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Purpose: Conjunctival melanoma is a rare neoplasm with high rates of recurrence and metastasis. Traditional management includes surgical excision and cryotherapy, followed by adjuvant therapy as needed. Immune checkpoint inhibitors, including nivolumab, are a targeted treatment option with improved survival rates. However, various immune-related adverse effects have been reported with these drugs. While systemic granulomatous inflammation is a documented systemic side effect, it has rarely been reported in the conjunctiva and ocular adnexa. Observation: A patient with a history of recurrent metastatic conjunctival melanoma presented with both a left sub-conjunctival and upper eyelid lesion after the commencement of treatment with nivolumab. The lesions were excised with a clinical suspicion for metastasis and consisted of noncaseating granulomatous inflammation with no evidence of malignancy on histopathologic examination. Infectious and primary autoimmune etiologies were ruled out. Conclusion and importance: This is a biopsy-proven case of periocular immune checkpoint inhibitor-associated granulomatous inflammation.

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This study aims to compare the levels of intrinsic protein disorder within the human lens and zonule proteomes and investigate the role of aging as a potential influencing factor on disorder levels. A cross-sectional proteomic analysis was employed, utilizing a dataset of 1466 proteins derived from the lens and zonule proteomes previously published by Wang et al. and De Maria et al. Bioinformatics tools, including a composition profiler and a rapid intrinsic disorder analysis online tool, were used to conduct a comparative analysis of protein disorder. Statistical tests such as ANOVA, Tukey's HSD, and chi-squared tests were applied to evaluate differences between groups. The study revealed distinct amino acid compositions for each proteome, showing a direct correlation between aging and increased protein disorder in the zonular proteomes, whereas the lens proteomes exhibited the opposite trend. Findings suggest that age-related changes in intrinsic protein disorder within the lens and zonule proteomes may be linked to structural transformations in these tissues. Understanding how protein disorder evolves with age could enhance knowledge of the molecular basis for age-related conditions such as cataracts and pseudoexfoliation, potentially leading to better therapeutic strategies.

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High-resolution optical coherence tomography (HR-OCT) has transformed the diagnosis and management of ocular surface lesions. Providing a detailed cross-sectional view of the cornea and conjunctiva, HR-OCT can be used to identify characteristic features of various benign and malignant ocular surface lesions, aiding in their diagnosis and guiding treatment. When incorporated into an ophthalmology clinic, HR-OCT provides morphological images of lesions in a noninvasive means, akin to an "optical biopsy". The characteristic HR-OCT features of several lesions have been well described in the literature, including for ocular surface squamous neoplasia, papilloma, melanoma, primary acquired melanosis, complexion associated melanosis, nevus, pterygium, pinguecula, lymphoma, and amyloidosis. HR-OCT can be used to differentiate between lesions with similar clinical features, lesions that co-exist on the same ocular surface, and atypically presenting lesions, such as pigmented ocular surface squamous neoplasia or amelanotic melanoma. The management of ocular surface lesions has been transformed by the implementation of HR-OCT, providing clinicians with the ability to monitor tumor response to topical chemotherapies, follow previously excised lesions for recurrence, and map out tumor borders intraoperatively. While there are some limitations to HR-OCT, including imaging of thick or deep lesions, it has become an essential tool for ocular oncologists in the management of ocular surface lesions.

