Heterogeneity and dynamic of EMT through the plasticity of ribosome and mRNA translation

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2022, Номер 1877(3), С. 188718 - 188718

Опубликована: Март 15, 2022

Язык: Английский

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A Randomized Multi-institutional Phase II Trial of Everolimus as Adjuvant Therapy in Patients with Locally Advanced Squamous Cell Cancer of the Head and Neck

Clinical Cancer Research, Год журнала: 2022, Номер 28(23), С. 5040 - 5048

Опубликована: Окт. 4, 2022

Investigate whether adjuvant everolimus, an mTOR inhibitor, improves progression-free survival (PFS) in advanced-stage head and neck squamous cell carcinoma (HNSCC) provide outcomes related to correlative biological factors associated with disease control.This was a prospective, randomized, double-blind phase II trial of patients HNSCC from 13 institutions who were confirmed disease-free post-definitive therapy enrolled between December 2010 March 2015. Patients received everolimus or placebo daily (10 mg, oral) for maximum 1 year. p16 IHC as surrogate marker human papillomavirus infection whole-exome sequencing performed. Cox proportional hazard models estimated rates. Log-rank tests evaluated differences survival. The primary endpoint PFS. Secondary endpoints objectives included overall (OS) toxicity assessment.52 [median (range) age, 58 (37-76) years; 43 men (83%), 9 women (17%)] randomized (n = 24) 28). PFS favored but not significant [log-rank P 0.093; HR 0.44; 95% confidence interval (CI), 0.17-1.17]. There no difference OS (P 0.29; 0.57; CI, 0.20-16.2). Everolimus resulted improvement p16-negative 31; 0.031; 0.26; 0.07-0.97), although subgroup analysis showed p16-positive 21; 0.93). Further, significantly higher TP53-mutated (TP53mut) treated compared (log-rank 0.027; 0.24; 0.06-0.95). No treatment seen TP53 wild-type tumors 0.79).p16-negative TP53mut may benefit everolimus.

Язык: Английский

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Exploring the pan-cancer landscape of posttranscriptional regulation

Cell Reports, Год журнала: 2023, Номер 42(10), С. 113172 - 113172

Опубликована: Сен. 25, 2023

Understanding the mechanisms underlying cancer gene expression is critical for precision oncology. Posttranscriptional regulation a key determinant of protein abundance and cell behavior. However, to what extent posttranscriptional regulatory impact levels progression an ongoing question. Here, we exploit proteogenomics data systematically compare mRNA-protein correlations across 14 different human types. We identify two clusters genes with particularly low all types, shed light on role driver drug targets, unveil cohort 55 mutations that alter systems-wide regulation. Surprisingly, find decreased control in patients correlate shorter overall survival multiple prompting further mechanistic studies into how affects patient outcomes. Our findings underscore importance comprehensive understanding landscape predicting progression.

Язык: Английский

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Early Onset Colorectal Cancer: An Emerging Cancer Risk in Patients with Diamond Blackfan Anemia

Genes, Год журнала: 2021, Номер 13(1), С. 56 - 56

Опубликована: Дек. 26, 2021

Diamond Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome, the founding member of class disorders known as ribosomopathies. Most cases result from loss function mutations or deletions in 1 23 genes encoding either small large subunit-associated ribosomal protein (RP), resulting RP haploinsufficiency. DBA characterized by red cell hypoplasia aplasia, poor linear growth and congenital anomalies. Small case series reports demonstrate to be cancer predisposition syndrome. Recent analyses Anemia Registry North America (DBAR) have quantified risk DBA. These studies reveal most prevalent solid tumor, presenting young adults children adolescents, colorectal (CRC) osteogenic sarcoma, respectively. Of concern that these cancers are typically detected at an advanced stage patients who, because their constitutional failure, may not tolerate full-dose chemotherapy. Thus, inability provide optimal therapy contributes outcomes. CRC screening individuals over age 50 years, now 45 has led early detection significant improvements outcomes for non-DBA with CRC. surveillance strategies been adapted detect familial onset With recognition moderately penetrant syndrome rational strategy will implemented. The downstream molecular events, haploinsufficiency leading cancer, subject scientific inquiry.

Язык: Английский

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An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Янв. 11, 2024

Summary Many neurodevelopmental defects are linked to perturbations in genes involved housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions can result tissue and developmental specific remains a mystery. Here we describe new allelic variants the factor AIRIM primarily associated with disorders. Using human cerebral organoids combination proteomic analysis, single-cell transcriptome analysis across multiple stages, single organoid translatome identify previously unappreciated mechanism linking changes levels timing of cell fate specification during early brain development. We find decrease neuroepithelial differentiation, making differentiating cells particularly vulnerable this time. Reduced availability more profoundly impacts translation transcripts, disrupting both survival commitment transitioning neuroepithelia. Enhancing mTOR activity by genetic pharmacologic approaches ameliorates growth intellectual disability variants, identifying potential treatment options for ribosomopathies. This work reveals cellular molecular origins protein synthesis defect-related disorders Highlights reduce specifically neural progenitor cells. Inappropriately low cause transient delay radial glia commitment. impair selected subset mRNAs. Genetic activation mTORC1 suppresses AIRIM-linked phenotypes.

Язык: Английский

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