Ocular Surface最新文献_第7页

HDAC1/2 and HDAC3 play distinct roles in controlling adult Meibomian gland homeostasis HDAC1/2 和 HDAC3 在控制成人睑板腺稳态中发挥着不同的作用

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-04-26 DOI: 10.1016/j.jtos.2024.04.005

Xuming Zhu , Mingang Xu , Sarah E. Millar

Purpose

To investigate the roles of HDAC1/2 and HDAC3 in adult Meibomian gland (MG) homeostasis.

Methods

HDAC1/2 or HDAC3 were inducibly deleted in MG epithelial cells of adult mice. The morphology of MG was examined. Proliferation, apoptosis, and expression of MG acinus and duct marker genes, meibocyte differentiation genes, and HDAC target genes, were analyzed via immunofluorescence, TUNEL assay, and RNA in situ hybridization.

Results

Co-deletion of HDAC1/2 in MG epithelium caused gradual loss of acini and formation of cyst-like structures in the central duct. These phenotypes required homozygous deletion of both HDAC1 and HDAC2, indicating that they function redundantly in the adult MG. Short-term deletion of HDAC1/2 in MG epithelium had little effect on meibocyte maturation but caused decreased proliferation of acinar basal cells, excessive DNA damage, ectopic apoptosis, and increased p53 acetylation and p16 expression in the MG. By contrast, HDAC3 deletion in MG epithelium caused dilation of central duct, atrophy of acini, defective meibocyte maturation, increased acinar basal cell proliferation, and ectopic apoptosis and DNA damage. Levels of p53 acetylation and p21 expression were elevated in HDAC3-deficient MGs, while the expression of the differentiation regulator PPARγ and the differentiation markers PLIN2 and FASN was downregulated.

Conclusions

HDAC1 and HDAC2 function redundantly in adult Meibomian gland epithelial progenitor cells and are essential for their proliferation and survival, but not for acinar differentiation, while HDAC3 is required to limit acinar progenitor cell proliferation and permit differentiation. HDAC1/2 and HDAC3 have partially overlapping roles in maintaining survival of MG cells.

目的研究 HDAC1/2 和 HDAC3 在成年小鼠睑板腺（MG）稳态中的作用。方法在成年小鼠的睑板腺上皮细胞中诱导性地删除 HDAC1/2 或 HDAC3。通过免疫荧光、TUNEL 检测和 RNA 原位杂交分析了 MG 上皮细胞的增殖、凋亡以及尖头和导管标记基因、腮腺细胞分化基因和 HDAC 靶基因的表达。这些表型需要同时同源缺失 HDAC1 和 HDAC2，这表明它们在成年 MG 中的功能是多余的。在MG上皮细胞中短期缺失HDAC1/2对窥视细胞的成熟几乎没有影响，但会导致MG中渐尖基底细胞增殖减少、DNA过度损伤、异位凋亡以及p53乙酰化和p16表达增加。相比之下，在 MG 上皮细胞中缺失 HDAC3 会导致中央导管扩张、尖头萎缩、meibocyte 成熟缺陷、尖头基底细胞增殖增加、异位凋亡和 DNA 损伤。结论HDAC1和HDAC2在成体睑板腺上皮祖细胞中具有冗余功能，对其增殖和存活至关重要，但对尖头分化并不重要，而HDAC3是限制尖头祖细胞增殖和允许分化所必需的。HDAC1/2和HDAC3在维持MG细胞存活方面的作用部分重叠。

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引用次数: 0

Readership awareness series – Paper 10: Open Access Publishing 读者意识系列--论文 10：开放存取出版

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-04-16 DOI: 10.1016/j.jtos.2024.04.001

Mohammad Javed Ali, Ali Djalilian

引用次数: 0

Corrigendum to “New insights into lacrimal gland anatomy using 7T MRI and electron microscopy: Relevance for lacrimal gland targeted therapies and bioengineering” [Ocul. Surf. 30 (October 2023) 204–212] 利用 7T 磁共振成像和电子显微镜对泪腺解剖学的新认识：对泪腺靶向治疗和生物工程的意义"[Ocul. Surf. 30 (October 2023) 204-212] 的更正

