Ocular drug delivery is a significant challenge due to the intricate anatomy of the eye and the various physiological barriers. Conventional therapeutic approaches, while effective to some extent, often fall short in effectively targeting ocular diseases, resulting in suboptimal therapeutic outcomes due to factors such as poor ocular bioavailability, frequent dosing requirements, systemic side effects, and limited penetration through ocular barriers. This review elucidates the eye's intricate anatomy and physiology, prevalent ocular diseases, traditional therapeutic modalities, and the inherent pharmacokinetic and pharmacodynamic limitations associated with these modalities. Subsequently, it delves into nanotechnology-based solutions, presenting breakthroughs in nanoformulations such as nanocrystals, liposomes, dendrimers, and nanoemulsions that have demonstrated enhanced drug stability, controlled release, and deeper ocular penetration. Additionally, it explores a range of nanosized carriers, including nano-structured lipid carriers, hydrogels, nanogels, nanoenzymes, microparticles, conjugates, exosomes, nanosuspensions, viral vectors, and polymeric nanoparticles, and their applications. Unique insights include emerging innovations such as nanowafers and transcorneal iontophoresis, which indicate paradigm shifts in non-invasive ocular drug delivery. Furthermore, it sheds light on the advantages and limitations of these nanotechnology-based platforms in addressing the challenges of ocular drug delivery. Though nano-based drug delivery systems are drawing increasing attention due to their potential to enhance bioavailability and therapeutic efficacy, the review ends up emphasizing the imperative need for further research to drive innovation and improve patient outcomes in ophthalmology.

Retinoblastoma (Rb) is a rare intraocular malignancy that originates in the retina of children under 5 years of age. Approximately one-third of children diagnosed with retinoblastoma are associated with germline mutations in one of the RB1 alleles. In this study, we aim to identify RB1 mutations in retinoblastoma patients using Sanger sequencing in combination with multiplex ligation-dependent probe amplification (MLPA).

The genomic DNA of 167 Rb patients was isolated from peripheral blood and their clinical information was extracted from medical records. The mutations in the RB1 gene were identified through PCR sequencing. Negative results from the PCR sequencing were further analyzed using MLPA reactions.

RB1 mutations were identified in 56 of the 167 (33.5%) patients. The common mutation types were frameshift mutations (n = 19), followed by nonsense (n = 20), splicing (n = 8), missense (n = 5), and whole exon deletion (n = 2). The overall survival rate was 98.2%, with an average follow-up duration of 59 months. Moreover, germline RB1 mutation's correlation with enucleation rates is less pronounced in unilateral cases (12.1%) compared to bilateral cases (65.5%). A total of 13 novel mutations have been identified, of which four are specifically associated with enucleation.

This study provides a comprehensive analysis of RB1 germline mutations in a group of cases with Rb, leading to the identification of 13 novel mutations in Rb patients at a referral center in Iran. We expect that our findings will yield valuable insights to inform the management and genetic counseling of Rb patients, as well as their relatives who are at a higher risk.

Tumor heterogeneity, characterized by the presence of diverse cell populations within a tumor, is a key feature of the complex nature of cancer. This diversity arises from the emergence of cells with varying genomic, epigenetic, transcriptomic, and phenotypic profiles over the course of the disease. Host factors and the tumor microenvironment play crucial roles in driving both inter-patient and intra-patient heterogeneity. These diverse cell populations can exhibit different behaviors, such as varying rates of proliferation, responses to treatment, and potential for metastasis. Both inter-patient heterogeneity and intra-patient heterogeneity pose significant challenges to cancer therapeutics and management. In retinoblastoma, while heterogeneity at the clinical presentation level has been recognized for some time, recent attention has shifted towards understanding the underlying cellular heterogeneity. This review primarily focuses on retinoblastoma heterogeneity and its implications for therapeutic strategies and disease management, emphasizing the need for further research and exploration in this complex and challenging area.

Douglas Hanahan added "non-mutational epigenetic reprogramming" and "unlocking phenotypic plasticity" as new hallmarks of cancer, proposing that cancer cells possess fundamental features that are not directly linked to their genetic abnormalities. In vivo reprogramming studies have demonstrated that non-mutational epigenetic regulation can cause cellular reprogramming, leading to cancer development at the organismal level. Given that epigenetic regulation functions as an interface between the cellular environment and gene expression, these results suggest that intercellular communications in the tumor microenvironment play a critical role in cancer development. This review first introduces genetic aberrations that cause cancer development. Then, it illustrates the impact of epigenetic abnormalities in cancer, especially with reference to studies that use in vivo reprogramming technologies. Finally, it discusses the importance of histological evaluations of tumor tissue to understand non-cell-autonomous epigenetic regulation that establishes cancer hallmarks.

The purpose of this review article is to provide an exhaustive overview of the genetic and epigenetic changes involved in retinoblastoma (RB) tumorigenesis along with their real-world applications.

We searched the Pubmed database using keywords: retinoblastoma, genetics, epigenetics, oncogenes, tumor suppressor genes and target genes.

RB oncogenesis is triggered by biallelic RB1 gene mutation but progression involves additional genetic and epigenetic events. Commonly seen genetic mutations include nonsense, small insertions/deletions and splice mutations. Additional changes include copy number alterations, single nucleotide polymorphisms and epigenetic alterations (dysregulation of microRNAs, differential methylations). These pathways have led to the identification of several potential target genes that can play a role in future in precision therapy.

