scholarly journals 72 Increasing Radiotherapy Induced DNA Damage by Inhibiting Repair Proteins

2021 ◽  
Vol 108 (Supplement_6) ◽  
Author(s):  
B Atkinson ◽  
J Wilson
Keyword(s):  
Dna Damage ◽  
Head And Neck ◽  
Genetic Disorder ◽  
Survival Rates ◽  
Surgical Excision ◽  
Primary Objective ◽  
Fanconi Anaemia ◽  
Mild Hyperthermia ◽  
Recombination Repair ◽  
Novel Concept

Abstract Introduction Fanconi anaemia (FA) is a rare genetic disorder displaying higher incidences of head and neck squamous cell carcinoma (SCC). The surgical excision of these cancers is challenging and often supplemented with radiotherapy. One novel concept to improve survival rates is to increase the susceptibility of SCCs to radiotherapy. ATR is a protein responsible for homologous recombination repair (HRR) within the FA pathway and has been identified as a possible target for cancer therapy. Inhibition of ATR induces subsequent DNA damage. The primary objective of this study was to identify whether the inhibition of ATR can be achieved by exposing SCCs to mild hyperthermia. This novel concept aims to improve survival rates of patients with SCCs who require surgical excision and subsequent radiotherapy. Method By using a HRR assay it was possible to examine levels of DNA repair in various SCC cell lines following the exposure to radiation. These were compared to cells treated with heat, an ATR inhibitor and a mixture of both to determine whether heat reduces HRR. Results Repeated HRR assay’s showed SCC’s treated with heat, ATR inhibitor and a mixture of both before exposure to radiation underwent significantly lower levels of HRR compared to cells within the control. Conclusions Reduced HRR following exposure to heat increases the susceptibility of SCCs to radiotherapy. It is hoped that in combination with the surgical excision, this study will help to improve the outcomes of patients with head and neck carcinomas by improving the efficacy of radiotherapy.

scholarly journals The Effect of Radiotherapy on Head and Neck Cancer Cell Lines Following Exposure to Heat

2020 ◽  
Author(s):  
Ben Atkinson ◽  
Jamie Wilson
Keyword(s):  
Head And Neck ◽  
Treatment Plan ◽  
Genetic Disorder ◽  
Fanconi Anaemia ◽  
Invasive Treatment ◽  
Oral Epithelial Dysplasia ◽  
Squamous Cells ◽  
Non Invasive ◽  
Recombination Repair ◽  
Potentially Malignant

AbstractFanconi anaemia (FA) is a rare, recessive, genetic disorder characterised by a predisposition to cancer. Patients with FA are 700 times more likely to develop head and neck squamouscell carcinomas including oral epithelial dysplasia (OED), a potentially malignant disorder of the oral mucosa. This increased likelihood suggests that the molecular mechanism responsible for dysplastic transformation may involve defects in the FA pathway. In this study, the significance of ataxia telangiectasia and Rad3-related protein (ATR), which is responsible for homologous recombination repair (HRR), was investigated. ATR protects against mutations in both normal squamous cells and cancer cells by inducing HRR, and thus is associated with radiotherapy resistance. This investigation was designed to study the effects of heat on DNA repair specific to the FA pathway. Western blotting was carried out to determine whether heat affects the ATR pathway, followed by survival assays to determine the viability of cells after heat treatment and then compared to cells treated with a specific ATR inhibitor. This project aims to discover whether heat could be used as a non-invasive treatment to increase the sensitivity of tumour cells towards radiotherapy leading to an improved treatment plan for patients suffering from head and neck cancers.

Solitary Neurogenous Sarcomas of the Head and Neck

1979 ◽  
Vol 87 (1) ◽  
pp. 35-41 ◽  
Author(s):  
Capt Hugh O. DeFries ◽  
Michael B. Nolph ◽  
Alan D. Kornblut
Keyword(s):  
Head And Neck ◽  
Combined Therapy ◽  
Survival Rates ◽  
Surgical Excision ◽  
Satisfactory Treatment ◽  
Potential Patient

The clinical histories of three patients with neurogenous sarcomas involving the head and neck are detailed. The most satisfactory treatment suggested for such tumors involves combined therapy with chemotherapy, radiation, and radical surgical excision. By so doing, potential patient cure might be further increased and survival rates further improved.

