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JCI Insight Nov 2023Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied...
Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.
Topics: Animals; Humans; Mice; Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nucleotidyltransferases; Poly(ADP-ribose) Polymerase Inhibitors; Retinoblastoma Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 37937640
DOI: 10.1172/jci.insight.165268 -
Advances in Ophthalmology Practice and... 2024Intraocular malignant tumors represent a severe disease that threatens vision as well as life. To better extend the life of the patient, preserve visual function, and... (Review)
Review
BACKGROUND
Intraocular malignant tumors represent a severe disease that threatens vision as well as life. To better extend the life of the patient, preserve visual function, and maintain ocular aesthetics, selecting the appropriate timing and methods of treatment becomes crucial.
MAIN TEXT
With the continuous advancement of medical technology, the techniques and methods for treating intraocular malignant tumors are constantly evolving. While surgery was once considered the optimal method to prolong patient survival and prevent local recurrence, the discovery and application of various treatments such as radiotherapy, laser therapy, chemotherapy, cryotherapy, and monoclonal antibodies have led to a greater diversity of treatment options. This diversity offers more possibilities to develop personalized treatment plans, and thereby maximize patient benefit. This article reviews the various treatment methods for intraocular malignant tumors, including indications for treatment, outcomes, and potential complications.
CONCLUSIONS
Differentiating small intraocular malignant tumors from pigmented lesions is challenging, and ongoing monitoring with regular follow-up is required. Small to medium-sized tumors can be treated with radiotherapy combined with transpupillary thermotherapy. Depending on the tumor's distance from the optic disc, surgery with partial resection may be considered for distant tumors, while proximal tumors may require complete enucleation. Systemic chemotherapy has been widely applied to patients with retinal tumors, lymphomas, and intraocular metastatic cancers, but has limited efficacy in patients with choroidal melanoma. Antagonists of Vascular Endothelial Growth Factor (Anti-VEGF) drugs can improve patient vision and quality of life, while the efficacy of immunotherapy and molecular targeted therapy is still under research.
PubMed: 38846623
DOI: 10.1016/j.aopr.2024.03.005 -
Archives of Pharmacal Research Jan 2024Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic... (Review)
Review
Ocular diseases are a growing global concern and have a significant impact on the quality of life. Cataracts, glaucoma, age-related macular degeneration, and diabetic retinopathy are the most prevalent ocular diseases. Their prevalence and the global market size are also increasing. However, the available pharmacotherapy is currently limited. These diseases share common pathophysiological features, including neovascularization, inflammation, and/or neurodegeneration. Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl groups from lysine residues of histone and nonhistone proteins. HDACs are crucial for regulating various cellular processes, such as gene expression, protein stability, localization, and function. They have also been studied in various research fields, including cancer, inflammatory diseases, neurological disorders, and vascular diseases. Our study aimed to investigate the relationship between HDACs and ocular diseases, to identify a new strategy for pharmacotherapy. This review article explores the role of HDACs in ocular diseases, specifically focusing on diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity, as well as optic nerve disorders, such as glaucoma and optic neuropathy. Additionally, we explore the interplay between HDACs and key regulators of fibrosis and angiogenesis, such as TGF-β and VEGF, highlighting the potential of targeting HDAC as novel therapeutic strategies for ocular diseases.
Topics: Infant, Newborn; Humans; Diabetic Retinopathy; Histone Deacetylases; Quality of Life; Macular Degeneration; Glaucoma; Histone Deacetylase Inhibitors
PubMed: 38151648
DOI: 10.1007/s12272-023-01482-x -
The Lancet. Child & Adolescent Health Sep 2023Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of...
BACKGROUND
Super-selected intra-arterial chemotherapy has increasingly been used as conservative management for retinoblastoma during the past decade. However, the absence of evidence from randomised controlled trials engendered controversy in the administration route of chemotherapy. We aimed to assess the efficacy and safety of intra-arterial chemotherapy compared with intravenous chemotherapy.