Genetic testing, counseling and risk stratification are integral to the management of RB. The latest genetic advancements herald the dawn of a new era with potential therapeutic approaches to RB and improved treatment outcomes.

Genetic information will be increasingly integrated into clinical eye care within the current generation of ophthalmologists. For monogenic diseases such as retinoblastoma, genetic studies have been relatively straightforward as these conditions result from pathogenic variants in a single gene resulting in large physiological effects. However, most eye diseases result from the cumulative effects of multiple genetic variants and environmental factors. In such diseases, because each variant usually has an individually small effect, genetic studies for complex diseases are comparatively more challenging. This article aims to provide an overview of three genetic epidemiology methods for polygenic (or complex) diseases: genome-wide association studies (GWAS), Polygenic Risk Scores (PRS) and Mendelian randomisation (MR). A GWAS systematically conducts association analyses of a trait of interest against millions of genetic variants, usually in the form of single nucleotide polymorphisms, across the genome. GWAS findings can then be used for PRS construction and MR analyses. To construct a PRS, the cumulative effect of many genetic variants associated with a trait from a prior GWAS is calculated and taken as a quantitative representation of an individual's genetic risk of a complex disease. MR studies analyse an outcome measure against the genetic variants of an exposure, and are particularly useful in investigating causal relations between two traits where randomised controlled trials are not possible or ethical. In addition to explaining the principles of these three genetic epidemiology concepts, this article provides a minimally technical description of their basic methodology that is accessible to the non-expert reader.

Retinoblastoma, the most common pediatric intraocular malignancy, arises from RB1 inactivation, leading to uncontrolled proliferation of retinal progenitor cells. Epigenetic dysregulation a key driver of retinoblastoma progression, yet the underlying mechanisms are poorly understood. UHRF1, a regulator of DNA methylation and chromatin remodeling, has been implicated in oncogenesis but its role in retinoblastoma has not been fully characterized. To investigate Uhrf1's role in tumor initiation and progression, we generated a genetically engineered mouse model of retinoblastoma with conditional Uhrf1 knockout. Remarkably, Uhrf1 loss completely blocked tumor formation, despite persistent early oncogenic events. Transcriptomic and epigenomic profiling revealed that Uhrf1 is essential for tumor progression, facilitating oncogenic transcription, chromatin accessibility, and aberrant DNA methylation. Beyond its epigenetic role, we found Uhrf1 modulates the tumor immune microenvironment, promoting chemokine secretion and microglial infiltration, suggesting that Uhrf1 promotes immune cell recruitment. Mechanistically, Uhrf1 enhances chemokine expression through NF-κB signaling, establishing a novel connection between epigenetic regulation and tumor-associated immune responses. These findings establish Uhrf1 as a critical driver of retinoblastoma progression, essential for tumor maintenance but not initiation. By sustaining oncogenic transcriptional programs and shaping a pro-tumor immune microenvironment, Uhrf1 emerges as a promising therapeutic target for inhibiting tumor growth and immune evasion.

Loss of RB1 function represents a defining characteristic of triple-negative breast cancer (TNBC) and is intricately associated with resistance to therapeutic interventions. In this study, we investigate the epigenetic mechanisms governing RB1 expression in TNBC. Employing a combination of bioinformatics analyses and experimental validations, we identified lysine histone methyltransferase EZH2 as a key upstream regulator of RB1 expression. EZH2 primarily mediates trimethylation of lysine 27 on histone H3 as the catalytic subunit of the Polycomb repressive complex 2 (PRC2) complex. Furthermore, our findings demonstrate that pharmacological inhibition of EZH2 leads to a significant upregulation of RB1 expression levels, mediated by enhanced enrichment of the activating histone marker H3K27ac at the RB1 enhancer region, as evidenced by ATAC-sequencing and ChIP-qPCR assays. These insights unveil a promising clinical avenue for combating RB1-mediated drug resistance in TNBC through the strategic integration of epigenetic-targeting agents.

The Retinoblastoma (RB) protein is crucial for regulating gene transcription and chromatin remodeling, impacting cell cycle progression, cellular senescence, and tumorigenesis. Cellular senescence, characterized by irreversible growth arrest and phenotypic alterations, serves as a vital barrier against tumor progression and age-related diseases. RB is crucial in mediating senescence and tumor suppression by modulating the RB-E2F pathway and cross talking with other key senescence effectors such as p53 and p16INK4a. The interplay between RB-mediated cell cycle arrest and cellular senescence offers critical insights into tumorigenesis and potential therapeutic strategies. Leveraging RB-mediated senescence presents promising opportunities for cancer therapy, including novel approaches in tumor immunotherapy designed to enhance treatment efficacy. This review highlights recent advancements in the RB signaling pathway, focusing on its roles in cellular senescence and tumor suppression, and discusses its potential to improve tumor management and clinical outcomes.