Cosmetic Results of Cryosurgery Versus Surgical Excision for Primary Uncomplicated Basal Cell Carcinomas of the Head and Neck

2000 ◽  
Vol 26 (8) ◽  
pp. 759-764 ◽  
Author(s):  
M. R. T. M. Thissen ◽  
F. H. M. Nieman ◽  
A. H. L. B. Ideler ◽  
P. J. M. Berretty ◽  
H. A. M. Neumann
Keyword(s):  
Head And Neck ◽  
Basal Cell ◽  
Surgical Excision ◽  
Cosmetic Results ◽  
Basal Cell Carcinomas

scholarly journals Roles of microRNAs in Regulating Cancer Stemness in Head and Neck Cancers

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1742
Author(s):  
Melysa Fitriana ◽  
Wei-Lun Hwang ◽  
Pak-Yue Chan ◽  
Tai-Yuan Hsueh ◽  
Tsai-Tsen Liao
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Cancer Stemness ◽  
Mesenchymal Transition

Head and neck squamous cell carcinomas (HNSCCs) are epithelial malignancies with 5-year overall survival rates of approximately 40–50%. Emerging evidence indicates that a small population of cells in HNSCC patients, named cancer stem cells (CSCs), play vital roles in the processes of tumor initiation, progression, metastasis, immune evasion, chemo-/radioresistance, and recurrence. The acquisition of stem-like properties of cancer cells further provides cellular plasticity for stress adaptation and contributes to therapeutic resistance, resulting in a worse clinical outcome. Thus, targeting cancer stemness is fundamental for cancer treatment. MicroRNAs (miRNAs) are known to regulate stem cell features in the development and tissue regeneration through a miRNA–target interactive network. In HNSCCs, miRNAs act as tumor suppressors and/or oncogenes to modulate cancer stemness and therapeutic efficacy by regulating the CSC-specific tumor microenvironment (TME) and signaling pathways, such as epithelial-to-mesenchymal transition (EMT), Wnt/β-catenin signaling, and epidermal growth factor receptor (EGFR) or insulin-like growth factor 1 receptor (IGF1R) signaling pathways. Owing to a deeper understanding of disease-relevant miRNAs and advances in in vivo delivery systems, the administration of miRNA-based therapeutics is feasible and safe in humans, with encouraging efficacy results in early-phase clinical trials. In this review, we summarize the present findings to better understand the mechanical actions of miRNAs in maintaining CSCs and acquiring the stem-like features of cancer cells during HNSCC pathogenesis.

scholarly journals DHX9-dependent recruitment of BRCA1 to RNA promotes DNA end resection in homologous recombination

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Prasun Chakraborty ◽  
Kevin Hiom
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Rna Polymerase Ii ◽  
Critical Role ◽  
Dna Breaks ◽  
Double Stranded Dna ◽  
Recombination Repair ◽  
Dna End Resection ◽  
End Resection ◽  
Rna Polymerase Ii Transcription

AbstractDouble stranded DNA Breaks (DSB) that occur in highly transcribed regions of the genome are preferentially repaired by homologous recombination repair (HR). However, the mechanisms that link transcription with HR are unknown. Here we identify a critical role for DHX9, a RNA helicase involved in the processing of pre-mRNA during transcription, in the initiation of HR. Cells that are deficient in DHX9 are impaired in the recruitment of RPA and RAD51 to sites of DNA damage and fail to repair DSB by HR. Consequently, these cells are hypersensitive to treatment with agents such as camptothecin and Olaparib that block transcription and generate DSB that specifically require HR for their repair. We show that DHX9 plays a critical role in HR by promoting the recruitment of BRCA1 to RNA as part of the RNA Polymerase II transcription complex, where it facilitates the resection of DSB. Moreover, defects in DHX9 also lead to impaired ATR-mediated damage signalling and an inability to restart DNA replication at camptothecin-induced DSB. Together, our data reveal a previously unknown role for DHX9 in the DNA Damage Response that provides a critical link between RNA, RNA Pol II and the repair of DNA damage by homologous recombination.

scholarly journals EGFR overexpression increases radiotherapy response in HPV-positive head and neck cancer through inhibition of DNA damage repair and HPV E6 downregulation

2021 ◽  
Vol 498 ◽  
pp. 80-97
Author(s):  
Elham Nafea Alsahafi ◽  
Selvam Thavaraj ◽  
Nazanin Sarvestani ◽  
Ofra Novoplansky ◽  
Moshe Elkabets ◽  
...  
Keyword(s):  
Dna Damage ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Neck Cancer ◽  
Dna Damage Repair ◽  
Hpv E6 ◽  
Damage Repair

scholarly journals NBS1 is regulated by two kind of mechanisms: ATM-dependent complex formation with MRE11 and RAD50, and cell cycle–dependent degradation of protein

2017 ◽  
Vol 58 (4) ◽  
pp. 487-494 ◽  
Author(s):  
Hui Zhou ◽  
Kasumi Kawamura ◽  
Hiromi Yanagihara ◽  
Junya Kobayashi ◽  
Qiu-Mei Zhang-Akiyama
Keyword(s):  
Dna Damage ◽  
Complex Formation ◽  
Genetic Disorder ◽  
Specific Inhibitor ◽  
Nijmegen Breakage Syndrome ◽  
End Joining ◽  
Mrn Complex ◽  
Pre Treatment ◽  
Non Homologous End Joining ◽  
Cycle Dependent