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OBJECTIVE: To present a series of conjunctival keratoacanthomas and provide clinical, histopathological, immunohistochemical, and imaging results that characterize this rare entity. METHODS: A retrospective chart review of records from 2005 to 2023 from the Florida Lions Ocular Pathology Laboratory was conducted. Nine patients with histologically proven conjunctival keratoacanthoma were identified. Data extracted includes demographics, clinical history, diagnostic testing, histopathological and immunohistochemical testing, treatment modalities, and recurrences. RESULTS: Patients' mean age was 55.2 ± 21.1 years (range: 22-83). 77.8% (7/9) of patients were male. 55.6% (5/9) were Hispanic. 55.6% of lesions (5/9) were in right eyes. 55.6% of lesions (5/9) were on the temporal, bulbar conjunctiva. The lesions were rapidly growing, with mean onset time of 4.71 ± 3.30 weeks (range: 2-12). High-resolution anterior segment optical coherence tomography of three lesions revealed hyper-reflective, thickened epithelium with abrupt transition between normal and abnormal epithelium. Underlying disorganized subepithelial tissue was noted. However, the overlying abnormal epithelium caused considerable shadowing, which obscured subepithelial structures. Prominent, keratin-filled, cup-shaped lesions with faulty maturational sequencing that extend full thickness, variably pale cytoplasm, and foci of dyskeratosis and hyperkeratosis were present on all lesions' histopathology. All lesions were surgically excised, but two demonstrated partial spontaneous resolution before surgery. Two patients were lost to follow-up; the remaining seven had no signs of recurrence at a of mean of 36.9 ± 45.4 months (range: 3 to 141 months) of follow-up. CONCLUSIONS: Conjunctival keratoacanthomas are rare lesions of the ocular surface with distinct clinical, histopathologic, and diagnostic features.

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This case report describes a diagnosis of conjunctival Kaposi sarcoma in a patient recently diagnosed with HIV infection and taking highly active antiretroviral therapy.

Asunto(s)

Infecciones por VIH , Humanos , Infecciones por VIH/diagnóstico , Infecciones por VIH/complicaciones , Masculino , Enfermedades de la Conjuntiva/diagnóstico , Enfermedades de la Conjuntiva/virología , Conjuntiva/patología , Adulto

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The vitreous is a vital component of the eye, occupying a substantial portion of its volume and maintaining its structure. This study delves into the presence and significance of intrinsically disordered proteins (IDPs) within the vitreous, utilizing a dataset of 1240 vitreous proteins previously discovered in the vitreous proteome by Murthy et al.in five healthy subjects. The results indicate that 26.9 % of vitreous proteins are highly disordered, 68.8 % possess moderate disorder, and only 4.3 % are highly ordered. A complex interaction network among these proteins suggests their biological importance, and approximately 25 % may undergo liquid-liquid phase separation (LLPS). These findings offer new perspectives on the vitreous' molecular composition and behavior, potentially impacting our understanding of eye-related diseases, physiological changes such as vitreous syneresis. Further research is needed to translate these insights into clinical applications, although the intrinsic protein disorder and its association with LLPS appears to play a role in vitreous proteome function.

Asunto(s)

Proteínas Intrínsecamente Desordenadas , Proteoma , Cuerpo Vítreo , Humanos , Proteínas Intrínsecamente Desordenadas/metabolismo , Proteínas Intrínsecamente Desordenadas/química , Proteoma/metabolismo , Cuerpo Vítreo/metabolismo , Proteínas del Ojo/metabolismo

RESUMEN

PURPOSE: Chronic inflammation is a predisposing factor for metaplastic changes and ultimately dysplasia. We describe cases of OSSN occurring in the setting of chronic ocular surface inflammation. METHODS: Sixteen eyes from 14 individuals were included from one ocular oncology clinic between 2010 and 2023. Patients presented with ocular surface squamous neoplasia (OSSN) in the setting of chronic inflammation. The diagnosis of OSSN was made using anterior segment high-resolution optical coherence tomography (HR-OCT) and confirmed by histopathological analysis in all cases. RESULTS: Median age on presentation was 61 [IQR 47.5-69.2] years. Eleven (86%) individuals were male and five (36%) identified as White Hispanic. Ten eyes were referred with ocular surface diagnoses including pannus (n = 4), scarring (n = 3), pterygium (n = 2), and herpetic keratitis (n = 1). Only six eyes were referred as possible neoplasia. All individuals had a history of ocular surface inflammation. The most common inflammatory conditions were ocular rosacea (seven individuals) and atopic keratoconjunctivitis (AKC) (five individuals). Two individuals were found to have bilateral OSSN, one in the setting of ocular rosacea and the other in the setting of AKC. All 16 eyes from 14 individuals were suspected to have OSSN based on HR-OCT findings which guided the location of the incisional biopsies that subsequently confirmed histopathological diagnosis in all cases. CONCLUSION: OSSN may arise in the setting of chronic inflammation on the ocular surface. Identification of the tumor can be challenging in these cases, and HR-OCT can be a key diagnostic tool in detecting OSSN.

