Eye Cancer Research Articles

Systematic drug screening and target analysis identify digitoxin as a potential therapy for uveal melanoma.

Cardiac glycosides (CGs), traditionally prescribed for heart failure and arrhythmias, show anticancer potential. However, their mechanisms for preferential inhibition of tumour tissue and constituent malignant cells are not fully elucidated. This study aims to elucidate the therapeutic benefits of CGs in targeting specific tumours and dissect their multi-targeting mechanisms that confer their cytotoxicity against malignant cells. We designed an integrated workflow to identify therapeutic CGs with high toxicity to certain cancers, investigating their multi-target effects, assessing their toxicity to malignant cells and analysing the prognostic relevance of CGs' target genes. The computational findings were confirmed through gene knockdown, cell viability assays, reactive oxygen species (ROS) measurements and so forth. CGs modulate multiple genes crucial for ion homeostasis, oxidative stress and apoptosis, with a particularly strong inhibitory effects on uveal melanoma (UVM). Notably, digitoxin suppresses UVM cell proliferation and induces ROS levels by simultaneously targeting STAT3 and KLF5. Single-cell transcriptomic analysis revealed that malignant cells are likely more vulnerable to CGs due to their higher expression of CG target genes compared with surrounding cells in the UVM microenvironment. Given UVM's limited options, our study highlights the potential of digitoxin as a promising novel therapeutic agent for this aggressive and rare ocular cancer. Our comprehensive approach is effective in identifying the potent, cancer-specific therapeutic agents from herbal plants.

EPCO-05. GENOMIC AND CLINICAL INSIGHTS FROM A LARGE-SCALE STUDY OF 172 RETINOBLASTOMAS

Abstract Retinoblastoma, a pediatric ocular cancer, is the only central nervous system tumor visible without specialized tools, readily detectable with the naked eye. This rare childhood cancer is mainly driven by mutations in RB1 or MYCN amplification, posing significant challenges in pediatric oncology. We conducted whole exome sequencing on 172 retinoblastoma tumors along with matched blood DNA from 171 patients, which included 119 unilateral, 49 bilateral, and three trilateral cases. Our analysis identified pathogenic variants in RB1 in 76 patients and MYCN duplication in 79 cases, highlighting their crucial roles in the disease. Additionally, we found mutations in RPTOR and TSC2, components of the mTOR signaling pathway, in two patients. Notably, our copy number alteration analysis revealed recurrent arm-level changes, including gains on 1q (23.3%), 2p (20.9%), and especially 6p (41.3%), along with other changes such as 5p gain (8.1%), 17q gain (8.1%), and 16q loss (5.8%). Our findings link these genetic alterations to specific clinical features; for instance, 6p gains were associated with Rubeosis, subretinal seeds, and tumor LC beyond, while 17q gains were linked to Rubeosis. Furthermore, gene collapsing techniques identified MATR3 and CYP4F2 as additional novel retinoblastoma-related genes, and module identification analysis pinpointed retinoblastoma-associated modules including HLA-DRB1-CBL, LPAR2, RB1, and TRIM28. Our study, the largest cohort of its kind, underscores the importance of next-generation sequencing from understudied populations in uncovering the complex genetic landscape of retinoblastoma, emphasizing the potential of precision medicine to enhance therapeutic strategies and improve outcomes for retinoblastoma patients.

Extending the acute skin response spectrum to include the far-UVC.

Guidance on maximal limits for ultraviolet (UV) exposure has been developed by national and international organizations to protect against adverse effects on human skin and eyes. These guidelines consider the risk of both acute effects (i.e., erythema and photokeratitis) and delayed effects (e.g., skin and ocular cancers) when determining exposure limits, and specify the dose a person can safely receive during an 8-h period without harmful effects. The determination of these exposure limits relies on the action spectra of photobiological responses triggered by UV radiation that quantify the effectiveness of each wavelength at eliciting each of these effects. With growing interest in using far-UVC (200-235 nm) radiation to control the spread of airborne pathogens, recent arguments have emerged about revisiting exposure limits for UV wavelengths. However, the standard erythema action spectrum, which provides some of the quantitative basis for these limits, has not been extended below 240 nm. This study assists to expand the erythema action spectrum to far-UVC wavelengths using a hairless albino mice model. We estimate that inducing acute effects on mouse skin with 222 nm radiation requires a dose of 1162 mJ/cm2, well above the current ACGIH skin exposure limit of 480 mJ/cm2.