METHODS
This open-label, multicentre, randomised trial was done at six hospitals in China. Patients with new-onset unilateral group D or E retinoblastoma (poorly defined, large, or very large tumours, according to the International Intraocular Retinoblastoma Classification) without high-risk clinical factors were included. Patients were randomly assigned (1:1) to receive intra-arterial chemotherapy (injections of 0·5 mg/kg [or depending on age] melphalan with 20 mg carboplatin [first and third cycles] or with 1 mg topotecan [second and fourth cycles]) or intravenous chemotherapy (0·05 mg/kg [or 1·5 mg/m] vincristine, 5 mg/kg [or 150 mg/m] etoposide, and 18·6 mg/kg [or 560 mg/m] carboplatin for six cycles). After intra-arterial chemotherapy, patients received a subcutaneous injection of 0·1 mL nadroparin calcium twice at a 12 h interval. Both intra-arterial and intravenous chemotherapy cycles were completed every 4 weeks. No masking was done, except of independent statisticians, who were masked to the allocation information. The primary outcome was 2-year progression-free globe salvage rate, defined as the time from randomisation to tumour progression or enucleation, whichever occurred first, and was analysed by intention to treat. We also recorded predefined safety outcomes (myelosuppression and ophthalmic arterial stenosis or occlusion) and severe adverse events likely to be related to study treatment. The study is registered with the Chinese Clinical Trial Registry, ChiCTR-IPR-15006469, and is complete.
FINDINGS
Between June 1, 2015, and June 1, 2018, 234 patients with newly diagnosed retinoblastoma were screened and 143 eligible patients (median age 23·6 months [IQR 14·0-31·9]) were enrolled and randomly assigned to the intra-arterial chemotherapy group (n=72) or the intravenous chemotherapy group (n=71). At a median follow-up of 35·8 months (IQR 28·4-43·0), the 2-year progression-free globe salvage rate was 53% (38 of 72 patients) in the intra-arterial chemotherapy group and 27% (19 of 71 patients) in the intravenous chemotherapy group (risk ratio 1·97, 95% CI 1·27-3·07, p=0·0020). Myelosuppression was less common in the intra-arterial chemotherapy group than in the intravenous chemotherapy group (37 [51%] of 72 patients vs 50 [70%] of 71 patients; 0·73, 95% CI 0·56-0·96, p=0·021) and less severe (p=0·0070). In the intra-arterial chemotherapy group, two (3%) of 72 patients had ophthalmic artery occlusion and 13 (18%) patients had ophthalmic artery stenosis.
INTERPRETATION
Our findings show that intra-arterial chemotherapy could significantly improve the globe salvage rate in children with advanced unilateral retinoblastoma compared with intravenous chemotherapy, with mild systemic complications and no difference in overall survival rate. Intra-arterial chemotherapy could be an acceptable first-line treatment in children with advanced unilateral retinoblastoma.
FUNDING
Scientific Research Program of the National Health and Family Planning Commission of China, the Clinical Research Plan of Shanghai Hospital Development Center, the National Natural Science Foundation of China, and the Science and Technology Commission of Shanghai Municipality.
Topics: Humans; Child; Infant; Child, Preschool; Retinoblastoma; Carboplatin; Constriction, Pathologic; China; Retinal Neoplasms; Randomized Controlled Trials as Topic
PubMed: 37536351
DOI: 10.1016/S2352-4642(23)00141-4 -
Nature Communications Oct 2023Meiosis is differently regulated in males and females. In females, germ cells initiate meiosis within a limited time period in the fetal ovary and undergo a prolonged...
Meiosis is differently regulated in males and females. In females, germ cells initiate meiosis within a limited time period in the fetal ovary and undergo a prolonged meiotic arrest until puberty. However, how meiosis initiation is coordinated with the cell cycle to coincide with S phase remains elusive. Here, we demonstrate that STRA8 binds to RB via the LXCXE motif. Mutation of the RB-binding site of STRA8 in female mice delays meiotic entry, which consequently delays progression of meiotic prophase and leads to precocious depletion of the oocyte pool. Single-cell RNA-sequencing analysis reveals that the STRA8-RB interaction is required for S phase entry and meiotic gene activation, ensuring precise timing of meiosis initiation in oocytes. Strikingly, the results suggest STRA8 could sequester RB from E2F during pre-meiotic G1/S transition. This study highlights the gene regulatory mechanisms underlying the female-specific mode of meiotic initiation in mice.
Topics: Animals; Female; Male; Mice; Adaptor Proteins, Signal Transducing; Gene Expression Regulation; Germ Cells; Meiosis; Sexual Maturation; Retinoblastoma Protein
PubMed: 37880249
DOI: 10.1038/s41467-023-42259-6 -
Indian Journal of Ophthalmology Jul 2023Retinoblastoma is a retinal cancer that affects children and is the most prevalent intraocular tumor worldwide. Despite tremendous breakthroughs in our understanding of... (Review)
Review
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.