Asunto(s)

Tomografía de Coherencia Óptica , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Factores de Riesgo , Tomografía de Coherencia Óptica/métodos , Enfermedad Crónica , Estudios Retrospectivos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/diagnóstico , Neoplasias del Ojo/patología , Neoplasias del Ojo/diagnóstico , Inflamación/patología , Neoplasias de la Conjuntiva/patología , Enfermedades de la Córnea/patología , Enfermedades de la Córnea/diagnóstico , Enfermedades de la Córnea/etiología

RESUMEN

PURPOSE: The purpose of this study was to describe the response of a papillomatous ocular surface squamous neoplasia (OSSN) to the intramuscular (IM) 9-valent human papillomavirus (HPV) vaccine after failed medical and surgical interventions. METHODS: A 79-year-old White man with a conjunctival lesion underwent a biopsy which revealed OSSN and positivity for high-risk HPV. Initially treated with medical therapy and surgical excisions, the patient developed a recurrence and refused further surgery. He was given 4 doses of IM HPV vaccine at the 6-week interval. RESULTS: A dramatic reduction in lesion size and reduced epithelial thickening and hyperreflectivity was noted on slitlamp examination and high-resolution anterior segment optical coherence tomography after receiving the IM HPV vaccine. Although lesion size was markedly reduced, the therapy did not achieve total resolution, resulting in further treatment with topical 1% 5-fluorouracil (5-FU) eye drops and later 0.04% mitomycin C eye drops. The patient then elected to discontinue further treatment and solely observe. CONCLUSIONS: This case report adds to the growing literature demonstrating the potential therapeutic use of vaccines in cancer treatment. Although HPV vaccination is currently approved for prophylaxis, the use of HPV vaccines as a therapeutic option for various HPV-mediated diseases, including OSSN, should be further explored. The HPV vaccine yielded significant initial improvement in this patient who refused further surgical interventions. The use of IM HPV vaccine as an adjunctive treatment of papillomatous OSSN may represent a potential therapeutic option in cases refractory to standard treatment modalities.

Asunto(s)

Neoplasias de la Conjuntiva , Infecciones Virales del Ojo , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Tomografía de Coherencia Óptica , Humanos , Masculino , Anciano , Neoplasias de la Conjuntiva/tratamiento farmacológico , Neoplasias de la Conjuntiva/virología , Neoplasias de la Conjuntiva/terapia , Neoplasias de la Conjuntiva/patología , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/administración & dosificación , Infecciones Virales del Ojo/virología , Infecciones Virales del Ojo/tratamiento farmacológico , Infecciones Virales del Ojo/diagnóstico , Infecciones Virales del Ojo/prevención & control , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/terapia , Inyecciones Intramusculares , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Soluciones Oftálmicas

RESUMEN

PURPOSE: To present the first known cases of punctal and canalicular stenosis following topical 5-fluorouracil (5-FU) eye drops for ocular surface squamous neoplasia (OSSN). METHODS: A retrospective chart review of patients with OSSN receiving topical 1% 5-FU eye drops as a primary or adjuvant treatment between 2013 and 2021 was performed. Individuals diagnosed with punctal or canalicular stenosis during or after topical 5-FU use were included in this study. Four individuals met these criteria; we report clinical findings and treatment course for each patient. RESULTS: We reviewed 303 patients (316 eyes) with OSSN. All patients were treated with topical 1% 5-FU eye drops in cycles, given 4 times daily for 1 week with 3 weeks off. Four patients (5 eyes) developed punctal stenosis, for a frequency of 1.3%. The mean age at 5-FU initiation in the 4 individuals was 61 years (range 53-69). Most individuals were male (75%), White (75%), and non-Hispanic (100%). The most common presenting symptom of stenosis was epiphora, noted 4.6 ± 3 months after initiating topical 5-FU (after 4.9 ± 2.0 cycles). This occurred in 4 eyes while on therapy (3, 2, 4, and 4 months since 5-FU initiation) and in 1 eye after stopping therapy (10.3 months since 5-FU initiation). In 1 eye, punctal stenosis and epiphora resolved spontaneously after stopping 5-FU. Punctal dilation led to symptom resolution in 2 eyes. Surgical intervention (punctoplasty and external dacryocystorhinostomy) was needed in 2 eyes for punctal and canalicular stenosis, respectively. CONCLUSIONS: Punctal or canalicular stenosis is a rare and previously unreported adverse effect of topical 5-FU that may require surgical treatment.