Молекулярно-генетический анализ персональных культур клеток увеальной меланомы

Relevance. Uveal melanoma (UM) is a subtype of melanoma that represents the majority of adult ocular cancers. The rare frequency of the disease does not allow to conduct large-scale clinical trials of new agents and approaches, which limits progress in its treatment. Half of patients with UM develop metastatic forms of the disease, which generally have unfavorable prognosis. Therefore, personal cell cultures derived from tumor material of patients are relevant for determining molecular and genetic features of tumor melanocytes and for testing new antitumor drugs. Purpose. To evaluate the aggressiveness of choroidal melanoma by molecular and genetic characterization of melanocytes isolated from the tumor. Material and methods. The study was performed using personal cultures of human UM cells. Karyotyping of cells was performed by GTG staining analysis of the metaphase plates, mutational burden was assessed by NGS sequencing, protein products were evaluated by western blotting. Results. In this work, three personal cultures of human UM cells, uMel1, uMel3 and uMel5, cultured for at least 22 passages, were obtained from tumor material of patients diagnosed with UM for the analysis of molecular and genetic characteristics. Since the development of the metastatic form of UM correlates with chromosomal alterations in tumor melanocytes, karyotyping was performed, which showed that in all cultures, most cells had a near-diploid phenotype. Only in uMel1 and uMel3 cells were chromosomal rearrangements specific for UM – in chromosomes 3, 6, and 8. In uMel5 cells, a deletion was found in the region of the long arm of chromosome 11. In addition, the patient with uMel5 tumor had a history of skin melanoma, for which the typical somatic mutation profile differs from that of UM. Somatic mutations in hotspots of ALK, BRAF, EGFR, HER2, IL17RA, KRAS, METand NRASgenes were analyzed by NGS-sequencing method. No mutations were detected at the tested loci in cells from all cultures tested. Analysis of tumor suppressor BAP1 (BRCA-associated protein) showed its low level in uMel3 and uMel5 cell cultures, which may indicate a high risk of metastasis. Conclusion. The obtained personalized cultures of UM cells are models that allow in vitroand in vivoinvestigation of UM with different molecular and genetic signatures. Key words: uveal melanoma, personalized cell cultures, karyotype, BAP1, BRAF, NGS-sequencing

Global Incidence and Trends of Ocular cancer: A bibliometric analysis

BackgroundOcular cancer represents a significant threat to vision and life among various eye diseases. Conjunctival melanoma is regarded as one of the most feared and unpredictable ocular tumors. Considering the global differences in the occurrence of ocular melanoma across different races and regions, this study provides a thorough examination of the current state of research pertaining to the epidemiology of ocular and conjunctival cancers. MethodsThis bibliometrics analysis used the Web of Science Core Collection (WoSCC) to collect data from publications on the epidemiology of ocular cancer, including relevant literature from 1951 to 2024. We examined indicators including t publication counts, citation rates, and data on contributing countries, institutions, and journals. Use VOSviewer and CiteSpace for network visualization and Microsoft Excel for data management. Our analysis reveals key trends in the epidemiology of ocular cancer across countries and identifies prominent keywords. ResultsA total of 406 articles on ocular cancer were identified, with significant contributions from the United States, the United Kingdom, and Germany. Denmark also plays a crucial role, particularly in conjunctival cancer research. Carol L. Shields is a leading figure widely recognized for her influential citations in ocular cancer epidemiology. The top publication platforms include the British Journal of Ophthalmology, Ophthalmic Epidemiology, and Ophthalmology. Key terms in ocular cancer research focus on prevalence, survival, and epidemiology, while conjunctival cancer studies emphasize malignant melanoma, conjunctiva, and epidemiology. Through keyword co-occurrence and burst analysis, trending topics include prevalence, risk factors, uveal melanoma, choroidal melanoma, malignant melanoma, squamous cell carcinoma, and conjunctiva. For conjunctival cancer, key research areas expected to remain prominent are cell carcinoma, management, recurrence, ocular surface squamous neoplasia, and pathology. ConclusionThis analysis represents the first comprehensive bibliometric review mapping the trends and the knowledge structure in ocular cancer research, specifically from an epidemiological viewpoint. The results meticulously explore and encapsulate the research frontiers for scholars dedicated to the epidemiology of conjunctival cancer.

