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Annals of Oncology : Official Journal... Mar 2022For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL.
PATIENTS AND METHODS
ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group.
RESULTS
A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP.
CONCLUSIONS
In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Brentuximab Vedotin; Humans; Ki-1 Antigen; Lymphoma, T-Cell, Peripheral; Vincristine
PubMed: 34921960
DOI: 10.1016/j.annonc.2021.12.002 -
Molecular Therapy : the Journal of the... Oct 2019Non-coding RNAs (ncRNAs) are unique RNA transcripts that have been widely identified in the eukaryotic genome and have been shown to play key roles in the development of... (Review)
Review
Non-coding RNAs (ncRNAs) are unique RNA transcripts that have been widely identified in the eukaryotic genome and have been shown to play key roles in the development of many cancers. However, the rapid development of genome-wide translation profiling and ribosome profiling has revealed that a small number of small open reading frames (sORFs) within ncRNAs actually have peptide- or protein-coding potential. The peptides or proteins encoded by ncRNA (HOXB-AS3, encoded by long ncRNA [lncRNA]; FBXW7-185aa, PINT-87aa, and SHPRH-146aa, encoded by circular RNA [circRNA]; and miPEP-200a and miPEP-200b, encoded by primary miRNAs) have been shown to be critical players in cancer development and progression, through effects upon the regulation of glucose metabolism, the epithelial-to-mesenchymal transition, and the ubiquitination pathway. In this review, we summarize the reported peptides or proteins encoded by ncRNAs in cancer and explore the application of these peptides or proteins in the development of anti-tumor drugs and the identification of relevant therapeutic targets and tumor biomarkers.
Topics: Disease Progression; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Glucose; Humans; Neoplasms; Peptides; Proteins; RNA, Untranslated; Ubiquitination
PubMed: 31526596
DOI: 10.1016/j.ymthe.2019.09.001 -
Annals of Oncology : Official Journal... Sep 2022
Topics: Endometrial Neoplasms; Female; Follow-Up Studies; Humans; Medical Oncology
PubMed: 35690222
DOI: 10.1016/j.annonc.2022.05.009 -
Theranostics 2021Recently, long non-coding RNAs (lncRNAs), known to be involved in human cancer progression, have been shown to encode peptides with biological functions, but the role...
Recently, long non-coding RNAs (lncRNAs), known to be involved in human cancer progression, have been shown to encode peptides with biological functions, but the role of lncRNA-encoded peptides in cellular senescence is largely unexplored. We previously reported the tumor-suppressive role of PINT87aa, a peptide encoded by the long intergenic non-protein coding RNA, p53 induced transcript ( Here, we investigated PINT87aa's role in hepatocellular carcinoma (HCC) cellular senescence. We examined PINT87aa and truncated PINT87aa functions by monitoring cell proliferation and performed flow cytometry, senescence-associated β-galactosidase staining, JC-1 staining indicative of mitochondrial membrane potential, the ratio of the overlapping area of light chain 3 beta (LC3B) and mitochondrial probes and the ratio of lysosomal associated membrane protein 1 (LAMP1) overlapping with cytochrome c oxidase subunit 4I1 (COXIV) denoting mitophagy. PINT87aa and truncated PINT87aa functions were verified by subcutaneously transplanted tumors in nude mice. The possible binding between PINT87aa and forkhead box M1 (FOXM1) was predicted through structural analysis and verified by co-immunoprecipitation and immunofluorescence co-localization. Rescue experiments were performed following FOXM1 overexpression. Further, chromatin immunoprecipitation, polymerase chain reaction, and dual-luciferase reporter gene assay were conducted to validate FOXM1 binding to the () promoter. PINT87aa was significantly increased in the hydrogen peroxide-induced HCC cell senescence model. Overexpression of PINT87aa induced growth inhibition, cellular senescence, and decreased mitophagy and . In contrast, FOXM1 gain-of-function could partially reduce the proportion of senescent HCC cells and enhance mitophagy. PINT87aa overexpression did not affect the expression of FOXM1 itself but reduced that of its target genes involved in cell cycle and proliferation, especially which was involved in mitophagy and transcribed by FOXM1. Structural analysis indicated that PINT87aa could bind to the DNA-binding domain of FOXM1, which was confirmed by co-immunoprecipitation and immunofluorescence co-localization. Furthermore, we demonstrated that the 2 to 39 amino acid truncated form of the peptide exerted effects similarly to the full form. Our study established the role of PINT87aa as a novel biomarker and a key regulator of cellular senescence in HCC and identified PINT87aa as a potential therapeutic target for HCC.