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-04-16 DOI: 10.1016/j.jtos.2024.04.002

Swati Singh , Zoltan Winter , Fabian Necker , Tobias Bäuerle , Michael Scholz , Lars Bräuer , Friedrich Paulsen

引用次数: 0

Visual outcomes of children undergoing penetrating keratoplasty in the US 美国接受穿透性角膜移植手术的儿童的视觉效果。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-04-01 DOI: 10.1016/j.jtos.2024.02.001

Lyvia J. Zhang, Reza Dana, Alice C. Lorch, Tobias Elze, Joan W. Miller, Thomas H. Dohlman, Isdin Oke, IRIS®Registry Analytic Center Consortium

引用次数: 0

Tear cytokine levels are reduced in patients treated with intravitreal injections 接受玻璃体内注射治疗的患者泪液细胞因子水平会降低。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-04-01 DOI: 10.1016/j.jtos.2024.03.004

Agni Malmin , Vilde M. Thomseth , Per T. Førland , Hans C.D. Aass , Sjur Reppe , Markus V.T. Olsen , Birger Lindtjørn , Xiangjun Chen , Inga B.K. Haugen , Tor P. Utheim , Vegard A. Forsaa

Purpose

To investigate cytokine levels in the tear fluid of patients receiving serial intravitreal injections (IVI) with anti-vascular endothelial growth factor (anti-VEGF) for neovascular age-related macular degeneration (nAMD).

Methods

Concentrations of six cytokines (IFN-γ, IL-1β, IL-6, IL-8, TNF and VEGF) in tears of patients receiving anti-VEGF in one eye were assayed using multiplex cytometric bead array. The fellow untreated eye served as control. Tear sampling was performed on a single occasion at a minimum of four weeks after IVI. Patients underwent a pre-IVI antisepsis protocol with povidone-iodine.

Results

Tear fluid from thirty patients with a mean age of 78.8 years (range 58–90) was assayed. Subjects received a median of 43.5 (range 22–106) IVI in one eye. The median level of IFN-γ was 0.33 (interquartile range (IQR) 0.22–0.52) pg/mg of total protein in injected eyes versus 0.41 (IQR 0.21–1.05) pg/mg in fellow eyes (p = 0.017). For TNF, a median level of 0.12 (IQR 0.08–0.18) pg/mg of total protein was found in injected eyes versus 0.14 (IQR 0.07–0.33) pg/mg of total protein in fellow eyes (p = 0.019). There were no differences between injected and fellow eyes regarding the levels of IL-1β, IL-6, IL-8 and VEGF.

Conclusion

Tear fluid in eyes receiving serial IVI with anti-VEGF and preoperative povidone-iodine antisepsis constitutes lower levels of the pro-inflammatory cytokines IFN-γ and TNF compared to fellow eyes. This provides biochemical support of previous findings of reduced signs of inflammation and healthier tear film parameters in patients treated with serial IVI.

目的：研究接受抗血管内皮生长因子（anti-VEGF）连续玻璃体内注射（IVI）治疗新生血管性年龄相关性黄斑变性（nAMD）患者泪液中的细胞因子水平：方法：使用多重细胞计数珠阵列检测一只眼接受抗血管内皮生长因子治疗的患者泪液中六种细胞因子（IFN-γ、IL-1β、IL-6、IL-8、TNF 和 VEGF）的浓度。另一只未接受治疗的眼睛作为对照。泪液取样在静脉输液后至少四周进行一次。患者在 IVI 前使用聚维酮碘进行防腐处理：检测了 30 名患者的泪液，他们的平均年龄为 78.8 岁（58-90 岁不等）。受试者单眼接受了中位数为 43.5（范围为 22-106）次的静脉滴注。注射眼的 IFN-γ 中位水平为 0.33（四分位距 0.22-0.52）pg/mg（总蛋白），而其他眼为 0.41（四分位距 0.21-1.05）pg/mg（P = 0.017）。在 TNF 方面，注射眼的中位水平为 0.12（IQR 0.08-0.18）pg/mg（总蛋白），而其他眼的中位水平为 0.14（IQR 0.07-0.33）pg/mg（总蛋白）（p = 0.019）。在 IL-1β、IL-6、IL-8 和血管内皮生长因子的水平方面，注射眼与其他眼没有差异：结论：接受抗血管内皮生长因子连续静脉滴注和术前聚维酮碘消毒的眼睛，其泪液中的促炎细胞因子 IFN-γ 和 TNF 水平低于同组眼睛。这为之前的研究结果提供了生化方面的支持，即接受连续 IVI 治疗的患者炎症症状减轻，泪膜参数更健康。

