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.
{"title":"Laryngeal Cancer With Lung Metastases Showing Long-Term Complete Response and Delayed Immune-Related Adverse Event After Nivolumab Discontinuation.","authors":"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","doi":"10.1177/01455613211031025","DOIUrl":"10.1177/01455613211031025","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"222-227"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39199785","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}
Pub Date : 2025-04-01Epub Date: 2025-03-11DOI: 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
{"title":"Reimagining Dearomatization: Arenophile-Mediated Single-Atom Insertions and π-Extensions.","authors":"Zohaib Siddiqi, David Sarlah","doi":"10.1021/acs.accounts.5c00035","DOIUrl":"10.1021/acs.accounts.5c00035","url":null,"abstract":"<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","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1134-1150"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602933","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}
Pub Date : 2025-04-01Epub Date: 2022-11-03DOI: 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.
{"title":"An Open Source Replication of a Winning Recidivism Prediction Model.","authors":"Giovanni M Circo, Andrew P Wheeler","doi":"10.1177/0306624X221133004","DOIUrl":"10.1177/0306624X221133004","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"438-453"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40662589","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}
Pub Date : 2025-04-01Epub Date: 2022-06-21DOI: 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。
{"title":"Effects of Hyaluronic Acid/Collagen Resorbable Gel Use in Endoscopic Dacryocystorhinostomy.","authors":"Hyunkyu Lee, Sumin Yoon, Sehyun Baek","doi":"10.1177/01455613221104438","DOIUrl":"10.1177/01455613221104438","url":null,"abstract":"<p><p>The purpose of this study was to investigate whether the use of hyaluronic acid/collagen resorbable gel (Regenwel<sup>®</sup>) 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%, <i>P</i> = .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%, <i>P</i> = .024). Among secondary outcomes, granulation formation occurred less frequently in the Regenwel group than in the Control group (9.2% vs 32.2%, <i>P</i> < .001), and there was no statistically significant difference in postoperative bleeding between the 2 groups (0% vs 1.4%, <i>P</i> = .478). The Regenwel group had fewer infections after surgery than the Control group (5.3% vs 8.9%, <i>P</i> = .012) and required less frequent revision surgery (2.0% vs 15.8%, <i>P</i> < .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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"NP223-NP228"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40121955","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}
Pub Date : 2025-04-01Epub Date: 2022-07-04DOI: 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.
{"title":"Prognostic significance of cystic nodal metastasis in HPV-positive oropharyngeal cancer.","authors":"Jure Pupić-Bakrač, Mario Rašić","doi":"10.1177/01455613221112340","DOIUrl":"10.1177/01455613221112340","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"201-203"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40562015","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}
Pub Date : 2025-04-01Epub Date: 2025-03-18DOI: 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":"<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","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}
Pub Date : 2025-04-01Epub Date: 2025-03-03DOI: 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
{"title":"The Photoactivated Depot (PAD): Light Triggered Control of Therapeutic Protein Solubility and Release.","authors":"Simon H Friedman","doi":"10.1021/acs.accounts.4c00718","DOIUrl":"10.1021/acs.accounts.4c00718","url":null,"abstract":"<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","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"1055-1064"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143539365","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}
Pub Date : 2025-04-01Epub Date: 2022-10-13DOI: 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.
{"title":"Do Socioeconomic Factors Influence Knowledge, Attitudes, and Representations of End-of-Life Practices? A Cross-Sectional Study.","authors":"A Bérubé, D Tapp, S Dupéré, A Plaisance, G Bravo, J Downar, V Couture","doi":"10.1177/08258597221131658","DOIUrl":"10.1177/08258597221131658","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"152-161"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11967092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33509091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-04-01Epub Date: 2022-06-29DOI: 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.
{"title":"Fourth branchial cleft anomaly in a 7-month-old infant: A case report and literature review.","authors":"Kateřina Sobotková, Milan Urík, Klára Perce, Barbora Petrová, Soňa Šikolová, Michal Bartoš, Jana Jančíková, Roman Kula, Petr Jabandžiev","doi":"10.1177/01455613221106211","DOIUrl":"10.1177/01455613221106211","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":" ","pages":"NP191-NP194"},"PeriodicalIF":16.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40405121","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}
Pub Date : 2025-04-01DOI: 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.
{"title":"Probing the E3 Ligase Adapter Cereblon with Chemical Biology","authors":"Wenqing Xu, Christina M. Woo","doi":"10.1021/acs.accounts.5c00059","DOIUrl":"https://doi.org/10.1021/acs.accounts.5c00059","url":null,"abstract":"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.","PeriodicalId":1,"journal":{"name":"Accounts of Chemical Research","volume":"8 1","pages":""},"PeriodicalIF":18.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143744904","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}