Topics: Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Cellular Senescence; Electron Transport Complex IV; Forkhead Box Protein M1; Hep G2 Cells; Humans; Liver Neoplasms; Lysosomal Membrane Proteins; Mice; Mice, Nude; Microtubule-Associated Proteins; Mitophagy; Neoplasm Transplantation; Peptides; Prohibitins; RNA, Long Noncoding; Repressor Proteins
PubMed: 33754036
DOI: 10.7150/thno.55672 -
Nature Communications Oct 2018Circular RNAs (circRNAs) are a large class of transcripts in the mammalian genome. Although the translation of circRNAs was reported, additional coding circRNAs and the...
Circular RNAs (circRNAs) are a large class of transcripts in the mammalian genome. Although the translation of circRNAs was reported, additional coding circRNAs and the functions of their translated products remain elusive. Here, we demonstrate that an endogenous circRNA generated from a long noncoding RNA encodes regulatory peptides. Through ribosome nascent-chain complex-bound RNA sequencing (RNC-seq), we discover several peptides potentially encoded by circRNAs. We identify an 87-amino-acid peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) that suppresses glioblastoma cell proliferation in vitro and in vivo. This peptide directly interacts with polymerase associated factor complex (PAF1c) and inhibits the transcriptional elongation of multiple oncogenes. The expression of this peptide and its corresponding circRNA are decreased in glioblastoma compared with the levels in normal tissues. Our results establish the existence of peptides encoded by circRNAs and demonstrate their potential functions in glioblastoma tumorigenesis.
Topics: Animals; Carcinogenesis; Cell Cycle; Cell Line; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Nuclear Proteins; Oncogenes; Peptides; RNA; RNA, Circular; RNA, Long Noncoding; Sequence Deletion; Survival Analysis; Tissue Distribution; Transcription Elongation, Genetic; Transcription Factors
PubMed: 30367041
DOI: 10.1038/s41467-018-06862-2 -
International Journal of Molecular... Jan 2023Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and... (Review)
Review
Aquaporin-5 (AQP5), belonging to the aquaporins (AQPs) family of transmembrane water channels, facilitates osmotically driven water flux across biological membranes and the movement of hydrogen peroxide and CO. Various mechanisms have been shown to dynamically regulate AQP5 expression, trafficking, and function. Besides fulfilling its primary water permeability function, AQP5 has been shown to regulate downstream effectors playing roles in various cellular processes. This review provides a comprehensive overview of the current knowledge of the upstream and downstream effectors of AQP5 to gain an in-depth understanding of the physiological and pathophysiological processes involving AQP5.
Topics: Aquaporin 5; Aquaporins; Cell Membrane; Permeability; Water
PubMed: 36768212
DOI: 10.3390/ijms24031889 -
Cancer Oct 2021TP53 mutation (TP53 ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients;...
BACKGROUND
TP53 mutation (TP53 ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).
METHODS
Patients with newly diagnosed AML received decitabine 20 mg/m for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53 was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.
RESULTS
Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53 AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53 AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53 versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53 AML were comparable to historical results with 10-day decitabine alone.