Prostate cancer is one of the most prevalent malignant tumors in men, particularly in regions with a high Human Development Index. While the long-term survival rate for localized prostate cancer is relatively high, the mortality rate remains significantly elevated once the disease progresses to advanced stages, even with various intensive treatment modalities. The primary obstacle to curing advanced prostate cancer is the absence of comprehensive treatment strategies that effectively target the highly heterogeneous tumors at both genetic and molecular levels. Prostate cancer development is a complex, multigenic, and multistep process that involves numerous gene mutations, alteration in gene expression, and changes in signaling pathways. Key genetic and pathway alterations include the amplification and/or mutation of the androgen receptor, the loss of Rb, PTEN, and p53, the activation of the WNT signaling pathway, and the amplification of the MYC oncogene. This review summarizes the mechanisms by which these genes influence the progression of prostate cancer and highlights the interactions between multiple genes and their relationship with prostate cancer. Additionally, we reviewed the current state of treatments targeting these genes and signaling pathways, providing a comprehensive overview of therapeutic approaches in the context of prostate cancer.

Cell division is a fundamental process shared across diverse life forms, from yeast to humans and plants. Multicellular organisms reproduce through the formation of specialized types of cells, the gametes, which at maturity enter a quiescent state that can last decades. At the point of fertilization, signalling lifts the quiescent state and triggers cell cycle reactivation. Studying how the cell cycle is regulated during plant gamete development and fertilization is challenging, and decades of research have provided valuable, yet sometimes contradictory, insights. This Review summarizes the current understanding of plant cell cycle regulation, gamete development, quiescence, and fertilization-triggered reactivation.

The objective of this work is to assess the current situation in the ophthalmology department of the tertiary care center for the conservative treatment of retinoblastoma in Niger. This was a retrospective study from January 2016 to October 2022 (6years and 10months). Retinoblastoma represents 43.27% of pediatric cancers, of which 10.92% of cases are bilateral. The mean age of our patients is 36months, with the range between 2-3years, with extremes ranging from 1month to 132months. The male sex represents 65.55% (n=78), with a sex ratio of 1.9. The distance traveled varies from 1355 kilometers in the furthest region (Diffa) from the capital to 113 kilometers in the nearest region (Tillabéry). Neighboring countries such as Mali and Benin represent 5.88% (n=5). It should be noted that 58% saw traditional healers before coming to the medical center. The most common clinical signs are leukocoria 39.5% (n=47), proptosis 34.45% (n=41) and exorbitism in 15.97% (n=19). An orbital/brain CT was ordered in 54.62% (n=65) of cases. We used the TNM classification; extraocular extension occurred in 47.90% (n=57) and intraocular cases 27.73% (n=33). Neoadjuvant chemotherapy was used in (63.03% n=74). Histology was carried out in (26.89% n=32), with the result obtained in 14days on average. The visit to traditional practitioners as well as the remoteness of certain regions contribute to the delay in diagnosis in our context. The continued implementation of the early diagnosis campaign program could reverse the trend.

Even if its completed form is complex, cancer originates from one or two events that happened to a single cell. A simplified model can play a role in understanding how cancer initiates at the beginning. The pathophysiology of leukemia has been studied in the most detailed manner among all human cancers. In this review, based on milestone papers and the latest research developments in hematology, acute promyelocytic leukemia (APL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML) with RUNX1-RUNX1T1 are selected to consider minimal requirements for cancer initiation. A one-hit model can be applied to the initiation of APL and CML whereas a two-hit model is more suitable to the initiation of AML with RUNX1-RUNX1T1 and other AMLs. Even in cancer cells with multiple genetic abnormalities, there must be a few mutant genes critical for the mutant clone to survive and proliferate. Such genes should be identified and characterized in each case in order to develop individualized target therapy.

Osteosarcoma (OS) is a primary malignant bone tumor that emanates from mesenchymal cells, commonly found in the epiphyseal end of long bones. The highly recurrent and metastatic nature of OS poses significant challenges to the efficacy of treatment and negatively affects patient prognosis. Currently, available clinical treatment strategies primarily focus on maximizing tumor resection and reducing localized symptoms rather than the complete eradication of malignant tumor cells to achieve ideal outcomes. The biomaterials-boosted immunotherapy for OS is characterized by high effectiveness and a favorable safety profile. This therapeutic approach manipulates the tumor microenvironments at the cellular and molecular levels to impede tumor progression. This review delves into the mechanisms underlying the treatment of OS, emphasizing biomaterials-enhanced tumor immunity. Moreover, it summarizes the immune cell phenotype and tumor microenvironment regulation, along with the ability of immune checkpoint blockade to activate the autoimmune system. Gaining a profound comprehension of biomaterials-boosted OS immunotherapy is imperative to explore more efficacious immunotherapy protocols and treatment options in this setting.