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引用次数: 0

Comparative analysis of human tear fluid and aqueous humor proteomes 人类泪液和眼房水蛋白质组的比较分析。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-03-30 DOI: 10.1016/j.jtos.2024.03.011

August Beisel , Garrett Jones , Joshua Glass , Tae Jin Lee , Marc Töteberg-Harms , Amy Estes , Lane Ulrich , Kathryn Bollinger , Shruti Sharma , Ashok Sharma

Purpose

Technological advancements allowing for the analysis of low-volume samples have led to the investigation of human tear fluid and aqueous humor (AH) as potential biomarker sources. However, acquiring AH samples poses significant challenges, making human tear fluid a more accessible alternative. This study aims to compare the protein compositions of these two biofluids to evaluate their suitability for biomarker discovery.

Methods

Paired tear and AH samples were collected from 20 patients undergoing cataract surgery. Tear samples were collected using Schirmer strips prior to surgery, and AH samples were collected from the anterior chamber immediately after corneal incision. Proteins were extracted and analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Results

A total of 481 proteins were identified in greater than 50% of the tear samples, and 191 proteins were detected in greater than 50% of the AH samples. Of these proteins, 82 were found to be common between the two biofluids, with ALB, LTF, TF, LCN1, and IGKC being the most abundant.

Conclusion

Although tear fluid and the AH are functionally independent and physically separated, many of the proteins detected in AH were also detected in tears. This direct comparison of the proteomic content of tear fluid and AH may aid in further investigation of tear fluid as a source of readily accessible biomarkers for various human diseases.

目的：分析低容量样本的技术进步促使人们将人类泪液和房水（AH）作为潜在的生物标记源进行研究。然而，获取 AH 样品面临着巨大的挑战，因此人类泪液成为更容易获取的替代品。本研究旨在比较这两种生物液体的蛋白质组成，以评估它们是否适合用于生物标记物的发现：方法：从 20 名接受白内障手术的患者身上采集了成对的泪液和 AH 样品。泪液样本是在手术前用施尔默试纸采集的，AH 样本是在角膜切开后立即从前房采集的。提取蛋白质并使用液相色谱-串联质谱法（LC-MS/MS）进行分析：结果：在超过 50% 的泪液样本中发现了 481 种蛋白质，在超过 50% 的 AH 样本中检测到了 191 种蛋白质。在这些蛋白质中，有 82 种蛋白质在两种生物流体中是共通的，其中含量最高的是 ALB、LTF、TF、LCN1 和 IGKC：结论：虽然泪液和AH在功能上是独立的，在物理上也是分离的，但在AH中检测到的许多蛋白质在泪液中也能检测到。直接比较泪液和AH的蛋白质组含量有助于进一步研究泪液作为各种人类疾病的易得生物标志物的来源。

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引用次数: 0

Predictive performance of corneal and lid margin sensitivity for dry eye disease: An investigator-masked, prospective, prognostic accuracy study 角膜和睑缘敏感度对干眼症的预测性能：一项由研究人员掩盖的前瞻性预后准确性研究。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-03-28 DOI: 10.1016/j.jtos.2024.03.010

Michael T.M. Wang , Jay J. Meyer , Ally L. Xue , Barry Power , Jennifer P. Craig

Purpose

To evaluate the prognostic ability of non-contact esthesiometry corneal and lid margin sensitivity measurements in detecting symptoms and signs of dry eye disease, as defined by the global consensus TFOS DEWS II criteria.