Lymphatic-specific methyltransferase-like 3-mediated m6A modification drives vascular patterning through prostaglandin metabolism reprogramming.

Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N 6-methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of methyltransferase-like 3 (METTL3)-mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures-induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin-endoperoxide synthase 2 expression through an m6A-YTHDF2-dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic-specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating lymphangiogenesis-related diseases.

Therapeutic potential of Buddleja Polystachya Fresen (stem and leaves) extracts: antimicrobial and cytotoxic properties for ocular disease management

This study on Buddleja polystachya highlights its phytochemical composition, antimicrobial activity, and cytotoxic impacts. The study emphasizes the plant’s potential to treat ocular diseases by identifying important compounds involved in the bioactivity through GC-MS analysis. This study explores the antimicrobial and cytotoxic potential of Buddleja polystachya (stem and leaves) extracts, with a focus on their application in treating bacterial ocular infections and their efficacy against MCF7, HT29, and HepG2 cancer cells. Through comprehensive GC-MS analysis, a diverse array of phytochemicals was identified within Buddleja polystachya stem and leaves extracts, including carbohydrates, phenolic derivatives, fatty acids, and steroidal components. The extracts were then evaluated for their biological activities, revealing significant antimicrobial properties against a range of bacterial strains implicated in ocular infections. The research findings demonstrate that stem extracts derived from Buddleja polystachya demonstrated high to moderate cytotoxic effects on cancer cell lines MCF7, HT29, and HepG2. Notably, these effects were characterized by varying IC50 values, which suggest distinct levels of sensitivity. In contrast, leaf extracts exhibited reduced cytotoxicity when tested against all these cell lines, although they did so with a significantly higher cytotoxicity aganist HepG2 cells. The results of this investigation highlight the potential therapeutic utilization of Buddleja polystachya extracts in the management of ocular infections and cancer. These results support the need for additional research to elucidate the underlying mechanisms of action of these extracts and explore their potential as drugs.

Neutrophils in Ocular Diseases.

Neutrophils, traditionally viewed as first responders to infection or tissue damage, exhibit dynamic and diverse roles in ocular health and disease. This review elaborates on previous findings that showed how neutrophils contribute to ocular diseases. In ocular infections, neutrophils play a pivotal role in host defense by orchestrating inflammatory responses to combat pathogens. Furthermore, in optic nerve neuropathies and retinal degenerative diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR), neutrophils are implicated in neuroinflammation and tissue damage owing to their ability to undergo neutrophil extracellular trap formation (NETosis) and secretion of inflammatory molecules. Targeting neutrophil-dependent processes holds promise as a therapeutic strategy, offering potential avenues for intervention in ocular infections, cancers, and retinal degenerative diseases. Understanding the multifaceted roles of neutrophils in ocular diseases is crucial for developing targeted therapies to improve patient outcomes.

RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma

Ocular melanoma, including uveal melanoma (UM) and conjunctival melanoma (CM), is the most common ocular cancer among adults with a high rate of recurrence and poor prognosis. Loss of epigenetic homeostasis disturbed gene expression patterns, resulting in oncogenesis. Herein, we comprehensively analyzed the DNA methylation, transcriptome profiles, and corresponding clinical information of UM patients through multiple machine-learning algorithms, finding that a methylation-driven gene RBMS1 was correlated with poor clinical outcomes of UM patients. RNA-seq and single-cell RNA-seq analyses revealed that RBMS1 reflected diverse tumor microenvironments, where high RBMS1 expression marked an immune active TME. Furthermore, we found that tumor cells were identified to have the higher communication probability in RBMS1+ state. The functional enrichment analysis revealed that RBMS1 was associated with pigment granule and melanosome, participating in cell proliferation as well as apoptotic signaling pathway. Biological experiments were performed and demonstrated that the silencing of RBMS1 inhibited ocular melanoma proliferation and promoted apoptosis. Our study highlighted that RBMS1 reflects a distinct microenvironment and promotes tumor progression in ocular melanoma, contributing to the therapeutic customization and clinical decision-making.