Budding yeast, Saccharomyces cerevisiae, is widely used as a model organism to study the genetics underlying eukaryotic cellular processes and growth critical to cancer development, such as cell division and cell cycle progression. The budding yeast cell cycle is also one of the best-studied dynamical systems owing to its thoroughly resolved genetics. However, the dynamics underlying the crucial cell cycle decision point called the START transition, at which the cell commits to a new round of DNA replication and cell division, are under-studied. The START machinery involves a central cyclin-dependent kinase; cyclins responsible for starting the transition, bud formation, and initiating DNA synthesis; and their transcriptional regulators. However, evidence has shown that the mechanism is more complicated than a simple irreversible transition switch. Activating a key transcription regulator SBF requires the phosphorylation of its inhibitor, Whi5, or an SBF/MBF monomeric component, Swi6, but not necessarily both. Also, the timing and mechanism of the inhibitor Whi5's nuclear export, while important, are not critical for the timing and execution of START. Therefore, there is a need for a consolidated model for the budding yeast START transition, reconciling regulatory and spatial dynamics. We built a detailed mathematical model (START-BYCC) for the START transition in the budding yeast cell cycle based on established molecular interactions and experimental phenotypes. START-BYCC recapitulates the underlying dynamics and correctly emulates key phenotypic traits of ~150 known START mutants, including regulation of size control, localization of inhibitor/transcription factor complexes, and the nutritional effects on size control. Such a detailed mechanistic understanding of the underlying dynamics gets us closer towards deconvoluting the aberrant cellular development in cancer.

Cancer accounted for 10 million deaths in 2020, nearly one in every six deaths annually. Despite advancements, the contemporary clinical management of human neoplasms faces a number of challenges. Surgical removal of tumor tissues is often not possible technically, while radiation and chemotherapy pose the risk of damaging healthy cells, tissues, and organs, presenting complex clinical challenges. These require a paradigm shift in developing new therapeutic modalities moving towards a more personalized and targeted approach. The tumor-agnostic philosophy, one of these new modalities, focuses on characteristic molecular signatures of transformed cells independently of their traditional histopathological classification. These include commonly occurring DNA aberrations in cancer cells, shared metabolic features of their homeostasis or immune evasion measures of the tumor tissues. The first dedicated, FDA-approved tumor-agnostic agent's profound progression-free survival of 78% in mismatch repair-deficient colorectal cancer paved the way for the accelerated FDA approvals of novel tumor-agnostic therapeutic compounds. Here, we review the historical background, current status, and future perspectives of this new era of clinical oncology.

As next-generation sequencing (NGS) has become more widely used, germline and rare genetic variations responsible for inherited illnesses, including cancer predisposition syndromes (CPSs) that account for up to 10% of childhood malignancies, have been found. The CPSs are a group of germline genetic disorders that have been identified as risk factors for pediatric cancer development. Excluding a few "classic" CPSs, there is no agreement regarding when and how to conduct germline genetic diagnostic studies in children with cancer due to the constant evolution of knowledge in NGS technologies. Various clinical screening tools have been suggested to aid in the identification of individuals who are at greater risk, using diverse strategies and with varied outcomes. We present here an overview of the primary clinical and molecular characteristics of various CPSs and summarize the existing clinical genomics data on the prevalence of CPSs in pediatric cancer patients. Additionally, we discuss several ethical issues, challenges, limitations, cost-effectiveness, and integration of genomic newborn screening for CPSs into a healthcare system. Furthermore, we assess the effectiveness of commonly utilized decision-support tools in identifying patients who may benefit from genetic counseling and/or direct genetic testing. This investigation highlights a tailored and systematic approach utilizing medical newborn screening tools such as the genome sequencing of high-risk newborns for CPSs, which could be a practical and cost-effective strategy in pediatric cancer care.

Tumor biomarkers, the substances which are produced by tumors or the body's responses to tumors during tumorigenesis and progression, have been demonstrated to possess critical and encouraging value in screening and early diagnosis, prognosis prediction, recurrence detection, and therapeutic efficacy monitoring of cancers. Over the past decades, continuous progress has been made in exploring and discovering novel, sensitive, specific, and accurate tumor biomarkers, which has significantly promoted personalized medicine and improved the outcomes of cancer patients, especially advances in molecular biology technologies developed for the detection of tumor biomarkers. Herein, we summarize the discovery and development of tumor biomarkers, including the history of tumor biomarkers, the conventional and innovative technologies used for biomarker discovery and detection, the classification of tumor biomarkers based on tissue origins, and the application of tumor biomarkers in clinical cancer management. In particular, we highlight the recent advancements in biomarker-based anticancer-targeted therapies which are emerging as breakthroughs and promising cancer therapeutic strategies. We also discuss limitations and challenges that need to be addressed and provide insights and perspectives to turn challenges into opportunities in this field. Collectively, the discovery and application of multiple tumor biomarkers emphasized in this review may provide guidance on improved precision medicine, broaden horizons in future research directions, and expedite the clinical classification of cancer patients according to their molecular biomarkers rather than organs of origin.

Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally considered a prerequisite for initiating RB development in most RB cases. Additional genetic mutations arising from genome instability following RB1 mutations are proposed to be required to promote RB development. Recent advancements in high throughput sequencing technologies allow a deeper and more comprehensive understanding of the etiology of RB that additional genetic alterations following RB1 biallelic loss are rare, yet epigenetic changes driven by RB1 loss emerge as a critical contributor promoting RB tumorigenesis. Multiple epigenetic regulators have been found to be dysregulated and to contribute to RB development, including noncoding RNAs, DNA methylations, RNA modifications, chromatin conformations, and histone modifications. A full understanding of the roles of genetic and epigenetic alterations in RB formation is crucial in facilitating the translation of these findings into effective treatment strategies for RB. In this review, we summarize current knowledge concerning genetic defects and epigenetic dysregulations in RB, aiming to help understand their links and roles in RB tumorigenesis.