Methods

A total of 87 community residents (58 females; mean ± SD age, 53 ± 16 years) were recruited in an investigator-masked, prospective, prognostic accuracy study. Dry eye symptomology, tear film parameters, and ocular surface characteristics were evaluated in a single clinical session, and non-contact esthesiometry corneal and lid margin sensitivity measurements performed by an independent masked assessor.

Results

Overall, 49 (56%) participants fulfilled the TFOS DEWS II criteria for dry eye disease, while 57 (66%) exhibited clinical symptoms, and 67 (77%) had positive signs. The prognostic abilities of corneal and lid margin sensitivity measurements were significantly greater than chance for the detection dry eye signs (both p ≤ 0.03), but not for symptoms or overall disease diagnosis (all p > 0.10). The Youden-optimal prognostic cut-offs for corneal and lid margin sensitivity thresholds were both ≥0.8 mbar for the detection of clinical dry eye signs. Lid margin sensitivity demonstrated marginally higher predictive performance than corneal sensitivity (C-statistic, 0.688 versus 0.658), and was significantly correlated with tear film stability, corneal, conjunctival and lid wiper staining (all p < 0.05).

Conclusions

Corneal and lid margin sensitivity demonstrated moderate prognostic utility for detecting clinical dry eye signs. Future research is warranted to investigate the utility of incorporating non-contact esthesiometry in the workup for dry eye disease and neurotrophic keratopathy.

目的：根据全球共识的 TFOS DEWS II 标准，评估非接触式眼压计角膜和睑缘敏感度测量在检测干眼症症状和体征方面的预后能力：共招募了 87 名社区居民（58 名女性；平均 ± SD 年龄，53 ± 16 岁）参加一项由调查人员掩蔽的前瞻性预后准确性研究。干眼症状、泪膜参数和眼表特征在单次临床治疗中进行评估，角膜和睑缘的非接触式眼压计敏感度测量由独立的盲人评估员进行：总体而言，49 人（56%）符合 TFOS DEWS II 干眼症标准，57 人（66%）有临床症状，67 人（77%）有阳性体征。角膜和睑缘敏感度测量对干眼症体征检测的预后能力明显高于偶然性（两者的 p 均小于 0.03），但对症状或总体疾病诊断的预后能力则不明显（所有 p 均大于 0.10）。角膜和睑缘敏感度测量的尤登最佳预后临界值均≥0.8 毫巴，可用于检测临床干眼症征兆。睑缘敏感度的预测性能略高于（C 统计量，0.688 对 0.658），并与泪膜稳定性、角膜、结膜和睑板染色显著相关（均为 p 结论）：角膜和睑缘敏感性在检测临床干眼症征兆方面显示出中等预后效用。今后有必要开展研究，探讨在干眼症和神经营养性角膜病的检查中采用非接触式眼压计的效用。

