both in vitro and in vivo settings. The main challenge with this first approach is that the polymer is left in the body after the protein is released, necessitating additional optimization to clear it, using biodegradation. In addition, it is very inefficient, with only a minority of the material being the therapeutic. In the second approach, we created polymers/oligomers out of the protein, using small light-cleaved links. The simplest of these, a trimer of proteins linked to a central core, is 90% therapeutic, and retains the preirradiation insolubility required of the PAD approach. In the third approach, we link charged groups to the protein to shift its iso-electric point, such that the material will be insoluble (and hence able to form a depot) at pH 7, but will release native, active protein after photolysis cleaves off the charged groups. Finally, in the fourth approach, we confer insolubility by attaching highly nonpolar groups to the therapeutic protein via a PC linkage. In this article, the challenges, strengths and weaknesses of each of these approaches will be described, and guidan
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引用次数: 0
Do Socioeconomic Factors Influence Knowledge, Attitudes, and Representations of End-of-Life Practices? A Cross-Sectional Study. 社会经济因素会影响对生命终结做法的认识、态度和表述吗?一项横断面研究。
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2022-10-13 DOI: 10.1177/08258597221131658
A Bérubé, D Tapp, S Dupéré, A Plaisance, G Bravo, J Downar, V Couture

ObjectiveAccess to palliative and end-of-life (EOL) care might be influenced by knowledge, attitudes, and representations of these practices. Socioeconomic factors might then affect what people know about EOL care practices, and how they perceive them. This study aims to compare knowledge, attitudes, and representations regarding EOL practices including assisted suicide, medical assistance in dying, and continuous palliative sedation of adults, according to socioeconomic variables.MethodsA cross-sectional community-based questionnaire study featuring two evolving vignettes and five end-of-life practices was conducted in Quebec, Canada. Three sample subgroups were created according to the participants' perceived financial situation and three according to educational attainment. Descriptive analysis was used to compare levels of knowledge, attitudes, and representations between the subgroups.ResultsNine hundred sixty-six (966) people completed the questionnaire. Two hundred and seventy participants (28.7%) had a high school diploma or less, and 42 participants (4.4%) were facing financial hardship. The majority of respondents supported all end-of-life options and the loosening of eligibility requirements for medical assistance in dying. Differences between subgroups were minor. While respondents in socioeconomically disadvantaged subgroups had less knowledge about EOL practices, those with lower educational attainment were more likely to be in favor of medical assistance in dying, and less likely to favor continuous palliative sedation.ConclusionsPeople living with situational social and economic vulnerabilities face multiple barriers in accessing health care. While they may have poorer knowledge about EOL practices, they have a positive attitude towards medical assistance in dying and assisted suicide, and a negative attitude towards continuous palliative sedation. This highlights the need for future research and interventions aimed at empowering this population and enhancing their access to EOL care.

目的:姑息治疗和临终关怀(EOL)的获得可能会受到这些实践的知识、态度和表现形式的影响。社会经济因素可能会影响人们对临终关怀实践的了解以及他们对这些实践的看法。本研究旨在比较不同社会经济变量对成人临终关怀实践(包括协助自杀、临终医疗协助和持续姑息镇静)的认知、态度和表述:方法:在加拿大魁北克省开展了一项基于社区的横断面问卷调查,调查内容包括两个不断演变的小故事和五种临终关怀实践。根据参与者的经济状况和受教育程度分别设立了三个样本分组。通过描述性分析,比较了各分组之间的知识、态度和表述水平:966(966)人完成了问卷调查。270名参与者(28.7%)只有高中或以下文凭,42名参与者(4.4%)面临经济困难。大多数受访者支持所有临终选择,并支持放宽临终医疗协助的资格要求。亚群体之间的差异较小。社会经济条件较差的亚群受访者对临终关怀实践的了解较少,而教育程度较低的受访者则更倾向于支持临终医疗协助,但不太赞成持续性姑息镇静:结论:生活在社会和经济弱势环境中的人在获得医疗服务方面面临多重障碍。虽然他们对临终关怀实践的了解可能较少,但他们对临终医疗协助和协助自杀持积极态度,而对持续性姑息镇静持消极态度。这凸显了未来研究和干预的必要性,其目的是增强这部分人群的能力,提高他们获得临终关怀的机会。
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引用次数: 0
Fourth branchial cleft anomaly in a 7-month-old infant: A case report and literature review. 一名 7 个月大婴儿的第四齿裂畸形:病例报告和文献综述。
IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 Epub Date: 2022-06-29 DOI: 10.1177/01455613221106211
Kateřina Sobotková, Milan Urík, Klára Perce, Barbora Petrová, Soňa Šikolová, Michal Bartoš, Jana Jančíková, Roman Kula, Petr Jabandžiev