Expression and functional significance of phosphoenolpyruvate carboxykinase 1 in uveal melanoma

Uveal melanoma (UVM), an uncommon yet potentially life-threatening ocular cancer, arises from melanocytes in the uveal tract of the eye. The exploration of novel oncotargets for UVM is of paramount importance. In this study, we show that PCK1 (phosphoenolpyruvate carboxykinase 1) expression is upregulated in various UVM tissues as well as in primary UVM cells and immortalized lines. Furthermore, bioinformatics studies reveal that PCK1 overexpression in UVM correlates with advanced disease stages and poor patient survival. Genetic silencing (utilizing viral shRNA) or knockout (via CRISPR/Cas9) of PCK1 significantly curtailed cell viability, proliferation, cell cycle progression, and motility, while provoking apoptosis in primary and immortalized UVM cells. Conversely, ectopic overexpression of PCK1, achieved through a viral construct, bolstered UVM cell proliferation and migration. Gαi3 expression and Akt phosphorylation were reduced following PCK1 silencing or knockout, but increased after PCK1 overexpression in UVM cells. Restoring Akt phosphorylation through a constitutively active mutant Akt1 (S473D) ameliorated the growth inhibition, migration suppression, and apoptosis induced by PCK1 silencing in UVM cells. Additionally, ectopic expression of Gαi3 restored Akt activation and counteracted the anti-UVM cell effects by PCK1 silencing. In vivo, the growth of subcutaneous xenografts of primary human UVM cells was significantly inhibited following intratumoral injection of adeno-associated virus (aav) expressing PCK1 shRNA. PCK1 depletion, Gαi3 downregulation, Akt inhibition, proliferation arrest, and apoptosis were detected in PCK1-silenced UVM xenografts. Collectively, our findings demonstrate that PCK1 promotes UVM cell growth possibly by modulating the Gαi3-Akt signaling pathway.

Abstract 3633: Multi-parametric characterization of extracellular vesicles in the aqueous humor of uveal melanoma eyes undergoing brachytherapy

Abstract Introduction: Aqueous humor (AH), fluid in the anterior chamber of the eye, is a liquid biopsy source of tumor information in uveal melanoma (UM). Extracellular vesicles (EVs) have recently been characterized in the AH of retinoblastoma eyes, however, have not been investigated in UM. EVs are small membrane-enclosed particles secreted by virtually every cell type with a role in intercellular communications. We hypothesize that tumor-derived EVs are detectable in the AH of UM eyes and that understanding the type of vesicles present may help us better understand their function, particularly for cancer. Small extracellular vesicles (sEVs) have been shown to promote tumorigenesis, treatment resistance, and metastasis, leading to the discovery of clinically-relevant biomarkers for multiple cancer types. As the diversity and role of sEVs in the AH of UM patients has never previously been reported, this project is a first step towards investigating new biomarkers of clinical utility. Our aim is to use single particle analysis to characterize sEV subpopulations in the AH of UM patients by quantifying their size, concentration, and phenotypes based on cell surface markers, specifically tetraspanin co-expression patterns. Methods: sEVs were analyzed from paired pre- and post-brachytherapy AH samples collected from 19 UM patients. AH samples from 5 glaucoma patients served as the control cohort. Unprocessed AH underwent Nanoparticle Tracking Analysis for size quantification and Single Particle-Interferometric Reflectance Imaging Sensor analysis for fluorescent particle count and tetraspanin immunophenotyping; counts were subsequently converted to percentages for analysis. Statistics were performed using Mann-Whitney U, ANOVA, and Tukey’s tests. Results: AH derived from UM eyes (pre-brachytherapy) displayed a broader sEV size distribution than glaucoma eyes, with more diverse sEV subpopulations. Both tumor and nontumor AH samples demonstrated a dominant CD63+ sEV subpopulation. A significantly higher percentage of CD63/81+ sEVs (P= 0.0217) and CD9/63/81+ sEVs (P= 0.0146) were found in post-brachytherapy samples compared to pre-brachytherapy. Conclusions: sEV subpopulations in UM eyes demonstrate increased heterogeneity in comparison to nontumor eyes. Our results are consistent with prior studies reporting that the CD63+ sEV subtype is an AH-specific biomarker enriched across multiple ocular diseases. The increase in CD63/81+ sEVs and CD9/63/81+ sEVs after brachytherapy is presumably a result of radiation-induced release of these vesicles, suggesting a tumor-derived origin of these subpopulations. CD63/81+ sEV subpopulation was previously reported to also be a tumor-derived subpopulation in AH of retinoblastoma eyes. Further study of the cargo carried by these sEV subpopulations may uncover molecular mechanisms pivotal to UM and other ocular cancers. Citation Format: Shreya Sirivolu, Chen-Ching Peng, Paolo Neviani, Jesse L. Berry, Liya Xu. Multi-parametric characterization of extracellular vesicles in the aqueous humor of uveal melanoma eyes undergoing brachytherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3633.

