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International Journal of Molecular... Feb 2024The N6-methyladenosine (M6A) modification is the most common internal chemical modification of RNA molecules in eukaryotes. This modification can affect mRNA metabolism,... (Review)
Review
The N6-methyladenosine (M6A) modification is the most common internal chemical modification of RNA molecules in eukaryotes. This modification can affect mRNA metabolism, regulate RNA transcription, nuclear export, splicing, degradation, and translation, and significantly impact various aspects of physiology and pathobiology. Radiotherapy is the most common method of tumor treatment. Different intrinsic cellular mechanisms affect the response of cells to ionizing radiation (IR) and the effectiveness of cancer radiotherapy. In this review, we summarize and discuss recent advances in understanding the roles and mechanisms of RNA M6A methylation in cellular responses to radiation-induced DNA damage and in determining the outcomes of cancer radiotherapy. Insights into RNA M6A methylation in radiation biology may facilitate the improvement of therapeutic strategies for cancer radiotherapy and radioprotection of normal tissues.
Topics: Humans; Methylation; RNA; Neoplasms; DNA Repair
PubMed: 38473842
DOI: 10.3390/ijms25052597 -
Cancer Letters Oct 2023Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of...
Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity.
Topics: Cisplatin; Animals; Humans; Pyridines; Benzamides; Cell Line, Tumor; Y-Box-Binding Protein 1; Pleural Neoplasms; Xenograft Model Antitumor Assays; Drug Synergism; Mesothelioma; Mice; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Mice, Nude; Antineoplastic Agents; Acetylation; Female; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 37730104
DOI: 10.1016/j.canlet.2023.216395 -
Tumor hypoxia and radiotherapy: A major driver of resistance even for novel radiotherapy modalities.Seminars in Cancer Biology Jan 2024Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced... (Review)
Review
Hypoxia in solid tumors is an important predictor of poor clinical outcome to radiotherapy. Both physicochemical and biological processes contribute to a reduced sensitivity of hypoxic tumor cells to ionizing radiation and hypoxia-related treatment resistances. A conventional low-dose fractionated radiotherapy regimen exploits iterative reoxygenation in between the individual fractions, nevertheless tumor hypoxia still remains a major hurdle for successful treatment outcome. The technological advances achieved in image guidance and highly conformal dose delivery make it nowadays possible to prescribe larger doses to the tumor as part of single high-dose or hypofractionated radiotherapy, while keeping an acceptable level of normal tissue complication in the co-irradiated organs at risk. However, we insufficiently understand the impact of tumor hypoxia to single high-doses of RT and hypofractionated RT. So-called FLASH radiotherapy, which delivers ionizing radiation at ultrahigh dose rates (> 40 Gy/sec), has recently emerged as an important breakthrough in the radiotherapy field to reduce normal tissue toxicity compared to irradiation at conventional dose rates (few Gy/min). Not surprisingly, oxygen consumption and tumor hypoxia also seem to play an intriguing role for FLASH radiotherapy. Here we will discuss the role of tumor hypoxia for radiotherapy in general and in the context of novel radiotherapy treatment approaches.
Topics: Humans; Tumor Hypoxia; Neoplasms; Radiation Dose Hypofractionation; Hypoxia; Treatment Outcome
PubMed: 38040401
DOI: 10.1016/j.semcancer.2023.11.006 -
Journal of Translational Medicine Nov 2023
Topics: Immunity; Radiotherapy; Humans
PubMed: 37968688
DOI: 10.1186/s12967-023-04692-5 -
Cells Sep 2023Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by a high resistance to conventional chemotherapy, late diagnosis, and a high... (Review)
Review
Hepatocellular carcinoma (HCC) is one of the most frequent cancers in humans, characterised by a high resistance to conventional chemotherapy, late diagnosis, and a high mortality rate. It is necessary to elucidate the molecular mechanisms involved in hepatocarcinogenesis to improve diagnosis and treatment outcomes. The Runt-related (RUNX) family of transcription factors (RUNX1, RUNX2, and RUNX3) participates in cardinal biological processes and plays paramount roles in the pathogenesis of numerous human malignancies. Their role is often controversial as they can act as oncogenes or tumour suppressors and depends on cellular context. Evidence shows that deregulated genes may be involved in hepatocarcinogenesis from the earliest to the latest stages. In this review, we summarise the topical evidence on the roles of gene family members in HCC. We discuss their possible application as non-invasive molecular markers for early diagnosis, prognosis, and development of novel treatment strategies in HCC patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Oncogenes; Carcinogenesis; Dwarfism
PubMed: 37759525
DOI: 10.3390/cells12182303 -
Radiotherapy and Oncology : Journal of... Oct 2023Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects...