Fourth branchial cleft anomalies are rare head and neck congenital lesions seen in children. They present as a neck inflammatory mass and arise essentially on the left side of the neck. We report the case of a 7-month-old female with a mass of the neck associated with respiratory distress. The mass was diagnosed as an incomplete fourth branchial cleft fistula. Surgical revision of the neck abscess from an external approach and plasma coblation of the orifice in the pyriform fossa by an endoscopic approach were performed.

第四杈裂畸形是儿童罕见的头颈部先天性病变。它们表现为颈部炎性肿块,主要发生在颈部左侧。我们报告了一例 7 个月大的女性病例,她的颈部肿块伴有呼吸困难。该肿块被诊断为不完全第四支裂瘘管。手术从外部对颈部脓肿进行了修补,并通过内窥镜方法对梨状窝的瘘口进行了等离子栓塞。
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引用次数: 0
Probing the E3 Ligase Adapter Cereblon with Chemical Biology
IF 18.3 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Pub Date : 2025-04-01 DOI: 10.1021/acs.accounts.5c00059
Wenqing Xu, Christina M. Woo
The E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological development and subsequently identified as the target of thalidomide and lenalidomide, therapeutic agents used in the treatment of hematopoietic malignancies. Both thalidomide and lenalidomide have been repurposed as ligands for targeted protein degradation therapeutic modalities. These agents were proposed to mimic a naturally occurring ligand, although the native substrate recognition mechanism of CRBN remained elusive. Chemical biology, which involves the use of chemical tools to modulate and probe biological systems, can provide unique insights into the molecular mechanisms and interactions of proteins with their cognate ligands. Here we describe our use of chemical biology approaches, including photoaffinity labeling, chemical proteomics, and targeted protein degradation, to interrogate the biological activities of CRBN in the presence or absence of its ligands. Our development of a photoaffinity labeling probe derived from lenalidomide, termed photolenalidomide, enabled mapping of the binding site on CRBN and identification of a new target recruited to CRBN by lenalidomide through chemical proteomics. Further derivatization of the lenalidomide scaffold afforded DEG-77, a potent degrader with therapeutic efficacy against acute myeloid leukemia. Our parallel development of chemically defined probes that are inspired by heterobifunctional targeted protein degradation agents and functionally engage CRBN in cells revealed that thalidomide is a peptidomimetic of an underappreciated protein modification termed the C-terminal cyclic imide, which arises from intramolecular cyclization of asparagine or glutamine residues and represents a degron endogenously recognized by CRBN. Protein engineering and proteomic efforts validated the CRBN-dependent regulation of proteins bearing the C-terminal cyclic imide modification in vitro and in cells and the prevalence of the C-terminal cyclic imide in the biological system. Application of C-terminal cyclic imides as a class of cyclimid ligands for targeted protein degradation led to the development of a variety of heterobifunctional degraders with distinct efficacy and target selectivity, whereas examination of the occurrence of C-terminal cyclic imides as a form of protein damage uncovered the intrinsic and extrinsic factors that predispose peptides and proteins to C-terminal cyclic imide formation and the role of CRBN in mitigating the accumulation of damaged proteins with a propensity for aggregation. Future investigation of C-terminal cyclic imides, synthetic ligands, and their relationship to CRBN biology will illuminate regulatory mechanisms that are controlled by CRBN and drive the pursuit of additional functional chemistries on proteins and the biological pathways that intercept them.
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引用次数: 0
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