Genetic Risk Factors and Clinical Outcomes in Childhood Eye Cancers: A Review.

Childhood eye cancers, although rare, present substantial health challenges, affecting the pediatric population with a remarkable impact on their lives and families. This comprehensive review provides insights into the various types of ocular tumors, primarily focusing on malignant eye tumors, their genetic predispositions, and advancements in managing these conditions. Understanding the genetic risk factors is crucial for early detection, risk assessment, and the development of targeted therapies. This review discusses genome-wide association (GWAS) and next-generation sequencing (NGS) studies to find common and rare genetic variants. Furthermore, it also explores the outcomes and implications of these genetic discoveries in treating pediatric ocular cancer. These findings underscore the significance of genetic research in guiding early interventions and improving outcomes in children with ocular cancers.

AIBI Modified Mesoporous Copper Sulfide Nanocomposites for Efficient Non-Oxygen Dependent Free Radicals-Assisted Photothermal Therapy in Uveal Melanoma.

Uveal melanoma (UM) is an ocular cancer predominantly affecting adults, characterized by challenging diagnostic outcomes. This research endeavors to develop an innovative multifunctional nanocomposite system sensitive to near-infrared (NIR) radiation, serving as both a non-oxygen free-radical generator and a photothermal agent. The designed system combines azobis isobutyl imidazoline hydrochloride (AIBI) with mesoporous copper sulfide (MCuS) nanoparticles. MCuS harnesses NIR laser energy to induce photothermal therapy, converting light energy into heat to destroy cancer cells. Simultaneously, AIBI is activated by the NIR laser to produce alkyl radicals, which induce DNA damage in remaining cancer cells. This distinctive feature equips the designed system to selectively eliminate cancers in the hypoxic tumor microenvironment. MCuS is also beneficial to scavenge the overexpressed glutathione (GSH) in the tumor microenvironment. GSH generally consumes free radicals and hiders the PDT effect. To enhance control over AIBI release in cancer cells, 1-tetradecyl alcohol (TD), a phase-changing material, is introduced onto the surface of MCuS nanoparticles to create the final AMPT nanoparticle system. In vitro and in vivo experiments confirm the remarkable anti-tumor efficacy of AMPT. Notably, the study introduces an orthotopic tumor model for UM, demonstrating the feasibility of precise and effective targeted treatment within the ocular system.

1,4-dihydroxy quininib activates ferroptosis pathways in metastatic uveal melanoma and reveals a novel prognostic biomarker signature

Uveal melanoma (UM) is an ocular cancer, with propensity for lethal liver metastases. When metastatic UM (MUM) occurs, as few as 8% of patients survive beyond two years. Efficacious treatments for MUM are urgently needed. 1,4-dihydroxy quininib, a cysteinyl leukotriene receptor 1 (CysLT1) antagonist, alters UM cancer hallmarks in vitro, ex vivo and in vivo. Here, we investigated the 1,4-dihydroxy quininib mechanism of action and its translational potential in MUM. Proteomic profiling of OMM2.5 cells identified proteins differentially expressed after 1,4-dihydroxy quininib treatment. Glutathione peroxidase 4 (GPX4), glutamate-cysteine ligase modifier subunit (GCLM), heme oxygenase 1 (HO-1) and 4 hydroxynonenal (4-HNE) expression were assessed by immunoblots. Biliverdin, glutathione and lipid hydroperoxide were measured biochemically. Association between the expression of a specific ferroptosis signature and UM patient survival was performed using public databases. Our data revealed that 1,4-dihydroxy quininib modulates the expression of ferroptosis markers in OMM2.5 cells. Biochemical assays validated that GPX4, biliverdin, GCLM, glutathione and lipid hydroperoxide were significantly altered. HO-1 and 4-HNE levels were significantly increased in MUM tumor explants from orthotopic patient-derived xenografts (OPDX). Expression of genes inhibiting ferroptosis is significantly increased in UM patients with chromosome 3 monosomy. We identified IFerr, a novel ferroptosis signature correlating with UM patient survival. Altogether, we demontrated that in MUM cells and tissues, 1,4-dihydroxy quininib modulates key markers that induce ferroptosis, a relatively new type of cell death driven by iron-dependent peroxidation of phospholipids. Furthermore, we showed that high expression of specific genes inhibiting ferroptosis is associated with a worse UM prognosis, thus, the IFerr signature is a potential prognosticator for which patients develop MUM. All in all, ferroptosis has potential as a clinical biomarker and therapeutic target for MUM.