CONCLUSIONS
Patients with TP53 AML have lower response rates and shorter survival with DEC10-VEN.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Sulfonamides; Tumor Suppressor Protein p53
PubMed: 34255353
DOI: 10.1002/cncr.33689 -
Journal of Biomedical Science Jun 2022Salivary gland (SG) dysfunction impairs the life quality of many patients, such as patients with radiation therapy for head and neck cancer and patients with Sjögren's... (Review)
Review
Salivary gland (SG) dysfunction impairs the life quality of many patients, such as patients with radiation therapy for head and neck cancer and patients with Sjögren's syndrome. Multiple SG engineering strategies have been considered for SG regeneration, repair, or whole organ replacement. An in-depth understanding of the development and differentiation of epithelial stem and progenitor cells niche during SG branching morphogenesis and signaling pathways involved in cell-cell communication constitute a prerequisite to the development of suitable bioengineering solutions. This review summarizes the essential bioengineering features to be considered to fabricate an engineered functional SG model using various cell types, biomaterials, active agents, and matrix fabrication methods. Furthermore, recent innovative and promising approaches to engineering SG models are described. Finally, this review discusses the different challenges and future perspectives in SG bioengineering.
Topics: Bioengineering; Humans; Regeneration; Salivary Glands; Stem Cells; Tissue Engineering
PubMed: 35668440
DOI: 10.1186/s12929-022-00819-w -
Biomedicine & Pharmacotherapy =... Mar 2021Osteosarcoma is rare malignancy of childhood and adolescence, with high morbidity and mortality despite accomplishment of diverse therapeutic modalities. Identification... (Review)
Review
Osteosarcoma is rare malignancy of childhood and adolescence, with high morbidity and mortality despite accomplishment of diverse therapeutic modalities. Identification of the underlying mechanism of osteosarcoma evolution would help in better management of this rare malignancy. Lots of investigations have described abnormal regulation of long non-coding RNAs (lncRNAs) in clinical specimens of osteosarcoma and the established cell lines. This malignancy has been associated with over-expression of TUG1, LOXL1-AS1, MIR100HG, NEAT1, HULC, ANRIL and a number of other lncRNAs, while under-expression of lots of lncRNAs including LncRNA-p21, FER1L4, GAS5, LncRNA NR_136400 and LINC-PINT. Expression amounts of LUCAT1, LINC00922, SNHG12, FOXC2-AS1 and OIP5-AS1 lncRNAs have been associated with response to a number of chemotherapeutic agents. Taken together, lncRNAs are possible targets for proposing novel advanced therapeutic modalities for osteosarcoma.
Topics: Animals; Bone Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Osteosarcoma; RNA, Long Noncoding; Signal Transduction
PubMed: 33433358
DOI: 10.1016/j.biopha.2021.111217 -
Cell Death & Disease May 2021Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and...
Radioresistance continues to be the leading cause of recurrence and metastasis in nasopharyngeal cancer. Long noncoding RNAs are emerging as regulators of DNA damage and radioresistance. LINC-PINT was originally identified as a tumor suppressor in various cancers. In this study, LINC-PINT was significantly downregulated in nasopharyngeal cancer tissues than in rhinitis tissues, and low LINC-PINT expressions showed poorer prognosis in patients who received radiotherapy. We further identified a functional role of LINC-PINT in inhibiting the malignant phenotypes and sensitizing cancer cells to irradiation in vitro and in vivo. Mechanistically, LINC-PINT was responsive to DNA damage, inhibiting DNA damage repair through ATM/ATR-Chk1/Chk2 signaling pathways. Moreover, LINC-PINT increased radiosensitivity by interacting with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and negatively regulated the expression and recruitment of DNA-PKcs. Therefore, these findings collectively support the possibility that LINC-PINT serves as an attractive target to overcome radioresistance in NPC.
Topics: Cell Line, Tumor; Cell Proliferation; DNA Damage; DNA Repair; DNA-Activated Protein Kinase; Humans; Nasopharyngeal Neoplasms; RNA, Long Noncoding
PubMed: 33963177
DOI: 10.1038/s41419-021-03728-2