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Survey of Ophthalmology May 2024Chromosomal abnormalities that involve the MYCN gene are rare; however, it is one of the most commonly mutated genes in retinoblastoma (RB) after the RB1 gene. MYCN is... (Review)
Review
Chromosomal abnormalities that involve the MYCN gene are rare; however, it is one of the most commonly mutated genes in retinoblastoma (RB) after the RB1 gene. MYCN is amplified in approximately 1-9 % of all RB tumors. It plays a role in RB oncogenesis via many mechanisms, including synergism with RB1 deletion, positive feedback with MDM2, upregulation of cell cycle regulating genes, upregulation of miRNA, and upregulation of glucose metabolism. MYCN amplifications are not mutually exclusive and can occur even in the presence of RB1 gene mutations. Clinically, RB1MYCN tumors present as sporadic, unilateral, advanced tumors in very young children and tend to follow an aggressive course. Magnetic resonance imaging features include peripheral tumor location, placoid configuration, retinal folding, tumor-associated hemorrhage, and anterior chamber enhancement. Genetic testing for MYCN is especially recommended in patients with unilateral RB where genetic blood testing and tumor tissue show a lack of RB1 mutation. MYCN-targeted therapies are evolving and hold promise for the future.
PubMed: 38796108
DOI: 10.1016/j.survophthal.2024.05.009 -
Molecules (Basel, Switzerland) May 2024The eye's complex anatomical structures present formidable barriers to effective drug delivery across a range of ocular diseases, from anterior to posterior segment... (Review)
Review
The eye's complex anatomical structures present formidable barriers to effective drug delivery across a range of ocular diseases, from anterior to posterior segment pathologies. Emerging as a promising solution to these challenges, nanotechnology-based platforms-including but not limited to liposomes, dendrimers, and micelles-have shown the potential to revolutionize ophthalmic therapeutics. These nanocarriers enhance drug bioavailability, increase residence time in targeted ocular tissues, and offer precise, localized delivery, minimizing systemic side effects. Focusing on pediatric ophthalmology, particularly on retinoblastoma, this review delves into the recent advancements in functionalized nanosystems for drug delivery. Covering the literature from 2017 to 2023, it comprehensively examines these nanocarriers' potential impact on transforming the treatment landscape for retinoblastoma. The review highlights the critical role of these platforms in overcoming the unique pediatric eye barriers, thus enhancing treatment efficacy. It underscores the necessity for ongoing research to realize the full clinical potential of these innovative drug delivery systems in pediatric ophthalmology.
Topics: Retinoblastoma; Humans; Drug Delivery Systems; Drug Carriers; Child; Nanoparticles; Micelles; Liposomes; Dendrimers; Retinal Neoplasms; Administration, Ophthalmic; Nanotechnology
PubMed: 38792122
DOI: 10.3390/molecules29102263 -
Cancers May 2024This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy...
This retrospective multicenter study examines therapy-induced orbital and ocular MRI findings in retinoblastoma patients following selective intra-arterial chemotherapy (SIAC) and quantifies the impact of SIAC on ocular and optic nerve growth. Patients were selected based on medical chart review, with inclusion criteria requiring the availability of posttreatment MR imaging encompassing T2-weighted and T1-weighted images (pre- and post-intravenous gadolinium administration). Qualitative features and quantitative measurements were independently scored by experienced radiologists, with deep learning segmentation aiding total eye volume assessment. Eyes were categorized into three groups: eyes receiving SIAC (Rb-SIAC), eyes treated with other eye-saving methods (Rb-control), and healthy eyes. The most prevalent adverse effects post-SIAC were inflammatory and vascular features, with therapy-induced contrast enhancement observed in the intraorbital optic nerve segment in 6% of patients. Quantitative analysis revealed significant growth arrest in Rb-SIAC eyes, particularly when treatment commenced ≤ 12 months of age. Optic nerve atrophy was a significant complication in Rb-SIAC eyes. In conclusion, this study highlights the vascular and inflammatory adverse effects observed post-SIAC in retinoblastoma patients and demonstrates a negative impact on eye and optic nerve growth, particularly in children treated ≤ 12 months of age, providing crucial insights for clinical management and future research.