BACKGROUND AND PURPOSE
Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy.
MATERIALS AND METHODS
A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure.
RESULTS
Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10), rs75912034 (p = 1.12 × 10), rs145328458 (p = 1.06 × 10) and rs61966612 (p = 1.23 × 10), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10) and rs34063419 (p = 1.21 × 10), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level.
CONCLUSIONS
This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.
Topics: Humans; Female; Breast Neoplasms; Genome-Wide Association Study; Cohort Studies; Prospective Studies; Radiation Injuries; Polymorphism, Single Nucleotide
PubMed: 37437607
DOI: 10.1016/j.radonc.2023.109806 -
Cancers Dec 2023Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but... (Review)
Review
Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but could also be secondary to the anticancer treatments. With the goal of offering a multidisciplinary approach to guaranteeing optimal cancer therapy and the early detection of related cardiac diseases, and in light of the recent ESC Cardio-Oncology Guideline recommendations, we developed a Cardio-Oncology unit devoted to the prevention and management of these specific complications. This document brings together important aspects to consider for the development and organization of a Cardio-Oncology program through our own experience and the current evidence.
PubMed: 38136428
DOI: 10.3390/cancers15245885 -
BMC Immunology Aug 2023New combinations based on standard therapeutic modalities and immunotherapy require understanding the immunomodulatory properties of traditional treatments. The...
BACKGROUND
New combinations based on standard therapeutic modalities and immunotherapy require understanding the immunomodulatory properties of traditional treatments. The objective was to evaluate the impact of brachytherapy (BT) on the immune system of cervical cancer and to identify the best modality, High-dose-rate brachytherapy (HDR-BT) vs. Pulsed-dose-rate (PDR-BT), to target it.
METHODS
Nineteen patients enrolled in a prospective study received chemoradiation (CRT) and subsequently HDR-BT or PDR-BT. Peripheral blood samples were obtained for immunophenotyping analysis by flow-cytometry before CRT, BT, and two and four weeks after BT. The Friedman one-way ANOVA, Conover post hoc test, and the Wilcoxon signed-rank test were used to compare changes in cell populations at different periods, perform multiple pairwise comparisons and assess differences between treatment groups (PDR and HDR).
RESULTS
Natural killer cells (NKs) were the best target for BT. Patients receiving HDR-BT achieved significantly higher values and longer time of the CD56dimCD16 + NK cells with greater cytotoxic capacity than the PDR-BT group, which presented their highest elevation of CD56-CD16 + NK cells. Furthermore, both BT modalities were associated with an increase in myeloid-derived suppressor cells (MDSCs), related to a worse clinical prognosis. However, there was a decrease in the percentage of CD4 + CD25 + Foxp3 + CD45RA + regulatory T cells (Tregs) in patients receiving HDR-BT, although there were no significant differences between BT.
CONCLUSIONS
Immune biomarkers are important predictive determinants in cervical cancer. Higher cytotoxic NK cells and a trend toward lower values of Tregs might support the use of HDR-BT to the detriment of PDR-BT and help develop effective combinations with immunotherapy.