{"title":"Predictive performance of corneal and lid margin sensitivity for dry eye disease: An investigator-masked, prospective, prognostic accuracy study","authors":"Michael T.M. Wang , Jay J. Meyer , Ally L. Xue , Barry Power , Jennifer P. Craig","doi":"10.1016/j.jtos.2024.03.010","DOIUrl":"10.1016/j.jtos.2024.03.010","url":null,"abstract":"<div><h3>Purpose</h3><p>To evaluate the prognostic ability of non-contact esthesiometry corneal and lid margin sensitivity measurements in detecting symptoms and signs of dry eye disease, as defined by the global consensus TFOS DEWS II criteria.</p></div><div><h3>Methods</h3><p>A total of 87 community residents (58 females; mean ± SD age, 53 ± 16 years) were recruited in an investigator-masked, prospective, prognostic accuracy study. Dry eye symptomology, tear film parameters, and ocular surface characteristics were evaluated in a single clinical session, and non-contact esthesiometry corneal and lid margin sensitivity measurements performed by an independent masked assessor.</p></div><div><h3>Results</h3><p>Overall, 49 (56%) participants fulfilled the TFOS DEWS II criteria for dry eye disease, while 57 (66%) exhibited clinical symptoms, and 67 (77%) had positive signs. The prognostic abilities of corneal and lid margin sensitivity measurements were significantly greater than chance for the detection dry eye signs (both p ≤ 0.03), but not for symptoms or overall disease diagnosis (all p > 0.10). The Youden-optimal prognostic cut-offs for corneal and lid margin sensitivity thresholds were both ≥0.8 mbar for the detection of clinical dry eye signs. Lid margin sensitivity demonstrated marginally higher predictive performance than corneal sensitivity (C-statistic, 0.688 versus 0.658), and was significantly correlated with tear film stability, corneal, conjunctival and lid wiper staining (all p < 0.05).</p></div><div><h3>Conclusions</h3><p>Corneal and lid margin sensitivity demonstrated moderate prognostic utility for detecting clinical dry eye signs. Future research is warranted to investigate the utility of incorporating non-contact esthesiometry in the workup for dry eye disease and neurotrophic keratopathy.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"33 ","pages":"Pages 11-15"},"PeriodicalIF":6.4,"publicationDate":"2024-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1542012424000399/pdfft?md5=ce0dce8ce6a262c8e730cd050187ca48&pid=1-s2.0-S1542012424000399-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140330477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New disposable esthesiometer (KeraSenseⓇ) to improve diagnosis and management of neurotrophic keratitis 改进神经营养性角膜炎诊断和管理的新型一次性雌激素扫描仪（KeraSenseⓇ）。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-03-21 DOI: 10.1016/j.jtos.2024.03.009

Francesca Giovannetti, Marta Sacchetti, Marco Marenco, Ludovico Alisi, Giacomo Visioli, Alice Bruscolini, Alessandro Lambiase

Purpose

To validate the use, repeatability, and reproducibility of a new, cost-effective, disposable, sterile device (KeraSenseⓇ, Dompè farmaceutici SpA, Milan Italy) compared to Cochet-Bonnet (CB) esthesiometer. Secondly, to identify a simple, safe, rapid, and low-cost test to diagnose neurotrophic keratitis (NK).

Methods

16 patients with diagnosis of NK stage I, 25 patients with diabetes mellitus (DM), and 26 healthy subjects were included in the study. Corneal sensitivity (CS) was assessed by CB and KeraSenseⓇ. Repeatability, accuracy, and reproducibility of the novel disposable aesthesiometer were assessed. Specificity, sensitivity, and cut-off value for NK diagnosis were calculated by ROC curve analysis.

Results

All NK patients showed a CS ≤ 40 mm, while none of the healthy patients showed a CS value < 50 mm. Significant agreement was found between CB measurements and the single use esthesiometer evaluations of CS (p < 0.001). Repeatability evaluations of the single use esthesiometer showed 100% agreement between different measurements (p < 0.001). Reproducibility evaluations showed 99.6% concordance between different operators (p < 0.001). A 55 mm value of the single use esthesiometer was adequate to exclude an NK diagnosis, while all NK patients showed a value ≤ 35 mm.

Conclusions

Corneal hypo/anaesthesia is considered the hallmark of NK. The use of the novel single-use esthesiometer will allow for a diagnostic improvement in NK, sparing time and guaranteeing patients’ safety. Diabetic patients despite normal corneal findings may show impairment of CS, suggesting a preclinical stage of NK, requiring a close follow-up.