Impact of RB1 gene screening from blood collected on a single day from 411 family members of 113 Retinoblastoma survivors in India.

To analyse the profile and implication of genetic testing in a cohort of retinoblastoma (RB) patients and their families conducted on a single day during World Retinoblastoma Awareness Week 2017. Retrospective analysis of blood samples were collected from 411 subjects, including 113 probands at a camp organised for RB awareness and were analysed for RB1 mutations by Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). If germline mutations were detected, the parents and siblings of the proband were tested for the same mutation. Germline RB1 mutations were identified in 61/113(54%) probands with a mutation detection rate of 96% (47/49) and 22% (14/64) for bilateral and unilateral RB, respectively. Ten novel pathogenic mutations were identified. Splice mutation was most common (31%) followed by nonsense mutation (26%). The mean age at RB diagnosis was significantly lower in patients having germline RB1 mutation (mean 10.7 months ±2.5) compared to those without (mean 27.2 months ±6.5) (p = <0.0001). Parental transmission of the mutant allele was detected in 15/61(25%) cases of which 11(18%) parents were unaffected indicating incomplete penetrance. The origin of the variant allele was both paternal (n = 7) and maternal (n = 4) wherein 5 were bilateral and 6 unilateral. The detection of a germline mutation impacts the proband and family members due to its implications on change in prognosis, frequency of subsequent evaluations, screening for ocular and non-ocular cancers, and surveillance of family and future progeny.

Genetically Engineered Mesenchymal Stem Cells Using Viral Vectors: A New Frontier in Anti-Angiogenic Therapy

Mesenchymal stem cells (MSCs) are adult stem cells that possess the remarkable ability to self-renew and differentiate into various cell lineages. Due to their regenerative potential, MSCs have emerged as the most commonly used stem cell type in clinical applications. Angiogenesis, the formation of new blood vessels, plays a critical role in several pathological conditions, including ocular neovascular diseases, cancer, and inflammatory disorders. Conventional anti-angiogenic therapies face limitations such as frequent visits for repeated doses, off-target effects and resistance development. Recent advances in genetic engineering techniques have opened up novel avenues in regenerative medicine. Genetically engineering MSCs using viral vectors presents a promising strategy to specifically target angiogenesis and enhance anti-angiogenic therapies' efficacy. Viral vectors, including lentiviruses, adeno-associated viruses and adenoviruses, provide an effective means of delivering therapeutic genes into MSCs, allowing the expression of a wide range of therapeutic agents, including anti-angiogenic proteins. This review explores the frontier of using genetically engineered MSCs delivered through viral vectors as a potent anti-angiogenic therapeutic approach. By leveraging the unique properties of MSCs and the targeted delivery capabilities of viral vectors, this approach initiates the potential to revolutionize anti-angiogenic therapy, offering new possibilities for the treatment of angiogenesis-related diseases.

Identification of dysregulation of sphingolipids in retinoblastoma using liquid chromatography-mass spectrometry

Retinoblastoma (RB) is a rare ocular cancer seen in children that counts for approximately 3% of all childhood cancers. It is found that mutation in RB1, a tumour Suppressor Gene on chromosome 13 as the cause of malignancy. Retinoblastoma protein is the target for ceramide to cause apoptosis. We studied lipidomics of two RB cell lines, one aggressive cell line (NCC–RbC-51) derived from a metastatic site and one non aggressive cell line (WERI-Rb1) in comparison with a control cell line (MIO-M1). Lipid profiles of all the cell lines were studied using high resolution mass spectrometer coupled to high performance liquid chromatography. Data acquired from all the three cell lines in positive mode were analyzed to identify differentially expressed metabolites. Several phospholipids and lysophospholipids were found to be dysregulated. We observed upregulation of hexosyl ceramides, and down regulation of dihydroceramides and higher order sphingoglycolipids hinting at a hindered sphingolipid biosynthesis. The results obtained from liquid chromatography-mass spectrometry are validated by using qPCR and it was observed that genes involved in ceramide biosynthesis pathway are getting down regulated.

