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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 -
Acta Medica Philippina 2024Retinoblastoma is the most common intraocular cancer in childhood in the Philippines. Most data though on demographics, clinical profile, treatment options, and outcomes...
BACKGROUND
Retinoblastoma is the most common intraocular cancer in childhood in the Philippines. Most data though on demographics, clinical profile, treatment options, and outcomes in the country are from the National Capital Region.
OBJECTIVES
This study aimed to describe the demographics, clinical profile, treatment done, and outcomes of retinoblastoma patients seen in a public tertiary referral center in Davao from 2011-2020 to make available literature more representative of the status of retinoblastoma in the Philippines.
METHODS
An analytical cross-sectional study was conducted using the records of retinoblastoma patients seen in a tertiary government hospital located in Davao Region from January 2011 to December 2020.
RESULTS
There were 157 patients included in the analysis. Seventy-three (46%) were female with 44% coming from the Davao Region. One hundred seven (69%) patients had unilateral disease. Median age at initial consultation for patients with unilateral disease was significantly older than those with bilateral disease (p<0.003). Tumors were extraocular in 82 (40%) eyes. In the intraocular group, 36% of the eyes belonged to International Classification of Retinoblastoma (ICRB) Groups D and E. Enucleation was the most commonly performed treatment. Survival rate was 28%.This is the first report to provide epidemiologic and clinical data on retinoblastoma in the literature, including survival data, from Mindanao. Advanced stages and extraocular cases of retinoblastoma remain high. Delay of consultation contributed to the prognosis and clinical outcome of the disease.
CONCLUSION
Advanced stages and extraocular cases of retinoblastoma remain significantly high in the country, even in Mindanao.
PubMed: 38846169
DOI: 10.47895/amp.vi0.6754 -
Journal of Experimental & Clinical... May 2024RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease...
BACKGROUND
RNA modifications of transfer RNAs (tRNAs) are critical for tRNA function. Growing evidence has revealed that tRNA modifications are related to various disease processes, including malignant tumors. However, the biological functions of methyltransferase-like 1 (METTL1)-regulated mG tRNA modifications in breast cancer (BC) remain largely obscure.
METHODS
The biological role of METTL1 in BC progression were examined by cellular loss- and gain-of-function tests and xenograft models both in vitro and in vivo. To investigate the change of mG tRNA modification and mRNA translation efficiency in BC, mG-methylated tRNA immunoprecipitation sequencing (mG tRNA MeRIP-seq), Ribosome profiling sequencing (Ribo-seq), and polysome-associated mRNA sequencing were performed. Rescue assays were conducted to decipher the underlying molecular mechanisms.
RESULTS
The tRNA mG methyltransferase complex components METTL1 and WD repeat domain 4 (WDR4) were down-regulated in BC tissues at both the mRNA and protein levels. Functionally, METTL1 inhibited BC cell proliferation, and cell cycle progression, relying on its enzymatic activity. Mechanistically, METTL1 increased mG levels of 19 tRNAs to modulate the translation of growth arrest and DNA damage 45 alpha (GADD45A) and retinoblastoma protein 1 (RB1) in a codon-dependent manner associated with mG. Furthermore, in vivo experiments showed that overexpression of METTL1 enhanced the anti-tumor effectiveness of abemaciclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor.
CONCLUSION
Our study uncovered the crucial tumor-suppressive role of METTL1-mediated tRNA mG modification in BC by promoting the translation of GADD45A and RB1 mRNAs, selectively blocking the G2/M phase of the cell cycle. These findings also provided a promising strategy for improving the therapeutic benefits of CDK4/6 inhibitors in the treatment of BC patients.
Topics: Humans; Breast Neoplasms; Female; Mice; Animals; Methyltransferases; RNA, Transfer; Methylation; Cell Line, Tumor; Cell Proliferation; Carcinogenesis; Cell Cycle Checkpoints; Protein Biosynthesis; Xenograft Model Antitumor Assays; Mice, Nude
PubMed: 38822363
DOI: 10.1186/s13046-024-03076-x -
JACS Au May 2024Cyclin-dependent kinases (CDKs), particularly CDK4 and CDK2, are crucial for cell cycle progression from the Gap 1 (G1) to the Synthesis (S) phase by phosphorylating...