RESUMEN

PURPOSE: The aim of this review was to elucidate treatment preferences for ocular surface squamous neoplasia and to examine the changes in treatment modalities over the past 2 decades. METHODS: An electronic survey was distributed to members of The Cornea Society, Ocular Microbiology and Immunology Group, and 4 international corneal specialist listservs. Questions examined medical and surgical treatment preferences, and results were compared with surveys administered in 2003 and 2012. RESULTS: A total of 285 individuals responded to the survey; 90% of respondents were self-classified as corneal specialists. Seventy-three percent reported using primary topical monotherapy to treat ocular surface squamous neoplasia as compared with 58% in 2012 ( P = 0.008). Compared with 2003, the percentage use of topical interferon significantly increased ( P < 0.0001) from 14% to 55%, 5-fluorouracil increased ( P < 0.0001) from 5% to 23%, and mitomycin C decreased ( P < 0.0001) from 76% to 19% as a primary monotherapy. The frequency of performing excision without the use of postoperative adjunctive medical therapy decreased significantly ( P < 0.0001), from 66% to 26% for lesions <2 mm, 64% to 12% for lesions between 2 and 8 mm, and 47% to 5% for lesions >8 mm from 2003 to 2022. More clinicians initiated topical immuno/chemotherapy without performing a biopsy as compared to 2003 (31% vs. 11%, P < 0.0001). CONCLUSIONS: These results demonstrate a paradigm shift in the management of ocular surface squamous neoplasia. The use of primary medical therapy as a first approach has significantly increased, with a reduction in the frequency of performing surgical excision alone.

Asunto(s)

Carcinoma de Células Escamosas , Enfermedades de la Córnea , Neoplasias del Ojo , Nivel de Atención , Humanos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Enfermedades de la Córnea/tratamiento farmacológico , Neoplasias del Ojo/tratamiento farmacológico , Neoplasias del Ojo/terapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Encuestas y Cuestionarios

RESUMEN

PURPOSE: The aim of this study was to report clinical observations suggesting the efficacy of topical 1% 5-fluorouracil (5-FU) in treating Demodex -associated blepharitis. METHODS: An observational retrospective review of 13 eyes from 13 individuals with conjunctival neoplastic lesions and concomitant Demodex lash infestation that received topical 1% 5-FU eye drops. Patients underwent slit-lamp examination at each follow-up visit. Clinical photographs of the lash line were obtained after treatment initiation. In a subset of patients, lashes were epilated bilaterally and microscopically analyzed for presence of Demodex mites before and after treatment initiation. RESULTS: The mean age of the population was 68 ± 14 years (range: 30-84 years) and 92% were male. In all 13 patients, a marked reduction in cylindrical dandruff was noted in the treated eye by slit-lamp examination after 2 cycles of 5-FU. There was complete resolution of cylindrical dandruff in 10 of 13 treated eyes compared with 0 resolution of cylindrical dandruff in untreated eyes ( P = 0.0001). In the 6 patients who received epilation, the lashes from the treated eye showed no Demodex , whereas lashes from the fellow untreated eye revealed persistent Demodex . CONCLUSIONS: Topical 1% 5-FU shows efficacy in treating Demodex -associated blepharitis. Further studies are indicated to reproduce our findings and evaluate the potential use of 5-FU as a treatment ingredient.

