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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 -
Oncoimmunology 2023The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification....
The analysis of peripheral blood mononuclear cells (PBMCs) by flow cytometry holds promise as a platform for immune checkpoint inhibition (ICI) biomarker identification. Our aim was to characterize the systemic immune compartment in resectable esophageal adenocarcinoma patients treated with neoadjuvant ICI therapy. In total, 24 patients treated with neoadjuvant chemoradiotherapy (nCRT) and anti-PD-L1 (atezolizumab) from the PERFECT study (NCT03087864) were included and 26 patients from a previously published nCRT cohort. Blood samples were collected at baseline, on-treatment, before and after surgery. Response groups for comparison were defined as pathological complete responders (pCR) or patients with pathological residual disease (non-pCR). Based on multicolor flow cytometry of PBMCs, an immunosuppressive phenotype was observed in the non-pCR group of the PERFECT cohort, characterized by a higher percentage of regulatory T cells (Tregs), intermediate monocytes, and a lower percentage of type-2 conventional dendritic cells. A further increase in activated Tregs was observed in non-pCR patients on-treatment. These findings were not associated with a poor response in the nCRT cohort. At baseline, immunosuppressive cytokines were elevated in the non-pCR group of the PERFECT study. The suppressive subsets correlated at baseline with a Wnt/β-Catenin gene expression signature and on-treatment with epithelial-mesenchymal transition and angiogenesis signatures from tumor biopsies. After surgery monocyte activation (CD40), low CD8+Ki67+ T cell rates, and the enrichment of CD206+ monocytes were related to early recurrence. These findings highlight systemic barriers to effective ICI and the need for optimized treatment regimens.
Topics: Humans; Adenocarcinoma; Esophageal Neoplasms; Leukocytes, Mononuclear; Monitoring, Immunologic; Neoadjuvant Therapy; Treatment Outcome; Immune Checkpoint Inhibitors
PubMed: 37470057
DOI: 10.1080/2162402X.2023.2233403 -
Strahlentherapie Und Onkologie : Organ... Dec 2023Osteoarthritis (OA) is one of the most common and socioeconomically relevant diseases, with rising incidence and prevalence especially with regard to an ageing... (Review)
Review
Osteoarthritis (OA) is one of the most common and socioeconomically relevant diseases, with rising incidence and prevalence especially with regard to an ageing population in the Western world. Over the decades, the scientific perception of OA has shifted from a simple degeneration of cartilage and bone to a multifactorial disease involving various cell types and immunomodulatory factors. Despite a wide range of conventional treatment modalities available, a significant proportion of patients remain treatment refractory. Low-dose radiotherapy (LDRT) has been used for decades in the treatment of patients with inflammatory and/or degenerative diseases and has proven a viable option even in cohorts of patients with a rather poor prognosis. While its justification mainly derives from a vast body of empirical evidence, prospective randomized trials have until now failed to prove the effectiveness of LDRT. Nevertheless, over the decades, adaptions of LDRT treatment modalities have evolved using lower dosages with establishment of different treatment schedules for which definitive clinical proof is still pending. Preclinical research has revealed that the immune system is modulated by LDRT and very recently osteoimmunological mechanisms have been described. Future studies and investigations further elucidating the underlying mechanisms are an essential key to clarify the optimal patient stratification and treatment procedure, considering the patients' inflammatory status, age, and sex. The present review aims not only to present clinical and preclinical knowledge about the mechanistic and beneficial effects of LDRT, but also to emphasize topics that will need to be addressed in future studies. Further, a concise overview of the current status of the underlying radiobiological knowledge of LDRT for clinicians is given, while seeking to stimulate further translational research.
Topics: Humans; Radiotherapy Dosage; Prospective Studies; Osteoarthritis; Prognosis; Forecasting
PubMed: 36602569
DOI: 10.1007/s00066-022-02038-6 -
EMBO Reports Dec 202353BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic...