Retinoblastoma, although rare, is one of the most common intraocular malignancies worldwide. Its prognosis has improved significantly in the past few decades, thanks to modern treatments, like systemic, intra-arterial, and intravitreal chemotherapy. However, regarding survival, there are significant differences between high- and low-income countries, eye salvage is still a challenge worldwide, and treatment-related toxicity needs to be carefully and sufficiently managed.

To appraise the strength of supporting evidence, we performed a systematic review of randomized controlled trials investigating any therapeutic protocol for retinoblastoma. Four trials with 174 participants (188 eyes) were eligible, all pertaining to different intravenous chemotherapy regimens. Vincristine, etoposide, and carboplatin (VEC) appear superior to a 5-drug combination for stage III retinoblastoma. Moreover, etoposide and carboplatin as neoadjuvant chemotherapy followed by thermochemotherapy seem to offer better local control than vincristine and carboplatin. However, increasing carboplatin dose in the VEC protocol failed to improve treatment efficacy.

Retinoblastoma is a success story of modern medicine. However, only intravenous chemotherapy has been studied through randomized trials, while evidence for the most novel retinoblastoma treatments has mainly stemmed from observational studies. International collaborations for multicenter randomized trials could overcome difficulties and increase certainty and precision in the field.

The retinoblastoma protein (RB)-mediated regulation of E2F is a component of a highly conserved cell cycle machine. However, RB's tumor suppressor activity, like RB's requirement in animal development, is tissue-specific, context-specific, and sometimes appears uncoupled from cell proliferation. Detailed new information about RB's genomic distribution provides a new perspective on the complexity of RB function, suggesting that some of its functional specificity results from context-specific RB association with chromatin. Here we summarize recent evidence showing that RB targets different types of chromatin regulatory elements at different cell cycle stages. RB controls traditional RB/E2F targets prior to S-phase, but, when cells proliferate, RB redistributes to cell type-specific chromatin loci. We discuss the broad implications of the new data for RB research.

Tumors of the eye, orbit, and ocular adnexa can arise in the pediatric population. These entities can be both vision- and life-threatening and may be associated with systemic disease. Given their relative rarity, pediatricians must be aware of these conditions and understand what findings warrant immediate referral to an ophthalmologist for initiation of further testing. We aimed to review these conditions and highlight clinical features to promote awareness and expedite diagnosis. Tumors are subdivided into the following categories for review: anterior tumors of the eyelid and ocular surface, orbital tumors, and intraocular tumors.

Retinoblastoma, the primary ocular malignancy in pediatric patients, poses a substantial threat to mortality without prompt and effective management. The prognosis for survival and preservation of visual acuity hinges upon the disease severity at the time of initial diagnosis. Notably, retinoblastoma has played a crucial role in unraveling the genetic foundations of oncogenesis. The process of tumorigenesis commonly begins with the occurrence of biallelic mutation in the RB1 tumor suppressor gene, which is then followed by a cascade of genetic and epigenetic alterations that correspond to the clinical stage and pathological features of the tumor. The RB1 gene, recognized as a tumor suppressor, encodes the retinoblastoma protein, which plays a vital role in governing cellular replication through interactions with E2F transcription factors and chromatin remodeling proteins. The diagnosis and treatment of retinoblastoma necessitate consideration of numerous factors, including disease staging, germline mutation status, family psychosocial factors, and the resources available within the institution. This review has systematically compiled and categorized the latest developments in the diagnosis and treatment of retinoblastoma which enhanced the quality of care for this pediatric malignancy.

Retinoblastoma (Rb) is the most common intraocular malignancy in childhood, originating from primitive retinal stem cells or cone precursor cells. It can be triggered by mutations of the RB1 gene or amplification of the MYCN gene. Rb may rarely present with polydactyly.

We conducted karyotype analysis, copy number variation sequencing, and whole-genome sequencing on the infant proband and his family. The clinical course and laboratory results of the proband's infant were documented and collected. We also reviewed the relevant literature.

A 68-day-old boy presented with preaxial polydactyly and corneal edema. His intraocular pressure (IOP) was 40/19 mmHg, and color Doppler imaging revealed vitreous solid mass-occupying lesions with calcification in the right eye. Ocular CT showed flaky high-density and calcification in the right eye. This was classified as an International Retinoblastoma Staging System group E retinoblastoma with an indication for enucleation. Enucleation and orbital implantation were performed on the child's right eye. Karyotype analysis revealed an abnormal 46, XY, 15pstk+ karyotype, and the mother exhibited diploidy of the short arm of chromosome 15. The Alx-4 development factor, 13q deletion syndrome, and the PAPA2 gene have been reported as potential mechanisms for Rb combined with polydactyly.

We report the case of a baby boy with Rb and polydactyly exhibiting a 46, XY, 15pstk+ Karyotype. We discuss potential genetic factors related to both Rb and polydactyly. Furthermore, there is a need for further exploration into the impact of chromosomal polymorphisms in Rb with polydactyly.