Abstract Nijmegen breakage syndrome (NBS), a condition similar to Ataxia-Telangiectasia (A-T), is a radiation-hypersensitive genetic disorder showing chromosomal instability, radio-resistant DNA synthesis, immunodeficiency, and predisposition to malignances. The product of the responsible gene, NBS1, forms a complex with MRE11 and RAD50 (MRN complex). The MRN complex is necessary for the DNA damage–induced activation of ATM. However, the regulation of MRN complex formation is still unclear. Here, we investigated the regulatory mechanisms of MRN complex formation. We used an immunoprecipitation assay to determine whether levels of the MRN complex were increased by radiation-induced DNA damage and found that the levels of these proteins and their mRNAs did not increase. ATM-dependent phosphorylation of NBS1 contributed to the DNA damage–induced MRN complex formation. However, pre-treatment of cells with an ATM-specific inhibitor did not affect homologous recombination (HR) and non-homologous end-joining (NHEJ) repair. G0 phase cells, decreasing NBS1 and HR activity but not NHEJ, gained HR-related chromatin association of RAD51 by overexpression of NBS1, suggesting that the amount of NBS1 may be important for repressing accidental activation of HR. These evidences suggest that NBS1 is regulated by two kind of mechanisms: complex formation dependent on ATM, and protein degradation mediated by an unknown MG132-resistant pathway. Such regulation of NBS1 may contribute to cellular responses to double-strand breaks.

scholarly journals Activation of Cilia-Independent Hedgehog/GLI1 Signaling as a Novel Concept for Neuroblastoma Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1908
Author(s):  
Anke Koeniger ◽  
Anna Brichkina ◽  
Iris Nee ◽  
Lukas Dempwolff ◽  
Anna Hupfer ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Survival Rates ◽  
Genetic Alterations ◽  
Novel Therapy ◽  
Therapeutic Concept ◽  
Pathway Activation ◽  
Starting Point ◽  
Novel Concept ◽  
Neural Crest Differentiation

Although being rare in absolute numbers, neuroblastoma (NB) represents the most frequent solid tumor in infants and young children. Therapy options and prognosis are comparably good for NB patients except for the high risk stage 4 class. Particularly in adolescent patients with certain genetic alterations, 5-year survival rates can drop below 30%, necessitating the development of novel therapy approaches. The developmentally important Hedgehog (Hh) pathway is involved in neural crest differentiation, the cell type being causal in the etiology of NB. However, and in contrast to its function in some other cancer types, Hedgehog signaling and its transcription factor GLI1 exert tumor-suppressive functions in NB, rendering GLI1 an interesting new candidate for anti-NB therapy. Unfortunately, the therapeutic concept of pharmacological Hh/GLI1 pathway activation is difficult to implement as NB cells have lost primary cilia, essential organelles for Hh perception and activation. In order to bypass this bottleneck, we have identified a GLI1-activating small molecule which stimulates endogenous GLI1 production without the need for upstream Hh pathway elements such as Smoothened or primary cilia. This isoxazole compound potently abrogates NB cell proliferation and might serve as a starting point for the development of a novel class of NB-suppressive molecules.

scholarly journals Nonmelanoma Cutaneous Head and Neck Cancer and Merkel Cell Carcinoma: Current Concepts, Advances, and Controversies

2015 ◽  
Vol 33 (29) ◽  
pp. 3338-3345 ◽  
Author(s):  
Sandro V. Porceddu ◽  
Michael J. Veness ◽  
Alexander Guminski
Keyword(s):  
Cell Carcinoma ◽  
Head And Neck ◽  
Merkel Cell Carcinoma ◽  
Surgical Excision ◽  
Current Evidence ◽  
Ageing Population ◽  
Merkel Cell ◽  
Tumor Boards ◽  
Solar Radiation Exposure ◽  
Cure Rates

Nonmelanoma skin cancer (NMSC) is the most common cancer worldwide and the most frequently observed malignancy in whites. Approximately 75% to 80% are basal cell carcinomas and 20% to 25% are squamous cell carcinomas. Incidence is increasing, partly reflecting an ageing population, and NMSC is more commonly seen in men. The predominant causative agent is ultraviolet solar radiation exposure, with the majority of cases occurring on the head and neck. Surgical excision is typically the treatment of choice, providing histopathologic information, high cure rates, and acceptable cosmetic and functional outcomes. Radiation therapy is reserved for cases where surgery is not the preferred choice or for high-risk cases where adjuvant therapy is recommended. Although overall mortality rates are low, patients with complex cases such as those with immunosuppression should be considered for management within multidisciplinary tumor boards. In contrast, Merkel cell carcinoma is a rare and aggressive malignancy, frequently arising on the head and neck in older whites, with a poorer prognosis. This article focuses on the current evidence guiding practice, recent advances, and areas of controversy in NMSC and Merkel cell carcinoma of the head and neck.

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