53BP1 acts at the crossroads between DNA repair and p53-mediated stress response. With its interactors p53 and USP28, it is part of the mitotic surveillance (or mitotic stopwatch) pathway (MSP), a sensor that monitors the duration of cell division, promoting p53-dependent cell cycle arrest when a critical time threshold is surpassed. Here, we show that Polo-like kinase 1 (PLK1) activity is essential for the time-dependent release of 53BP1 from kinetochores. PLK1 inhibition, which leads to 53BP1 persistence at kinetochores, prevents cytosolic 53BP1 association with p53 and results in a blunted MSP. Strikingly, the identification of CENP-F as the kinetochore docking partner of 53BP1 enabled us to show that measurement of mitotic timing by the MSP does not take place at kinetochores, as perturbing CENP-F-53BP1 binding had no measurable impact on the MSP. Taken together, we propose that PLK1 supports the MSP by generating a cytosolic pool of 53BP1 and that an unknown cytosolic mechanism enables the measurement of mitotic duration.
Topics: Humans; Cell Cycle Proteins; HeLa Cells; Kinetochores; Mitosis; Protein Serine-Threonine Kinases; Tumor Suppressor Protein p53; Ubiquitin Thiolesterase
PubMed: 37888778
DOI: 10.15252/embr.202357234 -
Strahlentherapie Und Onkologie : Organ... Dec 2023This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune... (Review)
Review
PURPOSE
This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors.
METHODS
A literature search was conducted in PubMed using the terms ("DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*") until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed.
RESULTS
Modern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here.
CONCLUSION
The combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.
Topics: Humans; Neoplasms; DNA Repair; DNA Damage
PubMed: 37420037
DOI: 10.1007/s00066-023-02103-8 -
Brain Sciences Oct 2023To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a...
To investigate the clinical impact of multiple courses of irradiation on pediatric patients with progressive diffuse intrinsic pontine glioma (DIPG), we conducted a retrospective case series on three children treated at our institution from 2018 to 2022. All children were candidates to receive systemic therapy with vinorelbine and nimotuzumab. Radiotherapy was administered to a total dose of 54 Gy. At any disease progression, our local tumor board evaluated the possibility of offering a new course of radiotherapy. To determine feasibility and assess toxicity rates, all children underwent clinical and hematological evaluation both during and after the treatment. To assess efficacy, all children performed contrast-enhanced MRI almost quarterly after the end of the treatment. In all children, following any treatment course, neurological improvement (>80%) was associated with a radiological response (41.7-46%). The longest overall survival (24 months) was observed in the child who underwent three courses of radiotherapy, without experiencing significant side effects. Even though it goes beyond the understanding of conventional radiobiology, first and second reirradiation in pediatric patients with progressive DIPG may represent a feasible and safe approach, capable of increasing overall survival and disease-free survival in selected patients and improving their quality of life.
PubMed: 37891817
DOI: 10.3390/brainsci13101449 -
BMC Cancer Nov 2023TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast...
TAB182 participates in DNA damage repair and radio-/chemosensitivity regulation in various tumors, but its role in tumorigenesis and therapeutic resistance in breast cancer remains unclear. In the current paper, we observed that triple-negative Breast Cancer (TNBC), a highly aggressive type of breast cancer, exhibits a lower expression of TAB182. TAB182 knockdown stimulates the proliferation, migration, and invasion of TNBC cells. Our study first obtained RNA-seq data to explore the cellular functions mediated by TAB182 at the genome level in TNBC cells. A transcriptome analysis and in vitro experiments enabled us to identify that TAB182 downregulation drives the enhanced properties of cancer stem-like cells (CSCs) in TNBC cells. Furthermore, TAB182 deletion contributes to the resistance of cells to olaparib or cisplatin, which can be rescued by silencing GLI2, a gene downstream of cancer stemness-related signaling pathways. Our results reveal a novel function of TAB182 as a potential negative regulator of cancer stem-like properties and drug sensitivity in TNBC cells, suggesting that TAB182 may be a tumor suppressor gene and is associated with increased therapeutic benefits for TNBC patients.
Topics: Humans; Cell Line, Tumor; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Neoplastic Stem Cells; Signal Transduction; Triple Negative Breast Neoplasms; Telomeric Repeat Binding Protein 1
PubMed: 37953246
DOI: 10.1186/s12885-023-11552-4 -
Frontiers in Pharmacology 2023Numerous studies have shown that neuroinflammation is involved in the process of neuronal damage in neurodegenerative diseases such as Parkinson's disease (PD), for...