Recurrence and extraocular metastasis in advanced intraocular retinoblastoma (RB) are still major obstacles for successful treatment of Chinese children. Tuberous sclerosis complex (TSC) is a very rare, multisystemic genetic disorder characterized by hamartomatous growth. In this study, we aimed to compare genomic and epigenomic profiles with human RB or TSC using recently developed nanopore sequencing, and to identify disease-associated variations or genes. Peripheral blood samples were collected from either RB or RB/TSC patients plus their normal siblings, followed by nanopore sequencing and identification of disease-specific structural variations (SVs) and differentially methylated regions (DMRs) by a systematic biology strategy named as multiomics-based joint screening framework. In total, 316 RB- and 1295 TSC-unique SVs were identified, as well as 1072 RB- and 1114 TSC-associated DMRs, respectively. We eventually identified 6 key genes for RB for further functional validation. Knockdown of CDK19 with specific siRNAs significantly inhibited Y79 cellular proliferation and increased sensitivity to carboplatin, whereas downregulation of AHNAK2 promoted the cell growth as well as drug resistance. Those two genes might serve as potential diagnostic markers or therapeutic targets of RB. The systematic biology strategy combined with functional validation might be an effective approach for rare pediatric malignances with limited samples and challenging collection process.

Retinoblastoma is a prevalent pediatric intraocular tumor. The suppressive effect of gentiopicroside (GPS) has been reported on various tumors. This study sought to determine the effect of GPS on retinoblastoma cell proliferation, apoptosis, invasion, and epithelial-mesenchymal transition (EMT), and tumorigenesis in nude mice. The effect and mechanism of GPS on growth, apoptosis, invasion, and EMT were determined by cell counting kit-8 (CCK-8), western blot, flow cytometry, and transwell assays in retinoblastoma cells. Y79 cells were injected into the vitreous cavity of BALB/c‑nude mice to construct a retinoblastoma mouse model. Tumor growth and mouse weight were monitored for sequential 5 weeks. The effect of GPS in vivo was assessed by immunohistochemistry (IHC), terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), and western blot assays. GPS decreased the cell viability of both Y79 and Weri-Rb1 cells with the IC50 of 18.85 μM and 27.57 μM, respectively. Besides, GPS reduced the relative expression of proteins involved in proliferation and EMT, and the number of invading cells, while increased the apoptosis rate and the relative expressions of apoptosis proteins in retinoblastoma cells. Mechanically, GPS decreased the relative protein level of PI3K/AKT pathway, which was then recovered after 740 Y-P was applied. Correspondingly, 740 Y-P reversed the inhibitory effect of GPS on growth, invasion, and EMT, and the increased effect of GPS on apoptosis. Additionally, GPS decreased tumor volume and weight as well as the relative level of Ki-67, VEGF, p-PI3K/PI3K, and p-AKT/AKT, while increased the apoptosis rate in vivo. GPS inhibited retinoblastoma cell proliferation and invasion via deactivating the PI3K/AKT pathway in both cell and animal models.

Cancer is one of the major public health challenges in China. Rare cancers collectively account for a considerable proportion of all malignancies. The lack of awareness of rare cancers among healthcare professionals and the general public, the typically complex and delayed diagnosis, and limited access to clinical trials are key challenges. Recent years have witnessed an increase in funding for research related to rare cancers in China. In this review, we provide a comprehensive overview of rare cancers and summarize the status of research on rare cancers in China and overseas, including the trends of funding and publications. We also highlight the challenges and perspectives regarding rare cancers in China.

In all cases tested, TFIIIB is responsible for recruiting pol III to its genetic templates. In mammalian cells, RB binds TFIIIB and prevents its interactions with both promoter DNA and pol III, thereby suppressing transcription. As TFIIIB is not recruited to its target genes when bound by RB, the mechanism predicts that pol III-dependent templates will not be occupied by RB; this contrasts with the situation at most genes controlled by RB, where it can be tethered by promoter-bound sequence-specific DNA-binding factors such as E2F. Contrary to this prediction, however, ChIP-seq data reveal the presence of RB in multiple cell types and the related protein p130 at many loci that rely on pol III for their expression, including RMRP, RN7SL, and a variety of tRNA genes. The sets of genes targeted varies according to cell type and growth state. In such cases, recruitment of RB and p130 can be explained by binding of E2F1, E2F4 and/or E2F5. Genes transcribed by pol III had not previously been identified as common targets of E2F family members. The data provide evidence that E2F may allow for the selective regulation of specific non-coding RNAs by RB, in addition to its influence on overall pol III output through its interaction with TFIIIB.

The transcription factor E2F links the RB pathway to the p53 pathway upon loss of function of pRB, thereby playing a pivotal role in the suppression of tumorigenesis. E2F fulfills a major role in cell proliferation by controlling a variety of growth-associated genes. The activity of E2F is controlled by the tumor suppressor pRB, which binds to E2F and actively suppresses target gene expression, thereby restraining cell proliferation. Signaling pathways originating from growth stimulative and growth suppressive signals converge on pRB (the RB pathway) to regulate E2F activity. In most cancers, the function of pRB is compromised by oncogenic mutations, and E2F activity is enhanced, thereby facilitating cell proliferation to promote tumorigenesis. Upon such events, E2F activates the Arf tumor suppressor gene, leading to activation of the tumor suppressor p53 to protect cells from tumorigenesis. ARF inactivates MDM2, which facilitates degradation of p53 through proteasome by ubiquitination (the p53 pathway). P53 suppresses tumorigenesis by inducing cellular senescence or apoptosis. Hence, in almost all cancers, the p53 pathway is also disabled. Here we will introduce the canonical functions of the RB-E2F-p53 pathway first and then the non-classical functions of each component, which may be relevant to cancer biology.