Asunto(s)

Blefaritis , Infecciones Parasitarias del Ojo , Fluorouracilo , Infestaciones por Ácaros , Ácaros , Soluciones Oftálmicas , Blefaritis/parasitología , Blefaritis/tratamiento farmacológico , Blefaritis/diagnóstico , Fluorouracilo/uso terapéutico , Fluorouracilo/administración & dosificación , Humanos , Estudios Retrospectivos , Infestaciones por Ácaros/tratamiento farmacológico , Infestaciones por Ácaros/parasitología , Infestaciones por Ácaros/diagnóstico , Masculino , Anciano , Persona de Mediana Edad , Infecciones Parasitarias del Ojo/tratamiento farmacológico , Infecciones Parasitarias del Ojo/parasitología , Infecciones Parasitarias del Ojo/diagnóstico , Femenino , Anciano de 80 o más Años , Adulto , Animales , Pestañas/parasitología , Antimetabolitos/uso terapéutico , Antimetabolitos/administración & dosificación , Administración Tópica

RESUMEN

PURPOSE: To report the genetic etiology of Lisch epithelial corneal dystrophy (LECD). DESIGN: Multicenter cohort study. METHODS: A discovery cohort of 27 individuals with LECD from 17 families, including 7 affected members from the original LECD family, 6 patients from 2 new families and 14 simplex cases, was recruited. A cohort of 6 individuals carrying a pathogenic MCOLN1 (mucolipin 1) variant was reviewed for signs of LECD. Next-generation sequencing or targeted Sanger sequencing were used in all patients to identify pathogenic or likely pathogenic variants and penetrance of variants. RESULTS: Nine rare heterozygous MCOLN1 variants were identified in 23 of 27 affected individuals from 13 families. The truncating nature of 7 variants and functional testing of 1 missense variant indicated that they result in MCOLN1 haploinsufficiency. Importantly, in the homozygous and compound-heterozygous state, 4 of 9 LECD-associated variants cause the rare lysosomal storage disorder mucolipidosis IV (MLIV). Autosomal recessive MLIV is a systemic disease and comprises neurodegeneration as well as corneal opacity of infantile-onset with epithelial autofluorescent lysosomal inclusions. However, the 6 parents of 3 patients with MLIV confirmed to carry pathogenic MCOLN1 variants did not have the LECD phenotype, suggesting MCOLN1 haploinsufficiency may be associated with reduced penetrance and variable expressivity. CONCLUSIONS: MCOLN1 haploinsufficiency is the major cause of LECD. Based on the overlapping clinical features of corneal epithelial cells with autofluorescent inclusions reported in both LECD and MLIV, it is concluded that some carriers of MCOLN1 haploinsufficiency-causing variants present with LECD.

Asunto(s)

Distrofias Hereditarias de la Córnea , Mucolipidosis , Canales de Potencial de Receptor Transitorio , Humanos , Canales de Potencial de Receptor Transitorio/genética , Estudios de Cohortes , Mucolipidosis/diagnóstico , Mucolipidosis/genética , Mucolipidosis/patología , Distrofias Hereditarias de la Córnea/diagnóstico , Distrofias Hereditarias de la Córnea/genética

RESUMEN

PURPOSE: The aim of this study was to compare clinical characteristics and high-resolution optical coherence tomography (HR-OCT) findings between corneal ocular surface squamous neoplasia (OSSN) and corneal pannus. METHODS: Retrospective study of 9 individuals, 3 with lesions histologically confirmed to be OSSN, 3 with lesions histologically confirmed to be pannus, 1 with lesions histologically confirmed to be OSSN followed by pannus, and 2 with long-standing, nonchanging lesions clinically diagnosed as pannus. All individuals presented to the Miami Veterans Affairs Medical Center eye clinic or Bascom Palmer Eye Institute between 2015 and 2023. Clinical characteristics and HR-OCT findings were evaluated and compared. RESULTS: Mean age of the population was 72.8 ± 5.1 years, 100% self-identified as male, 100% as White, and 11.1% as Hispanic. Clinically, all lesions appeared as whitish, opalescent, variably vascularized opacities extending from the limbus. None of the OSSN cases had vessels that extended to the border, whereas 4 cases of pannus (67%) had at least 1 vessel that reached the border. On HR-OCT, epithelial hyperreflectivity was observed in all cases of OSSN and pannus. Epithelial thickening was observed in all cases of OSSN, but in none of the cases of pannus. An important distinction between the 2 groups was the transition between normal and abnormal epithelium. All cases of OSSN had a vertical transition, whereas all cases of pannus had an angled transition. CONCLUSIONS: Corneal OSSN and corneal pannus can both present with clinical findings of an opalescent lesion and may have overlapping findings on HR-OCT. Although both entities may show epithelial hyperreflectivity on HR-OCT, OSSN demonstrates an abrupt transition at a vertical, 90 degrees angle perpendicular to the Bowman layer, whereas pannus appears as an angled transition around 45 degrees. Therefore, the angle of transition between normal and abnormal epithelium can be useful in distinguishing between the 2 entities.