Topics: Child; Humans; Retinoblastoma; Proteomics; Retinal Neoplasms; Combined Modality Therapy
PubMed: 37417104
DOI: 10.4103/IJO.IJO_3172_22 -
Biochimica Et Biophysica Acta. Gene... Sep 2023Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also...
Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP-qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.
Topics: Child; Humans; N-Myc Proto-Oncogene Protein; Retinoblastoma; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Retinal Neoplasms; SOXC Transcription Factors
PubMed: 37536559
DOI: 10.1016/j.bbagrm.2023.194964 -
The Journal of Clinical Investigation Oct 2023Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for...
Maturation arrest (MA) is a subtype of non-obstructive azoospermia, and male infertility is a known risk factor for testicular tumors. However, the genetic basis for many affected individuals remains unknown. Here, we identified a deleterious hemizygous variant of X-linked retinoblastoma-binding protein 7 (RBBP7) as a potential key cause of MA, which was also found to be associated with the development of Leydig cell tumors. This mutation resulted in premature protein translation termination, affecting the sixth WD40 domain of the RBBP7 and the interaction of the mutated RBBP7 with histone H4. Decreased BRCA1 and increased γH2AX were observed in the proband. In mouse spermatogonial and pachytene spermatocyte-derived cells, deprivation of rbbp7 led to cell cycle arrest and apoptosis. In Drosophila, knockdown of RBBP7/Caf1-55 in germ cells resulted in complete absence of germ cells and reduced testis size, whereas knockdown of RBBP7/Caf1-55 in cyst cells resulted in hyperproliferative testicular cells. Interestingly, male infertility caused by Caf1-55 deficiency was rescued by ectopic expression of wild-type human RBBP7 but not mutant variants, suggesting the importance of RBBP7 in spermatogenesis. Our study provides insights into the mechanisms underlying the co-occurrence of MA and testicular tumors and may pave the way for innovative genetic diagnostics of these 2 diseases.
Topics: Animals; Humans; Male; Mice; Azoospermia; Infertility, Male; Mutation; Retinoblastoma-Binding Protein 7; Spermatogenesis; Testicular Neoplasms; Testis
PubMed: 37843278
DOI: 10.1172/JCI171541 -
Current Stem Cell Research & Therapy 2024The theory of cancer stem cells is a breakthrough discovery that offers exciting possibilities for comprehending the biological behavior of tumors. More and more... (Review)
Review
The theory of cancer stem cells is a breakthrough discovery that offers exciting possibilities for comprehending the biological behavior of tumors. More and more evidence suggests that retinoblastoma cancer stem cells promote tumor growth and are likely to be the origin of tumor formation, drug resistance, recurrence, and metastasis. At present, some progress has been made in the verification, biological behavior, and drug resistance mechanism of retinoblastoma cancer stem cells. This article aims to review the relevant research and explore future development direction.
Topics: Humans; Retinoblastoma; Neoplastic Stem Cells; Drug Resistance, Neoplasm; Animals; Retinal Neoplasms
PubMed: 37815190
DOI: 10.2174/011574888X252989230921065809 -
Indian Journal of Pediatrics Mar 2024Retinoblastoma (RB) is the most common intraocular tumor in childhood. It is mainly caused by mutations in both alleles of the RB1 tumor suppressor gene that is found on... (Review)
Review
Retinoblastoma (RB) is the most common intraocular tumor in childhood. It is mainly caused by mutations in both alleles of the RB1 tumor suppressor gene that is found on chromosome 13 and regulates the cell cycle. Approximately 8000 children are diagnosed with RB globally each year, with an estimated 1500 cases occurring in India. The survival rate of RB has improved to more than 90% in the developed world. Leukocoria and proptosis are the most common presenting features of RB in Asian Indian populations. Most cases of RB are diagnosed by fundus examination followed by ultrasound. The International Classification of Retinoblastoma is the most used scheme for the staging and classification of intraocular RB in India. Prenatal testing and preimplantation genetic testing for RB may be beneficial in high-risk families. Histopathologic risk factors such as massive choroidal invasion and post-laminar optic nerve help in predicting the occurrence of metastasis in children with RB, while presence of microscopic residual disease requires aggressive adjuvant treatment in eyes enucleated for group E RB. The review provides a consensus document on diagnosis and genetics of RB in India.
PubMed: 38492167
DOI: 10.1007/s12098-024-05085-2