Retinoblastoma (RB) is a life-threatening malignancy that arises from the retina and is activated upon homozygous inactivation of the tumor suppressor RB1. Gene therapy targeting RB1 is an effective strategy to treat RB. However, it is difficult to target the RB1 gene by site-specific repair, with up to 3366 gene mutation sites identified in RB1. Thus, it is necessary to construct a promising and efficacious gene therapeutic strategy for patients with RB.

To recover the function of the RB1 protein, we constructed a recombinant adeno-associated virus 2 (rAAV2) expressing RB1 that can restore RB1 function and significantly inhibit RB progression. To confirm the clinical feasibility of rAAV2-RB1, the RB1 protein was validated in vitro and in vivo after transfection. To further evaluate the clinical efficacy, RB patient-derived xenograft models were established and applied. The biosafety of rAAV2-RB1 was also validated in immunocompetent mice.

rAAV2-RB1 was a rAAV2 expressing the RB1 protein, which was validated in vitro and in vivo. In vitro, rAAV2-RB1 was effectively expressed in patient-derived RB cells. In mice, intravitreal administration of rAAV2-RB1 in a population-based patient-derived xenograft trial induced limited tumor growth. Moreover, after transfection of rAAV2-RB1 in immunocompetent mice, rAAV2-RB1 did not replicate and was expressed in other important organs, except retinas, inducing minor local side effects.

Our study suggested a promising efficacy gene therapeutic strategy, which might provide a chemotherapy-independent treatment option for RB.

Cancer is a complex and multifaceted disease with a high global incidence and mortality rate. Although cancer therapy has evolved significantly over the years, numerous challenges persist on the path to effectively combating this multifaceted disease. Natural compounds derived from plants, fungi, or marine organisms have garnered considerable attention as potential therapeutic agents in the field of cancer research. Ellagic acid (EA), a natural polyphenolic compound found in various fruits and nuts, has emerged as a potential cancer prevention and treatment agent. This review summarizes the experimental evidence supporting the role of EA in targeting key hallmarks of cancer, including proliferation, angiogenesis, apoptosis evasion, immune evasion, inflammation, genomic instability, and more. We discuss the molecular mechanisms by which EA modulates signaling pathways and molecular targets involved in these cancer hallmarks, based on in vitro and in vivo studies. The multifaceted actions of EA make it a promising candidate for cancer prevention and therapy. Understanding its impact on cancer biology can pave the way for developing novel strategies to combat this complex disease.

Background: Very little was known about the molecular pathogenesis of thyroid cancer until the late 1980s. As part of the Centennial celebration of the American Thyroid Association, we review the historical discoveries that contributed to our current understanding of the genetic underpinnings of thyroid cancer. Summary: The pace of discovery was heavily dependent on scientific breakthroughs in nucleic acid sequencing technology, cancer biology, thyroid development, thyroid cell signaling, and growth regulation. Accordingly, we attempt to link the primary observations on thyroid cancer molecular genetics with the methodological and scientific advances that made them possible. Conclusions: The major genetic drivers of the common forms of thyroid cancer are now quite well established and contribute to a significant extent to how we diagnose and treat the disease. However, many challenges remain. Future work will need to unravel the complexity of thyroid cancer ecosystems, which is likely to be a major determinant of their biological behavior and on how they respond to therapy.

Lack of retinoblastoma (Rb) protein causes aggressive intraocular retinal tumors in children. Recently, Rb tumors have been shown to have a distinctly altered metabolic phenotype, such as reduced expression of glycolytic pathway proteins alongside altered pyruvate and fatty acid levels. In this study, we demonstrate that loss of hexokinase 1(HK1) in tumor cells rewires their metabolism allowing enhanced oxidative phosphorylation-dependent energy production. We show that rescuing HK1 or retinoblastoma protein 1 (RB1) in these Rb cells reduced cancer hallmarks such as proliferation, invasion, and spheroid formation and increased their sensitivity to chemotherapy drugs. Induction of HK1 was accompanied by a metabolic shift of the cells to glycolysis and a reduction in mitochondrial mass. Cytoplasmic HK1 bound Liver Kinase B1 and phosphorylated AMP-activated kinase-α (AMPKα Thr172), thereby reducing mitochondria-dependent energy production. We validated these findings in tumor samples from Rb patients compared to age-matched healthy retinae. HK1 or RB1 expression in Rb-/- cells led to a reduction in their respiratory capacity and glycolytic proton flux. HK1 overexpression reduced tumor burden in an intraocular tumor xenograft model. AMPKα activation by AICAR also enhanced the tumoricidal effects of the chemotherapeutic drug topotecan in vivo. Therefore, enhancing HK1 or AMPKα activity can reprogram cancer metabolism and sensitize Rb tumors to lower doses of existing treatments, a potential therapeutic modality for Rb.