Cyclin-dependent kinases (CDKs), particularly CDK4 and CDK2, are crucial for cell cycle progression from the Gap 1 (G1) to the Synthesis (S) phase by phosphorylating targets such as the Retinoblastoma Protein (Rb). CDK4, paired with cyclin-D, operates in the long G1 phase, while CDK2 with cyclin-E, manages the brief G1-to-S transition, enabling DNA replication. Aberrant CDK signaling leads to uncontrolled cell proliferation, which is a hallmark of cancer. Exactly how they accomplish their catalytic phosphorylation actions with distinct efficiencies poses the fundamental, albeit overlooked question. Here we combined available experimental data and modeling of the active complexes to establish their conformational functional landscapes to explain how the two cyclin/CDK complexes differentially populate their catalytically competent states for cell cycle progression. Our premise is that CDK could be more important for cell cycle progression than the cyclin-CDK biochemical binding specificity and that efficiency is likely the prime determinant of cell cycle progression. We observe that CDK4 is more dynamic than CDK2 in the ATP binding site, the regulatory spine, and the interaction with its cyclin partner. The N-terminus of cyclin-D acts as an allosteric regulator of the activation loop and the ATP-binding site in CDK4. Integrated with a suite of experimental data, we suggest that the CDK4 complex is less capable of remaining in the active catalytically competent conformation, and may have a lower catalytic efficiency than CDK2, befitting their cell cycle time scales, and point to critical residues and motifs that drive their differences. Our mechanistic landscape may apply broadly to kinases, and we propose two drug design strategies: (i) allosteric Inhibition by conformational stabilization for targeting allosteric CDK4 regulation by cyclin-D, and (ii) dynamic entropy-optimized targeting which leverages the dynamic, entropic aspects of CDK4 to optimize drug binding efficacy.
PubMed: 38818077
DOI: 10.1021/jacsau.4c00138 -
TouchREVIEWS in Endocrinology Apr 2024Previous studies have suggested that corticotroph tumours are associated with the overexpression of cyclin E and that the inactivation of cyclin-dependent kinases, which...
Previous studies have suggested that corticotroph tumours are associated with the overexpression of cyclin E and that the inactivation of cyclin-dependent kinases, which activate cyclin E, may have antisecretory and antiproliferative effects. Seliciclib, also known as R-roscovitine, is a pituitary-targeting agent shown to inhibit the growth of corticotroph tumour cells via cyclin E and retinoblastoma protein-mediated pathways. A recent study investigated the role of seliciclib in regulating biochemical parameters in a small number of patients with Cushing's disease, providing preliminary data on its possible therapeutic effectiveness in treating this disorder.
PubMed: 38812663
DOI: 10.17925/EE.2023.20.1.4 -
World Journal of Clinical Cases May 2024Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can...
Neuroendocrine prostate cancer (NEPC) shows an aggressive behavior compared to prostate cancer (PCa), also known as prostate adenocarcinoma. Scanty foci in PCa can harbor genetic alternation that can arise in a heterogeneity of prostate cancer. NEPC may arise or develop following androgen deprivation therapy (ADT). NEPC that arise following ADT has the nomenclature "treatment-emerging/induced NEPC (t-NEPC)". t-NEPC would be anticipated in castration resistant prostate cancer (CRPC) and metastatic PCa. t-NEPC is characterized by low or absent androgen receptor (AR) expression, independence of AR signaling, and gain of neuroendocrine phenotype. t-NEPC is an aggressive metastatic tumor, develops from PCa in response to drug induced ADT, and shows very short response to conventional therapy. t-NEPC occurs in 10%-17% of patients with CRPC. NEPC is rare and is accounting for less than 2% of all PCa. The molecular mechanisms underlying the trans-differentiation from CRPC to t-NEPC are not fully elucidated. Sphingosine kinase 1 plays a significant role in t-NEPC development. Although neuroendocrine markers: Synaptophysin, chromogranin A, and insulinoma associated protein 1 () are expressed in t-NEPC, they are non-specific for diagnosis, prognosis, and follow-up of therapy. t-NEPC shows enriched genomic alteration in tumor protein P53 () and retinoblastoma 1 (). There are evidences suggest that t-NEPC might develop through epigenetic evolution. There are genomic, epigenetic, and transcriptional alterations that are reported to be involved in development of t-NEPC. Knock-outs of and were found to contribute in development of t-NEPC. PCa is resistant to immunotherapy, and at present there are running trials to approach immunotherapy for PCa, CRPC, and t-NEPC.
