bims-ectoca 2025-01-12 papers

Issue of 2025–01–12
three papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Int J Mol Sci. 2024 Dec 20. pii: 13657. [Epub ahead of print]25(24):

Whole-Exome Analysis and Osteosarcoma: A Game Still Open.

Caterina Chiappetta, Carlo Della Rocca, Claudio Di Cristofano.

Osteosarcoma (OS) is the most prevalent malignant bone tumor in adolescents and young adults. OS cells grow in a permissive local microenvironment which modulates their behavior and facilitates all steps in tumor development (e.g., proliferation/quiescence, invasion/migration, and drug resistance) and contributes to their intrinsic heterogeneity. The lung parenchyma is the most common metastatic site in OS, and metastatic foci are frequently associated with a poor clinical outcome. Although multiple factors may be responsible for the disease, including genetic mutations (e.g., Rb and p53), the molecular mechanism of development of OS remains unclear, and the conventional treatment for OS is still based on a sequential approach that combines chemotherapy and surgery. Also, despite the increase in clinical trials, the survival rates for OS have not improved. Non-specific targeting therapies thus show poor therapeutic effects, along with side effects at high doses. For these reasons, many efforts have been made to characterize the complex genome of OS thanks to the whole-exome analysis, with the aim of identifying predictive biomarkers to give these patients a better therapeutic option. This review aims to summarize and discuss the main recent advances in OS molecular research for precision medicine.

Keywords: immunotherapy; next-generation sequencing; osteosarcoma; tumor targeted therapy

DOI: https://doi.org/10.3390/ijms252413657

Int J Mol Sci. 2024 Dec 19. pii: 13607. [Epub ahead of print]25(24):

Divergent Contribution of Cytoplasmic Actins to Nuclear Structure of Lung Cancer Cells.

Galina Shagieva, Vera Dugina, Anton Burakov, Yulia Levuschkina, Dmitry Kudlay, Sergei Boichuk, Natalia Khromova, Maria Vasileva, Pavel Kopnin.

A growing body of evidence suggests that actin plays a role in nuclear architecture, genome organisation, and regulation. Our study of human lung adenocarcinoma cells demonstrates that the equilibrium between actin isoforms affects the composition of the nuclear lamina, which in turn influences nuclear stiffness and cellular behaviour. The downregulation of β-actin resulted in an increase in nuclear area, accompanied by a decrease in A-type lamins and an enhancement in lamin B2. In contrast, the suppression of γ-actin led to upregulation of the lamin A/B ratio through an increase in A-type lamins. Histone H3 post-translational modifications display distinct patterns in response to decreased actin isoform expression. The level of dimethylated H3K9me2 declined while acetylated H3K9ac increased in β-actin-depleted A549 cells. In contrast, the inhibition of γ-actin expression resulted in a reduction in H3K9ac. Based on our observations, we propose that β-actin plays a role in chromatin compaction and deactivation, and is involved in the elevation of nuclear stiffness through the control of the lamins ratio. The non-muscle γ-actin is presumably responsible for chromatin decondensation and activation. The identification of novel functions for actin isoforms offers insights into the mechanisms through which they influence cell fate during development and cancer progression.

Keywords: chromatin; histone; lamin; nucleus; β-actin; γ-actin

DOI: https://doi.org/10.3390/ijms252413607

Radiat Oncol. 2025 Jan 09. 20(1): 6

Effects of EGFR-TKIs combined with intracranial radiotherapy in EGFR-mutant non-small cell lung cancer patients with brain metastases: a retrospective multi-institutional analysis.

Mingfeng He, Xue Wu, Li Li, Guangming Yi, Yitian Wang, Hengqiu He, Ying Ye, Ruiqin Zhou, Zaicheng Xu, Zhenzhou Yang.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) are prone to developing brain metastases (BMs), particularly those with epidermal growth factor receptor (EGFR) mutations. In clinical practice, treatment-naïve EGFR-mutant NSCLC patients with asymptomatic BMs tend to choose EGFR-tyrosine kinase inhibitors (TKIs) as first-line therapy and defer intracranial radiotherapy (RT). However, the effectiveness of upfront intracranial RT remains unclear.
METHODS: This was a retrospective study including 217 patients from two institutions between January 2018 and December 2022. Clinical data of NSCLC patients with BMs who received EGFR-TKIs were collected. The patients were assigned to one of the three groups according to the therapeutic modality used: the upfront TKI + stereotactic radiosurgery (SRS) / fractionated stereotactic radiotherapy (fSRS) group (upfront TKI + SRS/fSRS ), the upfront TKI + whole-brain radiotherapy (WBRT) group (upfront TKI + WBRT) and the upfront TKI group.
RESULTS: As of March 8, 2023, the median follow-up duration was 37.3 months (95% CI, 32.5-42.1). The median overall survival (OS) for the upfront TKI + SRS/fSRS, upfront TKI + WBRT, and upfront TKI groups were 37.8, 20.7, and 24.1 months, respectively (p = 0.015). In subgroup analysis, the upfront TKI + SRS/fSRS group demonstrated longer OS compared to the upfront TKI + WBRT and upfront TKI groups in patients treated with first or second-generation EGFR-TKIs (p = 0.021) and patients with L858R mutation (p = 0.017), whereas no survival benefit was observed in three-generation EGFR-TKIs or 19del subgroup. In the multivariable analysis, metachronous BMs, EGFR L858R mutation and nonclassic EGFR mutation were identified as independent risk factors for OS, while a DS-GPA score of 2.0-4.0 was the only independent protective factor.
CONCLUSIONS: This study demonstrated that upfront addition of SRS/fSRS to EGFR-TKIs was associated with longer OS compared to upfront WBRT or upfront TKI alone in EGFR-mutant NSCLC patients with BMs. This improvement was more significant in patients with L858R mutation and those treated with first or second-generation EGFR-TKIs. Further research with a larger sample size is warranted.

Keywords: Brain metastases; EGFR-TKI; Intracranial radiotherapy; Non-small-cell lung cancer; Overall survival

DOI: https://doi.org/10.1186/s13014-024-02578-4