Retinoblastoma is the most common intraocular malignancy in children. The treatment of this rare disease is still challenging in developing countries due to delayed diagnosis. The current therapies comprise mainly surgery, radiotherapy and chemotherapy. The adverse effects of radiation and chemotherapeutic drugs have been reported to contribute to the high mortality rate and affect patients' quality of life. The systemic side effects resulting from the distribution of chemotherapeutic drugs to non-cancerous cells are enormous and have been recognized as one of the reasons why most potent anticancer compounds fail in clinical trials. Nanoparticulate delivery systems have the potential to revolutionize cancer treatment by offering targeted delivery, enhanced penetration and retention effects, increased bioavailability, and an improved toxicity profile. Notwithstanding the plethora of evidence on the beneficial effects of nanoparticles in retinoblastoma, the clinical translation of this carrier is yet to be given the needed attention. This paper reviews the current and emerging treatment options for retinoblastoma, with emphasis on recent investigations on the use of various classes of nanoparticles in diagnosing and treating retinoblastoma. It also presents the use of ligand-conjugated and smart nanoparticles in the active targeting of anticancer and imaging agents to the tumour cells. In addition, this review discusses the prospects and challenges in translating this nanocarrier into clinical use for retinoblastoma therapy. This review may provide new insight for formulation scientists to explore in order to facilitate the development of more effective and safer medicines for children suffering from retinoblastoma.

With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. Video Abstract.

This review presents current knowledge on the molecular biology of retinoblastoma (RB). Retinoblastoma is an intraocular tumor with hereditary and sporadic forms. 8,000 new cases of this ocular malignancy of the developing retina are diagnosed each year worldwide. The major gene responsible for retinoblastoma is RB1, and it harbors a large spectrum of pathogenic variants. Tumorigenesis begins with mutations that cause RB1 biallelic inactivation preventing the production of functional pRB proteins. Depending on the type of mutation the penetrance of RB is different. However, in small percent of tumors additional genes may be required, such as MYCN, BCOR and CREBBP. Additionally, epigenetic changes contribute to the progression of retinoblastoma as well. Besides its role in the cell cycle, pRB plays many additional roles, it regulates the nucleosome structure, participates in apoptosis, DNA replication, cellular senescence, differentiation, DNA repair and angiogenesis. Notably, pRB has an important role as a modulator of chromatin remodeling. In recent years high-throughput techniques are becoming essential for credible biomarker identification and patient management improvement. In spite of remarkable advances in retinoblastoma therapy, primarily in high-income countries, our understanding of retinoblastoma and its specific genetics still needs further clarification in order to predict the course of this disease and improve therapy. One such approach is the tumor free DNA that can be obtained from the anterior segment of the eye and be useful in diagnostics and prognostics.

Owing to the variety and complexity of ocular diseases and the natural ocular barriers, drug therapy for ocular diseases has significant limitations, such as poor drug targeting to the site of the disease, poor drug penetration, and short drug retention time in the vitreous body. With the development of biotechnology, biomedical materials have reached the "smart" stage. To date, despite their inability to overcome all the aforementioned drawbacks, a variety of smart materials have been widely tested to treat various ocular diseases. This review analyses the most recent developments in multiple smart materials (inorganic particles, polymeric particles, lipid-based particles, hydrogels, and devices) to treat common ocular diseases and discusses the future directions and perspectives regarding clinical translation issues. This review can help researchers rationally design more smart materials for specific ocular applications.

The success of precision oncology-which aims to match the right therapies to the right patients based on molecular status-is predicated on a robust pipeline of molecular targets against which therapies can be developed. Recent advances in genomics and functional genetics have enabled the unbiased discovery of novel molecular targets at scale. We summarize the promise and challenges in integrating genomic and functional genetic landscapes of cancer to establish the next generation of cancer targets.

γ-Glutamylcyclotransferase (GGCT) is highly expressed in multiple types of cancer tissues and its knockdown suppresses the growth of cancer cells in vitro and in vivo. Although GGCT is a promising target for cancer therapy, the mechanisms underlying the antitumor effects remain unclear. The knockdown of GGCT inhibited the MEK-ERK pathway, and activated the tumor suppressor retinoblastoma gene (RB) at the protein level in cancer cell lines. c-Met was down-regulated by the knockdown of GGCT in cancer cells and its overexpression attenuated the dephosphorylation of RB and cell cycle arrest induced by the knockdown of GGCT in lung cancer A549 cells. STAT3 is a transcription factor that induces c-Met expression. STAT3 phosphorylation and its nuclear expression level were decreased in GGCT-depleted A549 and prostate cancer PC3 cells. The simultaneous knockdown of AMPK and GGCT restored the down-regulated expression of c-Met, and attenuated the dephosphorylation of STAT3 and MEK-ERK-RB induced by the knockdown of GGCT in PC3 cells. An intraperitoneal injection of a GGCT inhibitor decreased c-Met protein expression in a mouse xenograft model of PC3 cells. These results suggest that the knockdown of GGCT activates the RB protein by inhibiting the STAT3-c-Met-MEK-ERK pathway via AMPK activation.

Retinoblastoma is a retinal cancer that affects children and is the most prevalent intraocular tumor worldwide. Despite tremendous breakthroughs in our understanding of the fundamental mechanisms that regulate progression of retinoblastoma, the development of targeted therapeutics for retinoblastoma has lagged. Our review highlights the current developments in the genetic, epigenetic, transcriptomic, and proteomic landscapes of retinoblastoma. We also discuss their clinical relevance and potential implications for future therapeutic development, with the aim to create a frontline multimodal therapy for retinoblastoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.