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INTRODUCTION: The PReferentially expressed Antigen in MElanoma (PRAME) protein has been shown to be an independent biomarker for increased risk of metastasis in Class 1 uveal melanomas (UM). Intrinsically disordered proteins and regions of proteins (IDPs/IDPRs) are proteins that do not have a well-defined three-dimensional structure and have been linked to neoplastic development. Our study aimed to evaluate the presence of intrinsic disorder in PRAME and the role these structureless regions have in PRAME( +) Class 1 UM. METHODS: A bioinformatics study to characterize PRAME's propensity for the intrinsic disorder. We first used the AlphaFold tool to qualitatively assess the protein structure of PRAME. Then we used the Compositional Profiler and a set of per-residue intrinsic disorder predictors to quantify the intrinsic disorder. The Database of Disordered Protein Prediction (D2P2) platform, IUPred, FuzDrop, fIDPnn, AUCpred, SPOT-Disorder2, and metapredict V2 allowed us to evaluate the potential functional disorder of PRAME. Additionally, we used the Search Tool for the Retrieval of Interacting Genes (STRING) to analyze PRAME's potential interactions with other proteins. RESULTS: Our structural analysis showed that PRAME contains intrinsically disordered protein regions (IDPRs), which are structureless and flexible. We found that PRAME is significantly enriched with serine (p-value < 0.05), a disorder-promoting amino acid. PRAME was found to have an average disorder score of 16.49% (i.e., moderately disordered) across six per-residue intrinsic disorder predictors. Our IUPred analysis revealed the presence of disorder-to-order transition (DOT) regions in PRAME near the C-terminus of the protein (residues 475-509). The D2P2 platform predicted a region from approximately 140 and 175 to be highly concentrated with post-translational modifications (PTMs). FuzDrop predicted the PTM hot spot of PRAME to be a droplet-promoting region and an aggregation hotspot. Finally, our analysis using the STRING tool revealed that PRAME has significantly more interactions with other proteins than expected for randomly selected proteins of the same size, with the ability to interact with 84 different partners (STRING analysis result: p-value < 1.0 × 10-16; model confidence: 0.400). CONCLUSION: Our study revealed that PRAME has IDPRs that are possibly linked to its functionality in the context of Class 1 UM. The regions of functionality (i.e., DOT regions, PTM sites, droplet-promoting regions, and aggregation hotspots) are localized to regions of high levels of disorder. PRAME has a complex protein-protein interaction (PPI) network that may be secondary to the structureless features of the polypeptide. Our findings contribute to our understanding of UM and suggest that IDPRs and DOT regions in PRAME may be targeted in developing new therapies for this aggressive cancer. Video Abstract.

Asunto(s)

Proteínas Intrínsecamente Desordenadas , Melanoma , Neoplasias de la Úvea , Humanos , Factores de Transcripción , Antígenos de Neoplasias

RESUMEN

Purpose: We aimed to characterize the proteome of human tears and assess for the presence of intrinsically disordered proteins (IDPs). IDPs, despite lacking a rigid three-dimensional structure, maintain biological functionality and could shed light on the molecular interactions within tears. Methods: We analyzed a dataset of 1475 proteins identified in the tear film of three healthy subjects. We employed several computational tools, including the Compositional Profiler, Rapid Intrinsic Disorder Analysis Online, Search Tool for the Retrieval of Interacting Genes, and Database of Disordered Protein Predictors to evaluate the intrinsic disorder, protein interactions, and functional characterization of the disordered regions within this proteome. Results: Our analysis showed a notable inclination toward intrinsic disorder. Two out of 10 order-promoting residues and five out of 10 disorder-promoting residues were found enriched. Using the Predictor of Natural Disordered Regions (PONDR) VSL2 output, 95% of these proteins were classified as highly or moderately disordered. We revealed an extensive protein-protein interaction network with significant interaction enrichment. The most disordered proteins exhibited higher disorder binding sites and diverse posttranslational modifications compared to the most ordered ones. Conclusions: To the best of our knowledge, our study is the first comprehensive analysis of intrinsic disorder in the human tear film proteome, and it revealed an abundance of IDPs and their role in protein function and interaction networks. These findings suggest that variations in the intrinsic disorder of a tear film could be impacted by systemic and ocular conditions, offering promising avenues for disease biomarker identification and drug target development. Further research is needed to understand the implications of these findings in human health and disease.