目的：与 Cochet-Bonnet (CB) 血沉计相比，验证一种新型、经济、一次性无菌设备（KeraSenseⓇ，Dompè farmaceutici SpA，意大利米兰）的使用、重复性和再现性。其次，确定一种简单、安全、快速、低成本的检测方法来诊断神经营养性角膜炎（NK）。方法：研究纳入了 16 名诊断为 NK I 期的患者、25 名糖尿病（DM）患者和 26 名健康受试者。角膜敏感度（CS）通过 CB 和 KeraSenseⓇ 进行评估。对新型一次性验光仪的重复性、准确性和再现性进行了评估。通过 ROC 曲线分析计算了 NK 诊断的特异性、敏感性和临界值：结果：所有 NK 患者的 CS 值均小于 40 毫米，而健康患者均未显示 CS 值：角膜缺氧/麻醉被认为是 NK 的标志。使用新型一次性虹膜吸力计可改进 NK 的诊断，节省时间并保证患者的安全。尽管角膜检查结果正常，但糖尿病患者可能会出现 CS 损伤，这表明 NK 处于临床前阶段，需要密切随访。

{"title":"New disposable esthesiometer (KeraSenseⓇ) to improve diagnosis and management of neurotrophic keratitis","authors":"Francesca Giovannetti, Marta Sacchetti, Marco Marenco, Ludovico Alisi, Giacomo Visioli, Alice Bruscolini, Alessandro Lambiase","doi":"10.1016/j.jtos.2024.03.009","DOIUrl":"10.1016/j.jtos.2024.03.009","url":null,"abstract":"<div><h3>Purpose</h3><p>To validate the use, repeatability, and reproducibility of a new, cost-effective, disposable, sterile device (KeraSenseⓇ, Dompè farmaceutici SpA, Milan Italy) compared to Cochet-Bonnet (CB) esthesiometer. Secondly, to identify a simple, safe, rapid, and low-cost test to diagnose neurotrophic keratitis (NK).</p></div><div><h3>Methods</h3><p>16 patients with diagnosis of NK stage I, 25 patients with diabetes mellitus (DM), and 26 healthy subjects were included in the study. Corneal sensitivity (CS) was assessed by CB and KeraSenseⓇ. Repeatability, accuracy, and reproducibility of the novel disposable aesthesiometer were assessed. Specificity, sensitivity, and cut-off value for NK diagnosis were calculated by ROC curve analysis.</p></div><div><h3>Results</h3><p>All NK patients showed a CS ≤ 40 mm, while none of the healthy patients showed a CS value < 50 mm. Significant agreement was found between CB measurements and the single use esthesiometer evaluations of CS (p < 0.001). Repeatability evaluations of the single use esthesiometer showed 100% agreement between different measurements (p < 0.001). Reproducibility evaluations showed 99.6% concordance between different operators (p < 0.001). A 55 mm value of the single use esthesiometer was adequate to exclude an NK diagnosis, while all NK patients showed a value ≤ 35 mm.</p></div><div><h3>Conclusions</h3><p>Corneal hypo/anaesthesia is considered the hallmark of NK. The use of the novel single-use esthesiometer will allow for a diagnostic improvement in NK, sparing time and guaranteeing patients’ safety. Diabetic patients despite normal corneal findings may show impairment of CS, suggesting a preclinical stage of NK, requiring a close follow-up.</p></div>","PeriodicalId":54691,"journal":{"name":"Ocular Surface","volume":"32 ","pages":"Pages 192-197"},"PeriodicalIF":6.4,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140195344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

New-onset keratitis associated with epidermal growth factor receptor-based targeted therapies in Han Chinese patients with lung cancer: A multi-center cohort study 中国汉族肺癌患者接受表皮生长因子受体靶向治疗后出现的新发角膜炎：一项多中心队列研究

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-03-19 DOI: 10.1016/j.jtos.2024.03.008

Kevin Sheng-Kai Ma , Jui-En Lo , James Chodosh , Reza Dana

Purpose

To determine the risk and incidence of keratitis following treatment with epidermal growth factor receptor inhibitors (EGFRi) and subtypes of EGFRi-associated keratitis.