Advanced Technologies of Drug Delivery to the Posterior Eye Segment Targeting Angiogenesis and Ocular Cancer.

Retinoblastoma (RB), a childhood retinal cancer is caused due to RB1 gene mutation which affects the child below 5 years of age. Angiogenesis has been proven its role in RB metastasis due to the presence of vascular endothelial growth factor (VEGF) in RB cells. Therefore, exploring angiogenic pathway by inhibiting VEGF in treating RB would pave the way for future treatment. In preclinical studies, anti-VEGF molecule have shown their efficacy in treating RB. However, treatment requires recurrent intra-vitreal injections causing various side effects along with patient nonadherence. As a result, delivery of anti-VEGF agent to retina requires an ocular delivery system that can transport it in a non-invasive manner to achieve patient compliance. Moreover, development of these type of systems are challenging due to the complicated physiological barriers of eye. Adopting a non-invasive or minimally invasive approach for delivery of anti-VEGF agents would not only address the bioavailability issues but also improve patient adherence to therapy overcoming the side effects associated with invasive approach. The present review focuses on the eye cancer, angiogenesis and various novel ocular drug delivery systems that can facilitate inhibition of VEGF in the posterior eye segment by overcoming the eye barriers.

Clinicopathological Study of Xeroderma Pigmentosa: A Series of Eight Cases

Abstract Background: Xeroderma pigmentosa (XP) is a rare inherited (autosomal recessive) disease, resulting from impairment in DNA repair that involves recognition and repair of ultraviolet radiation (UVR)-induced DNA damage in the nucleotide excision repair pathway. This results in increased photosensitivity, UVR-induced damage to skin and eye, increased susceptibility to cutaneous and ocular cancers, and progressive neurodegeneration in some patients. Aims and Objective: The objective of the study was to describe the clinicopathological spectrum of eight cases of XP. Materials and Methods: An ambispective case series was conducted in a pediatric tertiary care hospital in eastern India during a 10-year period from 2013 to 2022. Results: All the children of our cohort were born of consanguineous marriage. The mean age of presentation was 1.2 years (range: 7 months–3 years), whereas three children presented during their infancy. The male-to-female ratio was 5:3. The most common findings were cutaneous (100%), followed by ophthalmic (75%) and/or neurological symptoms (25%). Patients had normal skin at birth but soon developed extreme photosensitivity followed by abnormal skin pigmentation and subsequently progressive xerosis, atrophy, wrinkling, and poikiloderma over time. Six patients had varied degrees of ocular involvement, whereas three of them had severe manifestations including madarosis, tylosis, ectropion, lagophthalmos, phthisis bulbi, clouding and scarring of the cornea with complete or partial loss of vision, and ophthalmic malignancies. Fifty percent (n = 4) of cases had cutaneous and ocular premalignant (actinic keratosis) and malignant lesions including melanoma and nonmelanoma skin cancer such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in their early childhood. One patient had simultaneous occurrence of multiple malignancies together (SCC, BCC, and melanoma). Neurological abnormalities (subnormal intelligence) were found in two cases. There was no evidence of sensory neural hearing loss, microcephaly, neuroregression, or neurodeficits. Conclusion: Although XP is associated with increased mortality and morbidity, early diagnosis followed by persistent vigorous photoprotection and regular screening for early detection of malignancies along with psychological support can drastically improve patients’ quality of life and life expectancy. Besides genetic counseling, further research is required on formulating optimal management of XP, specifically the role and possibilities of gene therapy in XP.

Artificial intelligence and machine learning a new frontier in the diagnosis of ocular adnexal tumors: A review.

In our article, we explore the transformative potential of Artificial Intelligence and Machine Learning in oculo-oncology, focusing on the diagnosis and management of ocular adnexal tumors. Delving into the intricacies of adnexal conditions such as conjunctival melanoma and squamous conjunctival carcinoma, the study emphasizes recent breakthroughs, such as Artificial Intelligence-driven early detection methods. While acknowledging challenges like the scarcity of specialized datasets and issues in standardizing image capture, the research underscores encouraging patient acceptance, as demonstrated in melanoma diagnosis studies. The abstract calls for overcoming obstacles, conducting clinical trials, establishing global regulatory norms and fostering collaboration between ophthalmologists and Artificial Intelligence experts. Overall, the article envisions Artificial Intelligence's imminent transformative impact on ocular and periocular cancer diagnosis.