Numerous studies have shown that neuroinflammation is involved in the process of neuronal damage in neurodegenerative diseases such as Parkinson's disease (PD), for example, and that inhibiting neuroinflammation help improve PD. Shikimic acid (SA) has anti-inflammatory, analgesic and antioxidant activities in numerous diseases. However, its effect and mechanism in PD remain unclear. In this experiment, we found that SA inhibits production of pro-inflammatory mediators and ROS in LPS-induced BV2 cells. Mechanistic studies demonstrated that SA suppresses neuro-inflammation by activating the AKT/Nrf2 pathway and inhibiting the NF-κB pathway. Further study, we confirmed that SA ameliorated the neurological damage and behavioral deficits caused by LPS injection in mice. In summary, these study highlighted the beneficial role of SA as a novel therapy with potential PD drug by targeting neuro-inflammation.
PubMed: 38026972
DOI: 10.3389/fphar.2023.1265571 -
Cureus Aug 2023The COVID-19 pandemic has made it abundantly clear how crucial biomedical science is to pandemic control and prevention on a global scale. The importance of biomedical... (Review)
Review
The COVID-19 pandemic has made it abundantly clear how crucial biomedical science is to pandemic control and prevention on a global scale. The importance of biomedical science in the fight against pandemics has increased with the appearance of new, deadly infectious diseases. Biomedical science and engineering have been presented as possible areas for combating the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to the unique challenges raised by the pandemic, as reported by epidemiologists, immunologists, and doctors, including the survival, symptoms, protein surface composition, and infection mechanisms of COVID-19. These multidisciplinary engineering concepts are applied to design and develop prevention methods, diagnostics, monitoring, and therapies. An infectious disease outbreak that has spread over a sizable region, such as several continents or the entire world, and is affecting a sizable number of people is referred to as a "pandemic. While current knowledge about the SARS-CoV-2 virus is still limited, various (old and new) biomedical approaches have been developed and tested. Here, we review the emerging applications of biomedical science in pandemic prevention and control, including rapid diagnosis tests, the development of vaccines, antiviral therapies, artificial intelligence, genome sequencing, and personal protective equipment. Biomedical science and nanotechnology are two fields that have the potential to combine to develop emerging applications for combating pandemics. In this review, we also discuss the intersection of biomedical science and nanotechnology in pandemic prevention and control.
PubMed: 37750154
DOI: 10.7759/cureus.44075 -
Bioactive Materials Apr 2024Skeletal stem cells (SSC) have gained attentions as candidates for the treatment of osteoarthritis due to their osteochondrogenic capacity. However, the immunomodulatory...
Skeletal stem cells (SSC) have gained attentions as candidates for the treatment of osteoarthritis due to their osteochondrogenic capacity. However, the immunomodulatory properties of SSC, especially under delivery operations, have been largely ignored. In the study, we found that Pdpn and Grem1 SSC subpopulations owned immunoregulatory potential, and the single-cell RNA sequencing (scRNA-seq) data suggested that the mechanical activation of microgel carriers on SSC induced the generation of PdpnGrem1Ptgs2 SSC subpopulation, which was potent at suppressing macrophage inflammation. The microgel carriers promoted the YAP nuclear translocation, and the activated YAP protein was necessary for the increased expression of Ptgs2 and PGE in microgels-delivered SSC, which further suppressed the expression of TNF-ɑ, IL-1β and promoted the expression of IL-10 in macrophages. SSC delivered with microgels yielded better preventive effects on articular lesions and macrophage activation in osteoarthritic rats than SSC without microgels. Chemically blocking the YAP and Ptgs2 in microgels-delivered SSC partially abolished the enhanced protection on articular tissues and suppression on osteoarthritic macrophages. Moreover, microgel carriers significantly prolonged SSC retention time without increasing SSC implanting into osteoarthritic joints. Together, our study demonstrated that microgel carriers enhanced SSC reprogramming towards immunomodulatory phenotype to regulate macrophage phenotype transformation for effectively osteoarthritic therapy by promoting YAP protein translocation into nucleus. The study not only complement and perfect the immunological mechanisms of SSC-based therapy at the single-cell level, but also provide new insight for microgel carriers in stem cell-based therapy.
PubMed: 38235309
DOI: 10.1016/j.bioactmat.2023.12.022