Methods

This multi-center cohort study included EGFRi-treated patients and non-users with lung cancer between 2010 and 2023. EGFRi included first-generation agent gefitinib and erlotinib, second-generation agent afatinib, and third-generation agent osimertinib. The primary outcome was new-onset keratitis. Cox proportional hazard models with multivariable adjustment were applied to determine the effect of EGFRi on keratitis over time. Subgroup analyses were conducted, stratified by agents of EGFRi. Sub-outcome analyses were performed to identify the subtypes of EGFRi-associated keratitis.

Results

A total of 1549 EGFRi-treated patients and 6146 non-users were included. 38 (2.5%) EGFRi-treated patients developed keratitis. The incidence of keratitis in EGFRi-treated patients was significantly higher than that in controls (incidence rate, IR, per 1000 person-years = 14.7 vs 4.49, p < 0.0001). EGFRi-treated patients presented with an increased risk for keratitis (adjusted hazard ratio, aHR = 3.14, 95% CI = 1.85–5.35, p < 0.001). Erlotinib (aHR = 2.64, 95% CI = 1.35–5.15, p = 0.004), afatinib (aHR = 4.42, 95% CI = 2.17–9.02, p < 0.001), and osimertinib (aHR = 4.67, 95% CI = 1.60–13.64, p = 0.005), but not gefitinib (aHR = 2.30, 95% CI = 0.96–5.55, p = 0.063), significantly contributed to the risk of keratitis. Subtypes of EGFRi-associated keratitis included corneal ulcer (IR = 2.31 vs 0.166, p < 0.0001) and keratoconjunctivitis (IR = 9.27 vs 2.91, p < 0.0001). None of the EGFRi-treated patients developed perforated corneal ulcer, interstitial and deep keratitis, or corneal neovascularization.

Conclusion

Treatment with EGFRi was associated with an increased risk of keratitis. Ocular toxicity of EGFRi was highest for third-generation agents, followed by second-generation agents, and then first-generation agents.

目的：确定表皮生长因子受体抑制剂（EGFRi）治疗后角膜炎的风险和发病率，以及EGFRi相关角膜炎的亚型。这项多中心队列研究纳入了2010年至2023年间接受表皮生长因子受体抑制剂治疗的肺癌患者和非患者。EGFRi包括第一代药物吉非替尼和厄洛替尼、第二代药物阿法替尼和第三代药物奥希替尼。主要研究结果为新发角膜炎。采用经多变量调整的 Cox 比例危险模型来确定表皮生长因子受体抑制剂对角膜炎随时间变化的影响。根据表皮生长因子受体（EGFRi）的药剂进行了分组分析。进行了子结果分析，以揭示表皮生长因子受体相关性角膜炎的亚型。共纳入了1549名接受过表皮生长因子受体治疗的患者和6146名未接受过表皮生长因子受体治疗的患者。38例（2.5%）接受过表皮生长因子受体（EGFRi）治疗的患者出现了角膜炎。EGFRi治疗患者的角膜炎发病率明显高于对照组（发病率，IR，每千人年=0.0594 vs 0.015，P < 0.0001）。表皮生长因子受体治疗患者发生角膜炎的风险增加（调整后危险比 aHR = 3.14，95% CI = 1.85-5.35，p < 0.001）。厄洛替尼（aHR = 2.64，95% CI = 1.35-5.15，p = 0.004）、阿法替尼（aHR = 4.42，95% CI = 2.17-9.02，p < 0.001）和奥西莫替尼（aHR = 4.67，95% CI = 1.60-13.64，p = 0.005），但吉非替尼（aHR = 2.30，95% CI = 0.96-5.55，p = 0.063）不显著增加角膜炎风险。表皮生长因子受体相关性角膜炎的亚型包括角膜溃疡（IR = 0.00516 vs 0.00130，p < 0.0001）和角结膜炎（IR = 0.0374 vs 0.00944，p < 0.0001）。接受表皮生长因子受体抑制剂治疗的患者均未出现角膜穿孔性溃疡、间质性和深层角膜炎或角膜新生血管。表皮生长因子受体（EGFRi）治疗与角膜炎风险增加有关。表皮生长因子受体生长因子受体（EGFRi）的眼部毒性在第三代药物中最大，其次是第二代药物，然后是第一代药物。