PubMed: 38791976
DOI: 10.3390/cancers16101899 -
Cancers May 2024French Guiana is a French territory in South America. The exposome of persons living there is quite different from that in mainland France and the ethnic make-up of the...
French Guiana is a French territory in South America. The exposome of persons living there is quite different from that in mainland France and the ethnic make-up of the population is also quite different. Poverty is also widespread with difficulties in accessing care magnified by the low medical-professional density. In this singular context, we aimed to measure the incidence of pediatric cancers and to compare it with other continents. We used French Guiana's certified cancer registry to study this between 2003 and 2017. Incidences were standardized using the world population with three strata: 0-4 years, 5-9 years, and 10-14 years. There were 164 solid tumors or hematologic malignancies diagnosed in children under the age of 15 (92 in boys and 72 in girls). Over the study period, the standardized incidence rate was 14.1 per 100,000 among children aged under 15 years. There was no significant trend during the study period. The three most common causes of cancer were leukemias-mostly lymphoblastic-CNS tumors, and sarcoma. The standardized incidence of pediatric cancers in French Guiana was similar to those in Western Europe and North America. As others have discovered, we found that males tended to be more likely to develop cancer, notably leukemia, CNS tumors, sarcoma, and retinoblastoma. As elsewhere, the predominant cancer types changed with age. Our initial assumption was that given the singular context of French Guiana, there may have been differences in pediatric cancer incidences. Here we showed that overall, contrary to our assumption and to trends in tropical countries, the incidence of pediatric cancers was in a range between Western Europe and North America with some apparent but non-significant differences in the main types of cancers observed in global statistics. Quality cancer registry data in this tropical region confirm the suspicion that lower incidences in tropical low- and middle-income countries are likely to result from incomplete diagnosis and data collection.
PubMed: 38791908
DOI: 10.3390/cancers16101829 -
Nature Communications May 2024Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone...
Histone deacetylases (HDACs) play a crucial role in transcriptional regulation and are implicated in various diseases, including cancer. They are involved in histone tail deacetylation and canonically linked to transcriptional repression. Previous studies suggested that HDAC recruitment to cell-cycle gene promoters via the retinoblastoma (RB) protein or the DREAM complex through SIN3B is essential for G1/S and G2/M gene repression during cell-cycle arrest and exit. Here we investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression. Knockout of SIN3B does not globally derepress cell-cycle genes in non-proliferating HCT116 and C2C12 cells. Loss of SIN3A/B moderately upregulates several cell-cycle genes in HCT116 cells but does so independently of DREAM/RB. HDAC inhibition does not induce general upregulation of RB/DREAM target genes in arrested transformed or non-transformed cells. Our findings suggest that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.
Topics: Humans; Histone Deacetylases; HCT116 Cells; Repressor Proteins; E2F Transcription Factors; Retinoblastoma Protein; Mice; Animals; Sin3 Histone Deacetylase and Corepressor Complex; Kv Channel-Interacting Proteins; Cell Cycle; Promoter Regions, Genetic; Gene Expression Regulation; Genes, cdc
PubMed: 38789411
DOI: 10.1038/s41467-024-48724-0 -
Asia-Pacific Journal of Ophthalmology... 2024Retinoblastoma (RB), originating from the developing retina, is an aggressive intraocular malignant neoplasm in childhood. Biallelic loss of RB1 is conventionally... (Review)
Review
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.
Topics: Retinoblastoma; Humans; Retinal Neoplasms; Epigenesis, Genetic; Mutation; DNA Methylation; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 38789041
DOI: 10.1016/j.apjo.2024.100072 -
Biochemical Pharmacology Jul 2024Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia...
Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a damage response signal transduction sensor, and its therapeutic potential in tumor cells needs to be precisely investigated. Herein, we identified a new axis that could be targeted by ATR inhibitors to decrease the DNA-dependent protein kinase catalytic subunit (DNAPKcs), downregulate the expression of the retinoblastoma (RB), and drive G1/S-phase transition. Four-way DNA Holliday junctions (FJs) assembled in this process could trigger S-phase arrest and induce lethal chromosome damage in RB-positive triple-negative breast cancer (TNBC) cells. Furthermore, these unrepaired junctions also exerted toxic effects to RB-deficient TNBC cells when the homologous recombination repair (HRR) was inhibited. This study proposes a precise strategy for treating TNBC by targeting the DDR and extends our understanding of ATR and HJ in tumor treatment.
Topics: Ataxia Telangiectasia Mutated Proteins; Humans; Triple Negative Breast Neoplasms; Cell Line, Tumor; DNA, Cruciform; Retinoblastoma Protein; Female; S Phase; Animals; Antineoplastic Agents; DNA Damage
PubMed: 38788960
DOI: 10.1016/j.bcp.2024.116310 -
Science Advances May 2024Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for...
Resistance to therapy commonly develops in patients with high-grade serous ovarian carcinoma (HGSC) and triple-negative breast cancer (TNBC), urging the search for improved therapeutic combinations and their predictive biomarkers. Starting from a CRISPR knockout screen, we identified that loss of RB1 in TNBC or HGSC cells generates a synthetic lethal dependency on casein kinase 2 (CK2) for surviving the treatment with replication-perturbing therapeutics such as carboplatin, gemcitabine, or PARP inhibitors. CK2 inhibition in RB1-deficient cells resulted in the degradation of another RB family cell cycle regulator, p130, which led to S phase accumulation, micronuclei formation, and accelerated PARP inhibition-induced aneuploidy and mitotic cell death. CK2 inhibition was also effective in primary patient-derived cells. It selectively prevented the regrowth of RB1-deficient patient HGSC organoids after treatment with carboplatin or niraparib. As about 25% of HGSCs and 40% of TNBCs have lost RB1 expression, CK2 inhibition is a promising approach to overcome resistance to standard therapeutics in large strata of patients.
Topics: Humans; Casein Kinase II; Retinoblastoma Binding Proteins; Female; Cell Line, Tumor; Triple Negative Breast Neoplasms; Ovarian Neoplasms; Ubiquitin-Protein Ligases; Carboplatin; Synthetic Lethal Mutations; DNA Replication; Drug Resistance, Neoplasm; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents
PubMed: 38781347
DOI: 10.1126/sciadv.adj1564 -
Journal of Clinical Pathology Jun 2024stands as the pioneering discovery in tumour-suppressor genes, marking a pivotal breakthrough in comprehending cancer development. This overview delves into the role of... (Review)
Review
stands as the pioneering discovery in tumour-suppressor genes, marking a pivotal breakthrough in comprehending cancer development. This overview delves into the role of in both health and disease, exploring its association with the tumourigenesis of various cancers and a distinct subset of soft-tissue neoplasms. Additionally, we discuss the application of immunohistochemistry and fluorescence in situ hybridisation to detect alterations.
Topics: Humans; Retinoblastoma Binding Proteins; Neoplasms; Cell Cycle; Pathologists; Ubiquitin-Protein Ligases; Immunohistochemistry; In Situ Hybridization, Fluorescence; Biomarkers, Tumor
PubMed: 38772617
DOI: 10.1136/jcp-2024-209480 -
International Journal of Molecular... Jul 2024Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in...
Following the publication of the above paper, it has been drawn to the Editors' attention by a concerned reader that certain of the lumen formation assay data shown in Fig. 5A on p. 112 were strikingly similar to data appearing in different form in another article written by different authors at different research institute, which had already been published in the journal prior to the submission of this paper to , and which has also subsequently been retracted. In view of the fact that the contentious data had already apparently been published previously, the Editor of has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 44: 103‑114, 2019; DOI: 10.3892/ijmm.2019.4183].
PubMed: 38757359
DOI: 10.3892/ijmm.2024.5382