Asunto(s)

Proteoma , Humanos , Proteoma/metabolismo , Sitios de Unión , Conformación Proteica

RESUMEN

BACKGROUND: Class 2 uveal melanomas are associated with the inactivation of the BRCA1 ((breast cancer type 1 susceptibility protein)-associated protein 1 (BAP1)) gene. Inactivation of BAP1 promotes the upregulation of vitamin K-dependent protein S (PROS1), which interacts with the tyrosine-protein kinase Mer (MERTK) receptor on M2 macrophages to induce an immunosuppressive environment. METHODS: We simulated the interaction of PROS1 with MERTK with ColabFold. We evaluated PROS1 and MERTK for the presence of intrinsically disordered protein regions (IDPRs) and disorder-to-order (DOT) regions to understand their protein-protein interaction (PPI). We first evaluated the structure of each protein with AlphaFold. We then analyzed specific sequence-based features of the PROS1 and MERTK with a suite of bioinformatics tools. RESULTS: With high-resolution, moderate confidence, we successfully modeled the interaction between PROS1 and MERTK (predicted local distance difference test score (pDLLT) = 70.68). Our structural analysis qualitatively demonstrated IDPRs (i.e., spaghetti-like entities) in PROS1 and MERK. PROS1 was 23.37 % disordered, and MERTK was 23.09 % disordered, classifying them as moderately disordered and flexible proteins. PROS1 was significantly enriched in cysteine, the most order-promoting residue (p-value <0.05). Our IUPred analysis demonstrated that there are two disorder-to-order transition (DOT) regions in PROS1. MERTK was significantly enriched in proline, the most disorder-promoting residue (p-value <0.05), but did not contain DOT regions. Our STRING analysis demonstrated that the PPI network between PROS1 and MERTK is more complex than their assumed one-to-one binding (p-value <2.0 × 10-6). CONCLUSION: Our findings present a novel prediction for the interaction between PROS1 and MERTK. Our findings show that PROS1 and MERTK contain elements of intrinsic disorder. PROS1 has two DOT regions that are attractive immunotherapy targets. We recommend that IDPRs and DOT regions found in PROS1 and MERTK should be considered when developing immunotherapies targeting this PPI.

Asunto(s)

Melanoma , Neoplasias de la Úvea , Humanos , Tirosina Quinasa c-Mer/genética , Tirosina Quinasa c-Mer/metabolismo , Melanoma/genética , Neoplasias de la Úvea/genética , Proteínas Portadoras/metabolismo , Proteína S/genética , Proteína S/metabolismo

RESUMEN

Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.

Asunto(s)

Amiloidosis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Nivel de Atención , Anticuerpos Monoclonales Humanizados/efectos adversos , Método Doble Ciego , Resultado del Tratamiento

RESUMEN

Infectious scleritis is a potentially devastating condition that can result in severe vision loss. When traditional management fails, a subpalpebral antibiotic lavage system (SAL) can be considered to bathe the infected area with a high volume and concentration of antibiotics. Several reports show that this method can be curative for infectious scleritis, otherwise refractory to care. However, surgical approaches for this technique are either not well described, advocate for transecting the levator aponeurosis, or do not expose the entire width of the superior fornix, which can lead to postoperative ptosis. The authors describe a case where a novel approach was utilized, using a fenestrated angiocather in the superior lateral fornix, to maximize outcomes and minimize postoperative complications. In the setting of infectious scleritis refractory to traditional management, a SAL can be safely and effectively placed with the technique detailed in this report.

Asunto(s)

Blefaroplastia , Blefaroptosis , Escleritis , Humanos , Antibacterianos/uso terapéutico , Irrigación Terapéutica , Blefaroptosis/cirugía , Blefaroplastia/métodos