PubMed: 38808339
DOI: 10.12998/wjcc.v12.i13.2143 -
Indian Journal of Ophthalmology Jun 2024Retinoblastoma is the most common pediatric ocular malignancy. It is triggered by a biallelic mutation in the RB1 gene or MYCN oncogene amplification. Retinoblastomas... (Review)
Review
Retinoblastoma is the most common pediatric ocular malignancy. It is triggered by a biallelic mutation in the RB1 gene or MYCN oncogene amplification. Retinoblastomas can be unilateral (60%-70%) or bilateral (30%-40%); bilateral tumors are always heritable and present at an earlier age as compared to unilateral ones (18-24 months vs. 36 months in India). High prevalence rates, delayed presentation, and inaccessibility to healthcare lead to worse outcomes in developing countries. The past few decades have seen a paradigm change in the treatment of retinoblastomas, shifting from enucleation and external beam radiotherapy to less aggressive modalities for eye salvage. Multimodality treatment is now the standard of care and includes intraarterial or intravenous chemotherapy along with focal consolidation therapies such as transpupillary thermotherapy, cryotherapy, and laser photocoagulation. Intravitreal and intracameral chemotherapy can help in controlling intraocular seeds. Advanced extraocular or metastatic tumors still have a poor prognosis. Genetic testing, counseling, and screening of at-risk family members must be incorporated as essential parts of management. A better understanding of the genetics and molecular basis of retinoblastoma has opened up the path for potential targeted therapy in the future. Novel recent advances such as liquid biopsy, prenatal diagnosis, prognostic biomarkers, tylectomy, and chemoplaque point to promising future directions.
Topics: Humans; Retinoblastoma; Retinal Neoplasms; Global Health; Combined Modality Therapy
PubMed: 38804799
DOI: 10.4103/IJO.IJO_2414_23 -
The Lancet Regional Health. Europe Apr 2024Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability...
BACKGROUND
Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.
METHODS
gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.
FINDINGS
The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).
INTERPRETATION
Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
FUNDING
The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
PubMed: 38803632
DOI: 10.1016/j.lanepe.2024.100881 -
BioRxiv : the Preprint Server For... May 2024Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained...
UNLABELLED
Ovarian cancer remains a major health threat with limited treatment options available. It is characterized by immunosuppressive tumor microenvironment (TME) maintained by tumor- associated macrophages (TAMs) hindering anti-tumor responses and immunotherapy efficacy. Here we show that targeting retinoblastoma protein (Rb) by disruption of its LxCxE cleft pocket, causes cell death in TAMs by induction of ER stress, p53 and mitochondria-related cell death pathways. A reduction of pro-tumor Rb M2-type macrophages from TME in vivo enhanced T cell infiltration and inhibited cancer progression. We demonstrate an increased Rb expression in TAMs in women with ovarian cancer is associated with poorer prognosis. Ex vivo, we show analogous cell death induction by therapeutic Rb targeting in TAMs in post-surgery ascites from ovarian cancer patients. Overall, our data elucidates therapeutic targeting of the Rb LxCxE cleft pocket as a novel promising approach for ovarian cancer treatment through depletion of TAMs and re-shaping TME immune landscape.
STATEMENT OF SIGNIFICANCE
Currently, targeting immunosuppressive myeloid cells in ovarian cancer microenvironment is the first priority need to enable successful immunotherapy, but no effective solutions are clinically available. We show that targeting LxCxE cleft pocket of Retinoblastoma protein unexpectedly induces preferential cell death in M2 tumor-associated macrophages. Depletion of immunosuppressive M2 tumor-associated macrophages reshapes tumor microenvironment, enhances anti-tumor T cell responses, and inhibits ovarian cancer. Thus, we identify a novel paradoxical function of Retinoblastoma protein in regulating macrophage viability as well as a promising target to enhance immunotherapy efficacy in ovarian cancer.
PubMed: 38798466
DOI: 10.1101/2024.05.10.593562 -
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