Topics: Brachytherapy; Humans; Female; Middle Aged; Uterine Cervical Neoplasms; Myeloid-Derived Suppressor Cells; Killer Cells, Natural; T-Lymphocytes, Regulatory; Prospective Studies
PubMed: 37559025
DOI: 10.1186/s12865-023-00559-y -
BMJ Open Nov 2023This study assessed perceived barriers, precancerous cervical lesion screening acceptance, and associated factors among women in Eastern Ethiopia.
OBJECTIVE
This study assessed perceived barriers, precancerous cervical lesion screening acceptance, and associated factors among women in Eastern Ethiopia.
SETTING
This study was conducted in Hiwot Fana Specialized Hospital and Jugal Hospital.
STUDY DESIGN
This study is a facility-based cross-sectional study.
STUDY PARTICIPANTS
This study included 1181 women aged 25-49 years. Bivariate and multivariable logistic regression was used to evaluate the relationship between variables and control confounders.
RESULTS
Nearly half of the participants (587 or 49.7%) agreed to be screened for precancerous cervical lesions. Seventy-six per cent of those checked were negative for visual inspection with acetic acid, 18.5% were positive, and 5.7% had cancer-like lesions. In multivariable analysis, fear of discomfort from the screening procedure, having a male screener, and embarrassment were the perceived barriers that were inversely associated with screening acceptance.
CONCLUSIONS
The uptake of the screening service in the study area was not satisfactory, indicating that the programme was underutilised in the area.
Topics: Female; Male; Humans; Uterine Cervical Neoplasms; Ethiopia; Cross-Sectional Studies; Cervix Uteri; Precancerous Conditions; Early Detection of Cancer
PubMed: 37931971
DOI: 10.1136/bmjopen-2023-073721 -
BMC Cancer Nov 2023Immunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to...
BACKGROUND
Immunotherapy targeting the PD-1/PD-L1 pathway is a standard of care in a number of metastatic malignancies, but less than a fifth of patients are expected to respond to ICIs (Immune Checkpoint Inhibitors). In a clinical trial, combining the anti-TIGIT (T cell immunoreceptor with Ig and ITIM domains) Mab (monoclonal antibody) tiragolumab with atezolizumab improved outcomes in non-small cell lung cancer. In preclinical models, SBRT (Stereotactic Body Radiation Therapy) could increase expression levels of the inhibitory co-receptors TIGIT and PD-L1. We aim to assess the combination of tiragolumab with atezolizumab and SBRT in metastatic, previously treated by ICIs, non-small cell lung cancer, head and neck cancer, bladder cancer, and renal cell cancer.
METHODS
This phase I study (ClinicalTrials.gov NCT05259319) will assess the efficacy and safety of the combination of atezolizumab with tiragolumab and stereotactic body radiation therapy in patients with histologically proven metastatic non-small cell lung cancer, renal cell cancer, bladder cancer, and head and neck cancer previously treated. First part: 2 different schedules of SBRT in association with a fixed dose of atezolizumab and tiragolumab will be investigated only with metastatic non-small cell lung cancer patients (cohort 1). The expansion cohorts phase will be a multicentric, open-label study at the recommended scheme of administration and enroll additional patients with metastatic bladder cancer, renal cell cancer, and head and neck cancer (cohort 2, 3 and 4). Patients will be treated until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment, or patient refusal in the absence of progression or intolerance. The primary endpoint of the first phase is the safety of the combination in a sequential or concomitant scheme and to determine the expansion cohorts phase recommended scheme of administration. The primary endpoint of phase II is to evaluate the efficacy of tiragolumab + atezolizumab + SBRT in terms of 6-month PFS (Progression-Free Survival). Ancillary analyses will be performed with peripheral and intratumoral immune biomarker assessments.
TRIAL REGISTRATION
This study is registered on ClinicalTrials.gov: NCT05259319, since February 28th, 2022.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; B7-H1 Antigen; Carcinoma, Renal Cell; Radiosurgery; Lung Neoplasms; Antineoplastic Agents; Antibodies, Monoclonal; Kidney Neoplasms; Head and Neck Neoplasms; Urinary Bladder Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37946136
DOI: 10.1186/s12885-023-11534-6