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引用次数: 0

Cellular senescence promotes meibomian gland dysfunction in a chronic graft-versus-host disease mouse model 在慢性移植物抗宿主病小鼠模型中，细胞衰老会促进睑板腺功能障碍。

IF 6.4 1区医学 Q1 OPHTHALMOLOGY

Ocular Surface

Pub Date : 2024-03-16 DOI: 10.1016/j.jtos.2024.03.006

Shinri Sato , Yoko Ogawa , Eisuke Shimizu , Kazuki Asai , Takahiro Okazaki , Robert Rusch , Masatoshi Hirayama , Shigeto Shimmura , Kazuno Negishi , Kazuo Tsubota

Purpose

Aging is a well-established risk factor for meibomian gland dysfunction (MGD). We previously reported an accelerated cellular senescence phenomenon in the lacrimal glands of a murine model of chronic graft-versus-host disease (cGVHD). Herein, we aimed to elucidate the relationship between cellular senescence and MGD in cGVHD mice, utilizing the senolytic agent ABT-263.

Methods

A cGVHD mouse model was established through allogeneic bone marrow transplantation (BMT) from B10.D2 to BALB/c mice. Subsequently, cGVHD mice were treated with either ABT-263 or vehicle. The eyelids of recipients were analyzed at 4-week intervals post-BMT in both groups.

Results

Meibomian gland (MG) area was significantly smaller in cGVHD mice than in syngeneic control mice. ABT-263-treated mice retained a significantly larger MG area than their vehicle-treated counterparts. Pathological and immunohistochemical examinations revealed significant reductions in eyelid tissue inflammation and pathological fibrosis in the ABT-263 group compared to that in the vehicle-treated group. Additionally, expression of DNA damage markers, senescent cell markers, and senescence-associated secretory phenotype (SASP) factors was elevated in the eyelids of cGVHD mice compared with that in syngeneic mice. The expression of these cellular senescence-associated molecules was considerably suppressed in ABT-263-treated eyelids compared to that in vehicle-treated ones.

Conclusions

Cellular senescence, along with expression of SASP factors, exhibited increased activity in the eyelids, particularly in the MGs of cGVHD mice. ABT-263 mitigated the severity of MGD. These findings highlight the potential of targeting cellular senescence as an effective approach for MGD treatment in cGVHD.

目的：衰老是导致睑板腺功能障碍（MGD）的一个公认的危险因素。我们以前曾报道过慢性移植物抗宿主病（cGVHD）小鼠模型泪腺中的细胞加速衰老现象。在此，我们旨在利用衰老分解剂 ABT-263 阐明 cGVHD 小鼠的细胞衰老与 MGD 之间的关系：方法：通过将 B10.D2 小鼠的异体骨髓移植（BMT）至 BALB/c 小鼠，建立了 cGVHD 小鼠模型。随后，用 ABT-263 或药物治疗 cGVHD 小鼠。两组小鼠均在BMT术后4周对受者眼睑进行分析：结果：cGVHD小鼠的睑板腺（MG）面积明显小于同种异体对照小鼠。ABT-263治疗的小鼠保留的睑板腺面积明显大于药物治疗的小鼠。病理和免疫组化检查显示，ABT-263 组的眼睑组织炎症和病理纤维化程度明显低于药物治疗组。此外，DNA损伤标志物、衰老细胞标志物和衰老相关分泌表型（SASP）因子在cGVHD小鼠眼睑中的表达量比在合成小鼠中的表达量高。这些细胞衰老相关分子在 ABT-263 处理的眼睑中的表达与在车辆处理的眼睑中的表达相比明显受到抑制：结论：细胞衰老以及SASP因子的表达在眼睑中表现出更高的活性，尤其是在cGVHD小鼠的MG中。ABT-263 可减轻 MGD 的严重程度。这些发现凸显了靶向细胞衰老作为一种有效方法来治疗 cGVHD 中的 MGD 的潜力。

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引用次数: 0